Effects of clozapine and sulpiride on morphine state-dependent memory in the step-down passive avoidance test.
The effects of antipsychotic drugs sulpiride and clozapine on morphine state-dependent memory of passive avoidance task were examined in mice. Post-training administration of morphine (5 mg/kg) led to state-dependent learning with impaired memory retrieval on the test day which was reversed by pre-test administration of the same dose of the opioid (5 mg/kg). In animals where memory was impaired by post-training morphine, the administration of either sulpiride or clozapine before pre-test morphine reduced the improvement of memory produced by the opioid. Co-administration of sulpiride with clozapine did not potentiate their antagonistic response. In conclusion, the inhibition of improvement of memory retrieval by morphine treatment on the test day by the two dopamine receptor antagonists seems to be induced through two different receptor mechanisms.


Role of alveolar macrophage-T cell adherence in accessory cell function in human immunodeficiency virus-infected individuals.
Previous work has shown that alveolar macrophages (AM) from human immunodeficiency virus (HIV)-infected patients are superior accessory cells (AC) and secrete greater amounts of T cell-stimulatory cytokines than do normal AM. We now examine the role of AM-T cell adherence in AM AC function by examining the ability of beta 2 integrins and intercellular adhesion molecule-1 (ICAM-1) to block adherence and lymphoproliferation. Mitogen-induced (concanavalin A, pokeweed mitogen) adhesion and proliferation were studied in the presence and absence of mAb directed against beta 2 integrins and ICAM-1. AM from normal subjects and HIV-positive patients were used as AC, and normal T cells were used as responders. Normal and HIV AM bound equal numbers of T cells under similar conditions. Adherence was blocked by antibodies to beta 2 integrins and ICAM-1 in both groups. Con A-induced lymphoproliferation was positively correlated with adherence in normal volunteers. In contrast, greater Con A-induced AM-T cell adherence in HIV-positive patients was associated with worse AC function. Antibodies that impaired AM-T cell adherence completely inhibited AC function in both groups when added at the beginning of mitogen assays, indicating that initial contact was required. However, the addition of antibodies after 4 h inhibited lymphoproliferation less in HIV-infected individuals than in normal volunteers, suggesting that prolonged AM-T cell adherence was less important for optimal AC function in these patients. Using these and previous results, we present a model for AM AC function in normal volunteers and HIV-infected individuals.


[Results of leflunomide treatment of psoriatic arthritis].
To study efficacy and tolerance of leflunomide (LF) in patients with polyarticular psoriatic arthritis (PsA). The analysis was made in 58 patients: 35 (60%) females, 23 (40%) males. Mean age of the patients was 44.9 +/- 10.8 years, PsA duration--9.7 +/- 7.5 years. LF was given by a standard scheme: 100 mg/day for 3 days then 20 mg/day for 6 months. PsA activity was assessed by the number of painful and inflamed joints, pain intensity, VAS, Likert quastionnaire data. Functional status of the patients was estimated according to Health Assessment Questionnaire. Skin syndrome was rated by pruritus scale, 5-score Likert scale and PASI (psoriasis Area and Severity Index). PASI was applied in patients with affected area 3% at least. Quality of life was assessed by Dermatology Life Quality Index. Basic criterion of the treatment efficacy was response by PsARC (Psoriatic Arthritis Response Criteria). The additional evaluation was made of the number of patients with improvement by criteria ACR 20, ACR 50 and ACR 75 as well as those with 50 and 75% response by PASI (PASI 50 and PASI 75). To the end of the treatment the number of painful and inflamed joints decreased significantly (p < 0.001) as well as pain, VAS and Likert scores. To the treatment month 6 HAQ index diminished by 36%. According to PsARC, of 58 patients 36 (62%) patients responded. Improvement by ACR 20 was observed in 34 (59%) of 58 patients. PASI changes were not significant (p = 0. 144). DLQI diminished by 36% (p = 0.028). As shown by acute phase indices, LF had no effect on ESR (p = 0.45). CRP fell significantly to treatment month 3 (p < or = 0.001) and further changes were insignificant. LF tolerance was satisfactory. Ten patients (17%) withdrew because of side effects which were standard. Severe myelo- and hepatotoxicity were absent. LF is highly effective in therapy of polyarticular PsA and has satisfactory tolerance. Perspectives of further use of LF in combined treatment of PsA are associated with its potential to inhibit the disease progression.


Cloning of long sterile lemma (lsl2), a single recessive gene that regulates spike germination in rice (Oryza sativa L.).
Rice is a typical monocotyledonous plant and an important cereal crop. The structural units of rice flowers are spikelets and florets, and floral organ development and spike germination affect rice reproduction and yield. In this study, we identified a novel long sterile lemma (lsl2) mutant from an EMS population. First, we mapped the lsl2 gene between the markers Indel7-22 and Indel7-27, which encompasses a 25-kb region. The rice genome annotation indicated the presence of four candidate genes in this region. Through gene prediction and cDNA sequencing, we confirmed that the target gene in the lsl2 mutant is allelic to LONG STERILE LEMMA1 (G1)/ELONGATED EMPTY GLUME (ELE), hereafter referred to as lsl2. Further analysis of the lsl2 and LSL2 proteins showed a one-amino-acid change, namely, the mutation of serine (Ser) 79 to proline (Pro) in lsl2 compared with LSL2, and this mutation might change the function of the protein. Knockout experiments showed that the lsl2 gene is responsible for the long sterile lemma phenotype. The lsl2 gene might reduce the damage induced by spike germination by decreasing the seed germination rate, but other agronomic traits of rice were not changed in the lsl2 mutant. Taken together, our results demonstrate that the lsl2 gene will have specific application prospects in future rice breeding. The lsl2 gene is responsible for the long sterile lemma phenotype and might reduce the damage induced by spike germination by decreasing the seed germination rate.


Macrophage depletion combined with anticoagulant therapy increases therapeutic window of systemic treatment with oncolytic adenovirus.
Liver tropism of systemically delivered adenoviruses (Ad) represents a considerable challenge for their use as anticancer therapeutics. More than 90% of i.v. injected Ad is rapidly taken up by the liver leading to hepatotoxicity, reduced virus uptake by target tumor tissue, and diminished therapeutic efficacy. The lack of clinical activity of systemically given oncolytic Ad demands for better understanding and improvement of virus pharmacokinetics. We studied the effects of Ad "detargeting" from liver macrophages (Kupffer cells) and hepatocytes on toxicity and anticancer efficacy using a nonattenuated oncolytic Ad expressing enhanced green fluorescent protein-firefly luciferase fusion protein (Ad-EGFPLuc). Kupffer cell depletion before i.v. injection of Ad-EGFPLuc increased transgene expression in the liver 40.7-fold on day 3 after the injection indicating compensatory enhancement of hepatocyte transduction due to increased bioavailability of the virus. Pretreatment of mice with the anticoagulant drug warfarin to block blood factor-dependent binding of the virus to hepatocytes markedly reduced luciferase expression in the liver and mediated the corresponding decrease of hepatotoxicity in mice with intact and depleted liver macrophages. Combined depletion of Kupffer cells and pretreatment with warfarin before a single i.v. injection of Ad-EGFPLuc significantly reduced tumor growth and prolonged survival of nude mice bearing subcutaneous xenografts of aggressive human hepatocellular carcinoma. The improved antitumor activity correlated with enhanced transgene expression and virus spread in the tumors. These data suggest that detargeting oncolytic Ad from liver macrophages and hepatocytes is an effective strategy to increase the therapeutic window for therapy against disseminated tumor sites.


Comparison of formats for the development of fiber-optic biosensors utilizing sol-gel derived materials entrapping fluorescently-labelled protein.
The development of fiber-optic biosensors requires that a biorecognition element and a fluorescent reporter group be immobilized at or near the surface of an optical element such as a planar waveguide or optical fiber. In this study, we examined a model biorecognition element-reporter group couple consisting of human serum albumin that was site-selectively labelled at Cys 34 with iodoacetoxy-nitrobenzoxadiazole (HSA-NBD). The labelled protein was encapsulated into sol-gel derived materials that were prepared either as monoliths, as beads that were formed at the distal tip of a fused silica optical fiber, or as thin films that were dipcast along the length of a glass slide or optical fiber. For fiber-based studies, the entrapped protein was excited using a helium-cadmium laser that was launched into a single optical fiber, and emission was separated from the incident radiation using a perforated mirror beam-splitter, and detected using a monochromator-photomultiplier tube assembly. Changes in fluorescence intensity were generated by denaturant-induced conformational changes in the protein or by iodide quenching. The analytical parameters of merit for the different encapsulation formats, including minimum protein loading level, response time and limit-of-detection, were examined, as were factors such as protein accessibility, leaching and photobleaching. Overall, the results indicated that both beads and films were suitable for biosensor development. In both formats, a substantial fraction of the entrapped protein remained accessible, and the entrapped protein retained a large degree of conformational flexibility. Thin films showed the most rapid response times, and provided good detection limits for a model analyte. However, the entrapment of proteins into beads at the distal tip of fibers provided better signal-to-noise and signal-to-background ratios, and required less protein for preparation. Hence, beads appear to be the most viable method for interfacing of proteins to optical fibers.


HBV infection: prevalence of core antibody and other markers in urban based, black school children in Kenya.
This paper reports a study of 279 sera obtained from children attending five schools in Nairobi, the capital of Kenya which is situated in a non-malarious zone. Their ages ranged from six to 16 years. The surface antigen of hepatitis B virus (HBV) was detected in 13 children (4.7%) including seven boys and six girls. The core and surface antibodies were measured by radioimmunoassay on 125 of the samples to study the pattern of infection in childhood and the interrelationships of different parameters of the infection. The core antibody by itself was observed in four children (3.2%). A total of 31 samples (24.8%) had both core and surface antibodies, 19 (15.2%) had only surface antibody. Thus, 48% of all school children tested had serological evidence of past exposure to the virus. The implications of these findings are discussed.


On the asymmetry of bifurcations in the bronchial tree.
The branching pattern of the conducting airways is significantly asymmetrical in the human, and even more so in other species. Although this asymmetry is believed to have an important effect on air flow and other transport processes in the bronchial tree, both experimental and theoretical studies have predominantly employed symmetrical model bifurcations. In this paper, published morphometric data for four species (human, dog, rat and hamster) is used to calculate the frequencies with which different degrees of asymmetry occur, and to examine the relationships between four of its manifestations, asymmetry of the cross-sectional areas, the lengths, the branching angles and the flow rates of the daughter branches. The observed characteristics are compared with some of the theoretical 'branching laws' which have been proposed. Quantification of the correlations between the different manifestations of asymmetry allows the geometrical characteristics to be specified for a range of realistic asymmetrical bifurcations, for use in either theoretical or experimental studies of transport in the bronchial tree.


Skin cancer-related coping appraisal among farmers of rural areas: Applying protection motivation theory.
Skin cancers are the most common malignancies in Iran. According to the statistics, skin cancer is the most prevalent cancer in Ilam city. This study is conducted to evaluate skin cancer coping of farmers in rural areas of Ilam city. This is a cross-sectional study. Samples were collected by multistage random sampling. The required data were collected by a researcher-made questionnaire from 248 farmers in rural areas of Ilam city. Questions were based on the protection motivation theory, and they were related to the subscales of response efficacy, self-efficacy, and response costs. Collected data were analyzed by SPSS software version 16. Results of this study indicated that efficacy and perceived self-efficacy in farmers were low and response cost was high. The efficacy and perceived self-efficacy were high in 18.1% and 4.8% of farmers, respectively, and only 4.4% of them had low response costs, in association with protective behaviors. Regarding coping appraisal status also results showed that 204 people of farmers (82.3%) were unacceptable, one person (0.4%) was in the borderline, and 43 people (17.3%) were acceptable. There was a statistically significant association between coping appraisal status and education level and also income amount (P < 0.001) but there was no statistically significant association between coping appraisal status and family size (P > 0.670). The founding proved that a coping appraisal is a beneficial approach for predicting cognitive determinants of skin cancer behavior among rural farmers. The most farmers have been the low level of coping appraisal (82.3% were unacceptable).


Effect of replacing alfalfa with panicled-tick clover or sericea lespedeza in corn-alfalfa-based substrates on in vitro ruminal methane production.
Methane emissions from ruminant livestock contribute to total anthropogenic greenhouse gas emissions and reduce metabolizable energy intake by the animal. Condensed tannins (CT) are polyphenolic plant secondary compounds commonly produced by some perennial forage legumes that characteristically bind to protein, carbohydrates, and minerals. The degree to which CT may affect ruminant nutrition depends upon the concentration, structural composition, and biological activity of the CT. The objective of our experiment was to determine the effect of replacing alfalfa in a corn-alfalfa-based substrate with a legume containing CT on in vitro CH4 production and the dynamics of fermentation using an in vitro gas production technique. All fermented substrates contained 50% ground corn as the energy concentrate portion, whereas the forage portion (50%) of each diet was comprised of alfalfa (control) or some combination of alfalfa and sericea lespedeza (SL) or panicled-tick clover (PTC). Our treatments consisted of PTC or SL 15, 30, and 45, which corresponded with 15, 30, or 45% replacement of the diet (alfalfa component) with either PTC or SL. Substrates containing 45% PTC or SL reduced in vitro CH4 production. Treatments did not affect total gas production as compared with that of the control. Replacement of alfalfa with SL or PTC increased fermentable organic matter (FOM). The PTC treatment increased FOM by as much as 1.8% at the 45% replacement level, whereas FOM of SL 45 was increased by less than 1%. The replacement of alfalfa with PTC increased substrate nutritive value greater than replacement with SL. There were no correlations between any physicochemical constituent of the substrates and CH4 production. A combination of factors associated with the inclusion of PTC and SL contributed to the in vitro CH4 production, and CT in these forages was likely a major contributing factor. Further confirmation of these results on in situ or in vivo animal systems is required. If proven effective in an in vivo production scenario, replacement of commonly fed non-CT-containing legumes, such as alfalfa, with legumes containing CT might be a viable method to decrease the effect of animal agriculture on greenhouse gas production.


The role of intraminority relations in perceptions of cultural appropriation.
Adopting the customs of outgroup cultures (e.g., cultural appropriation) is controversial. Across six experiments, we examined perceptions of cultural appropriation from the perspective of Black Americans (N = 2,069), particularly focusing on the identity of the appropriator and its implications for theoretical understanding of appropriation. Participants expressed more negative emotion and considered appropriation of their cultural practices less acceptable than comparable behaviors that were not appropriative (Studies A1-A3). However, participants perceived White appropriators more negatively than Latine (but not Asian) appropriators, ultimately suggesting that negative perceptions of appropriation do not merely stem from concerns about preserving rigid ingroup-outgroup boundaries. We originally predicted that shared oppression experiences would be key to different responses to appropriation. Instead, our findings most strongly supported the notion that differences in judgments of appropriation by different cultural groups are primarily tied to perceptions of similarity (or difference) across groups-rather than oppression similarity itself. For example, when Asian Americans and Black Americans were framed as part of a common ingroup, Black American participants expressed less negativity toward Asian Americans' appropriative acts. These findings suggest that perceived similarities or shared experiences shape the likelihood of welcoming outgroups into one's cultural practices. More broadly, they suggest that the construction of identities is key to perceptions of appropriation, even independent from the way in which people appropriate. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Prevalence, genotyping and risk factors of thermophilic Campylobacter spreading in organic turkey farms in Germany.
The need for organic food of animal origin has increased rapidly in recent years. However, effects of organic animal husbandry on food safety have not been rigorously tested especially in meat turkey flocks. This study provides for the first time an overview on the prevalence and genetic diversity of Campylobacter species (spp.) in five organic meat turkey farms located in different regions in Germany, as well as on potential risk factors of bacterial spreading. Thirty cloacal swabs as well as water samples and darkling beetles were collected from each flock and examined for the presence of Campylobacter by conventional and molecular biological methods. The isolates were genotyped by flaA-RFLP. Campylobacter spp. were detected in cloacal swabs in all 5 turkey flocks with prevalence ranged from 90.0 to 100 %. 13 cloacal swabs collected from birds in farm III and IV were harboured mixed population of thermophilic campylobacters. In total, from 158 Campylobacter isolated from turkeys 89 (56.33 %) were identified as C. coli and 69 (43.76 %) as C. jejuni. Three Campylobacter (2 C. jejuni and 1 C. coli) were detected in drinkers of two farms and 3 C. coli were isolated from darkling beetles of one farm. No Campylobacter were isolated from main water tanks. flaA-RFLP assay showed that turkey farms can harbour more than one genotype. In a single turkey two different genotypes could be detected. The genotypes of campylobacters isolated from water samples or beetles were identical with those isolated from turkeys. No effect was found of some environmental parameters [ammonia concentration (NH3), carbon dioxide concentration (CO2), relative humidity (RH) and air temperature)] on Campylobacter prevalence in organic turkey farms. Additionally, drinking water and darkling beetles might be considered as risk factors for the spreading of Campylobacter in turkey flocks. This study highlights the high prevalence and genotypic diversity of Campylobacter spp. isolated from organic turkey flocks. Further research is needed to assess other potential risk factors responsible for bacteria spreading in order to mitigate the spread of Campylobacter in organic turkey flocks by improving biosecurity control measures.


Pituitary adenylate-cyclase-activating peptides relax human coronary arteries by activating K(ATP) and K(Ca) channels in smooth muscle cells.
Pituitary adenylate-cyclase-activating peptides (PACAPs) are potent dilators of arteries, including human coronary arteries. We tested the importance of specific K+ channel regulatory mechanisms in human arterial smooth muscle relaxation induced by PACAPs, using contraction and patch clamp measurements on human coronary artery vascular smooth muscle cells. PACAP27 and PACAP38 produced dose-dependent relaxations of 5 microM PGF2alpha-preconstricted rings, with half-maximal relaxations at 1.0 nM and 2.0 nM, respectively. Both peptides induced complete relaxation at 100 nM. Pretreatment of the vessels with the ATP-dependent K+ (K(ATP)) channel blocker glibenclamide (1 microM) or with the Ca2+-activated K+ (K(Ca)) channel blocker iberiotoxin (100 nM) inhibited PACAP27-induced relaxation in an additive manner. Moreover, in the patch clamp experiments on freshly isolated cells from human coronary arteries, PACAP27 (100 nM) induced a large, nonrectifying, outward (I(K)(ATP)) K+ current in a proportion of cells and a voltage-dependent outward (I(K)(Ca)) K+ current in other cells. The PACAP27-induced I(K)(ATP) was blocked by glibenclamide (3 microM), while the PACAP27-stimulated I(K)(Ca) was blocked by iberiotoxin (100 nM). These findings provide the first evidence that relaxation of arterial smooth muscle cells by PACAPs is mediated by opening of K(ATP) and K(Ca) channels. The data indicate that both K(ATP) and K(Ca) channels in vascular smooth muscle cells may serve as final common pathway to induce vasorelaxation by endogenous vasoactive signals in man.


Localisation and characterization of the fatty acid synthesizing system in cells of Glycine max (soubean) suspension cultures.
In course of a study of fatty acid synthetase in higher plants, non-green cell suspension cultures of Glycine max (soybean) served as model tissues. For the first time, a fatty acid synthesizing system was characterized in cell cultures of higher plants and was found to be solely located in proplastids of the cells. Optimum activity of the fatty acid synthesizing system in proplastids was observed between pH 8.0 and 8.2; with [1-14C]acetate as substrate, cofactors required were CoA, ATP, Mn2+, Mg2+, HCO3-, NADH and NADPH. The system was more sensitive towards NADH than NADHP. [1-14C]Acetate,[2-14C]-malonate and [3-14C]pyruvate served as precursors for fatty acids, indicating the presence of pyruvate dehydrogenase activity in proplastids. In disrupted proplastids, [2-14C]malonylCoA was a better precursor than [1-14C]acetylCoA. After incubation of proplastids with [2-14C]malonate, a small shift, from palmitic acid to higher homologs, of label incorporated was observed, as compared to incorporation of label from [1-14C]acetate and [3-14C]pyruvate. Under the conditions of the experiment, only small amounts of polyunsaturated fatty acids, the main fatty acid components of this organelle, were synthesized. In respect to fatty acid synthesis, the non-green cell suspension culture resembles photosynthetic leaf tissue.


Combined domain-decomposition and matrix-decomposition scheme for large-scale diffuse optical tomography.
Image reconstruction in diffuse optical tomography (DOT) is, in general, posed as a model-based, nonlinear optimization problem, which requires repeated use of the three-dimensional (3D) forward and inverse solvers. To cope with the computation and storage problem for some applications, such as breast tumor diagnosis, it is preferable to develop a subdomain-based parallel computation scheme. In this study, we propose a two-level image reconstruction scheme for 3D DOT, which combines the Schwarz-type domain-decomposition (DD)-based forward calculation and the matrix-decomposition (MD)-based inversion. In the forward calculation, the solution to the diffusion equation is initially obtained using a whole-domain finite difference method at a coarse grid, and then updated with a parallel DD scheme at a fine grid. The inversion procedure starts with the wavelet-decomposition-based reconstruction at a coarse grid, and then follows with a Levenberg-Marquardt least-squares solution at a fine grid, where an MD strategy is adopted for the relevant linear inversion. It is demonstrated that the combination of the DD-based forward solver and MD-based inversion allows for coarse-grain parallel implementation of both the forward and inverse issues and effectively reduces computation and storage loads for the large-scale problem. Also, both numerical simulations and phantom experiments show that MD-based linear inversion is superior to the row-fashioned algebraic reconstruction technique.


Application of MR in stereotactic radiosurgery.
Radiosurgery, a bladeless brain surgery without opening skull, requires higher imaging accuracy as compared to microsurgery. Accordingly, we must refine the ways we use the MR scanner and interpret the obtained images. A well tuned and regularly calibrated MR scanner provides excellent images, which allow us to define detailed intracranial structures without distortion. This enables us to obtain a reliable imaging diagnosis despite the fact that pathologic diagnosis is not available in many radiosurgical patients. Due to its three-dimensional imaging and excellence in tissue and spatial contrast, MR is important in exploring new radiosurgical indications. Large arteriovenous malformations (AVM), dural AVM of cavernous sinus and trigeminal neuralgia are some of the successful examples. By using MR, longitudinal investigation of radiosurgical effects becomes feasible. For tumors, the longitudinal studies are important in optimization of dose selection. For AVM, MR is reliable in verification of radiosurgical result. The reliability is comparable to conventional x-ray angiography. Application of MR enhances the essence of noninvasiveness of radiosurgery.


Wrapping double-mattress anastomosis for pancreaticojejunostomy in minimally invasive pancreaticoduodenectomy can significantly reduce postoperative pancreatic fistula rate compared with conventional pancreaticojejunostomy in open surgery: An analysis of a propensity score-matched sample.
Minimally invasive pancreaticoduodenectomy (MIPD), including laparoscopic pancreaticoduodenectomy (LPD) and robotic pancreaticoduodenectomy (RPD), is technically demanding because of pancreaticojejunostomy (PJ). Postoperative pancreatic fistula (POPF) is the most serious complication of MIPD and open pancreaticoduodenectomy (OPD). Contrary to expectations, conventional PJ in MIPD did not improve POPF rate and length of hospital stay. High POPF rates are attributed to technical issues encountered during MIPD, which include motion restriction and insufficient water tightness. Therefore, we developed wrapping double-mattress anastomosis, the Kiguchi method, which is a novel PJ technique that can improve MIPD. Herein, we describe the Kiguchi method for PJ in MIPD and compare the outcomes between this technique and conventional PJ in OPD. The current retrospective study included 83 patients in whom the complete obstruction of the main pancreatic duct by pancreatic tumors was absent on preoperative imaging. This research was performed from September 2016 to August 2020 at Fujita Health University Hospital. All patients were evaluated as having a soft pancreatic texture, which is the most important factor associated with POPF development. Briefly, 50 patients underwent OPD with conventional PJ (OPD group). Meanwhile, 33 patients, including 15 and 18 who had LPD and RPD, respectively, underwent MIPD using the Kiguchi method (MIPD group). After a 1:1 propensity score matching, 30 patients in the OPD group were matched to 30 patients in the MIPD group. The patients' preoperative data did not differ. The grade B/C POPF rate was significantly lower in the MIPD group than in the OPD group (6.7% vs 40.0%, p = 0.002). The MIPD group had a significantly shorter median length of hospital stay than the OPD group (24 vs 30 days, p = 0.004). The novel Kiguchi method in MIPD significantly reduced the POPF rate in patients without complete obstruction of the main pancreatic duct.


Pim-1 kinase phosphorylates and stabilizes 130 kDa FLT3 and promotes aberrant STAT5 signaling in acute myeloid leukemia with FLT3 internal tandem duplication.
The type III receptor tyrosine kinase fms-like tyrosine kinase 3 (FLT3) is expressed on both normal hematopoietic stem cells and acute myeloid leukemia (AML) cells and regulates their proliferation. Internal tandem duplication (ITD) mutation of FLT3 is present in a third of AML cases, results in constitutive activation and aberrant signaling of FLT3, and is associated with adverse treatment outcomes. While wild-type (WT) FLT3 is predominantly a 150 kDa complex glycosylated cell surface protein, FLT3-ITD is partially retained in the endoplasmic reticulum as a 130 kDa underglycosylated species associated with the chaperones calnexin and heat shock protein (HSP) 90, and mediates aberrant STAT5 signaling, which upregulates the oncogenic serine/threonine kinase Pim-1. FLT3 contains a Pim-1 substrate consensus serine phosphorylation site, and we hypothesized that it might be a Pim-1 substrate. Pim-1 was indeed found to directly interact with and serine-phosphorylate FLT3. Pim-1 inhibition decreased the expression and half-life of 130 kDa FLT3, with partial abrogation by proteasome inhibition, in association with decreased FLT3 binding to calnexin and HSP90, and increased 150 kDa FLT3 expression and half-life, with abrogation by inhibition of glycosylation. These findings were consistent with Pim-1 stabilizing FLT3-ITD as a 130 kDa species associated with calnexin and HSP90 and inhibiting its glycosylation to form the 150 kDa species. Pim-1 knockdown effects were similar. Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway. Finally, Pim-1 inhibition synergized with FLT3 inhibition in inducing apoptosis of FLT3-ITD cells. This is, to our knowledge, the first demonstration of a role of Pim-1 in a positive feedback loop promoting aberrant signaling in malignant cells.


Combined arterial gas embolism and decompression sickness following no-stop dives.
Decompression sickness (DCS) has been clinically classified as Type I (predominantly joint pain) or Type II (predominantly spinal cord lesions). We present 3 cases that are all characterized by severe (Type II) DCS with signs and symptoms of spinal cord injury occurring in conjunction with arterial gas embolism (AGE). We consider the AGE "minor" because only 2 of the 3 subjects initially lost consciousness, and in all cases the signs and symptoms of the AGE had essentially resolved within 1 h or by the time recompression therapy began. DCS was resistant to recompression therapy, even though treatment began promptly after the accident in 2 of the 3 cases. None of the cases had a good neurologic outcome and there has been one death. None of the divers exceeded the U.S. Navy "no-stop" limits for the depths at which they were diving. We have observed a previously unreported clinical syndrome characterized by severe Type II DCS subsequent to AGE following pressure-time exposures that would normally not be expected to produce DCS. We postulate that AGE may have precipitated or predisposed to this form of DCS.


Staphylococcus aureus α-hemolysin mediates virulence in a murine model of severe pneumonia through activation of the NLRP3 inflammasome.
Staphylococcus aureus is a dangerous pathogen that can cause necrotizing infections characterized by massive inflammatory responses and tissue destruction. Staphylococcal α-hemolysin is an essential virulence factor in severe S. aureus pneumonia. It activates the nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 (NLRP3) inflammasome to induce production of interleukin-1β and programmed necrotic cell death. We sought to determine the role of α-hemolysin-mediated activation of NLRP3 in the pathogenesis of S. aureus pneumonia. We show that α-hemolysin activates the NLRP3 inflammasome during S. aureus pneumonia, inducing necrotic pulmonary injury. Moreover, Nlrp3(-/-) mice have less-severe pneumonia. Pulmonary injury induced by isolated α-hemolysin or live S. aureus is independent of interleukin-1β signaling, implicating NLRP3-induced necrosis in the pathogenesis of severe infection. This work demonstrates the exploitation of host inflammatory signaling by S. aureus and suggests the NLRP3 inflammasome as a potential target for pharmacologic interventions in severe S. aureus infections.


Dynamic chromosomal tuning of a novel GAU1 lncing driver at chr12p13.32 accelerates tumorigenesis.
Aberrant chromatin transformation dysregulates gene expression and may be an important driver of tumorigenesis. However, the functional role of chromosomal dynamics in tumorigenesis remains to be elucidated. Here, using in vitro and in vivo experiments, we reveal a novel long noncoding (lncing) driver at chr12p13.3, in which a novel lncRNA GALNT8 Antisense Upstream 1 (GAU1) is initially activated by an open chromatin status, triggering recruitment of the transcription elongation factor TCEA1 at the oncogene GALNT8 promoter and cis-activates the expression of GALNT8. Analysis of The Cancer Genome Atlas (TCGA) clinical database revealed that the GAU1/GALNT8 driver serves as an important indicative biomarker, and targeted silencing of GAU1 via the HKP-encapsulated method exhibited therapeutic efficacy in orthotopic xenografts. Our study presents a novel oncogenetic mechanism in which aberrant tuning of the chromatin state at specific chromosomal loci exposes factor-binding sites, leading to recruitment of trans-factor and activation of oncogenetic driver, thereby provide a novel alternative concept of chromatin dynamics in tumorigenesis.


Perceived benefit of a telemedicine consultative service in a highly staffed intensive care unit.
The aim of this study was to evaluate whether a nocturnal telemedicine service improves culture, staff satisfaction, and perceptions of quality of care in a highly staffed university critical care system. We conducted an experiment to determine the effect of telemedicine on nursing-staff satisfaction and perceptions of the quality of care in an intensive care unit (ICU). We surveyed ICU nurses using a modified version of a previously validated tool before deployment and after a 2-month experimental program of tele-ICU. Nurses in another, similar ICU within the same hospital academic medical center served as concurrent controls for the survey responses. Survey responses were measured using a 5-point Likert scale, and results were analyzed using paired t testing. Survey responses of the nurses in the intervention ICU (n = 27) improved significantly after implementation of the tele-ICU program in the relations and communication subscale (2.99 ± 1.13 pre vs 3.27 ± 1.27 post, P < .01), the psychological working conditions and burnout subscale (3.10 ± 1.10 pre vs 3.23 ± 1.11 post, P < .02), and the education subscale (3.52 ± 0.84 pre vs 3.76 ± 0.78 post, P < .03). In contrast, responses in the control ICU (n = 11) declined in the patient care and perceived effectiveness (3.94 ± 0.80 pre vs 3.48 ± 0.86 post, P < .01) and the education (3.95 ± 0.39 pre vs 3.50 ± 0.80 post, P < .05) subscales. Telemedicine has the potential to improve staff satisfaction and communication in highly staffed ICUs.


Activation of human neutrophil nicotinamide adenine dinucleotide phosphate, reduced (triphosphopyridine nucleotide, reduced) oxidase by arachidonic acid in a cell-free system.
Sonicates from unstimulated human neutrophils produce no measurable superoxide since the superoxide-generating enzyme, NADPH oxidase, is inactive in these preparations. Previous attempts to activate the oxidase in disrupted cells with conventional neutrophil stimuli have been unsuccessful. This report describes a cell-free system in which arachidonic acid (82 microM) was able to activate superoxide generation that was dependent upon the presence of NADPH and the sonicate. For activation to occur, both the particulate and supernatant fractions of the sonicate must be present. Calcium ions, which are required for activation of intact neutrophils by arachidonate, were not necessary in the cell-free system. In quantitative terms, the superoxide-generating activity in the cell-free system could account for at least 20-50% of the superoxide rate observed in intact neutrophils stimulated with arachidonate. Sonicates from patients with chronic granulomatous disease (CGD) could not be activated by arachidonic acid in the cell-free system. In three patients representing both genetic forms of CGD, the defect appeared to reside in the particulate fraction. The soluble cofactor was normal in all three patients and could be used to activate normal neutrophil pellets in the presence of arachidonic acid. Thus, at least a portion of the activation mechanism in the neutrophil, that residing in the soluble phase, appeared to be normal in patients with CGD.


Reliability of an image analysis system for quantifying the radiographic trabecular pattern.
A reliability evaluation technique was used to examine the reliability of an image analysis system of the trabecular pattern and to determine the contribution of three possible sources of error variance. Two series of radiographs were taken of 14 lumbar vertebral slices (28 radiographs). Every radiograph was placed on a viewing box for digitization four times by a single operator (112 positions of radiographs) and from every position of a radiograph an area of 15 mm x 15 mm was digitized twice (224 samples for analysis). Ten geometrical characteristics of the trabecular pattern were studied and its orientation was analyzed in 12 directions. Reliability was determined by calculating Cronbach's alpha. This design enabled dividing the measurement error (1-alpha) into fractions associated with the X-ray procedure, the operator and the system. Using this reliability evaluation technique, it was found that the orientation variables are more reliable than the geometric variables. It was found that effort to increase the reliability should be directed toward improving the technical procedure of this image analysis system. Also, repeated measurements will increase the reliability. The number of repeated measurements based on a desired reliability can be calculated. This procedure of evaluation gives the opportunity to select a source of error variance which have to be reduced to increase reliability most effectively.


Specific activity of alpha1proteinase inhibitor and alpha2macroglobulin in human serum: application to insulin-dependent diabetes mellitus.
The shifting balance between proteinases and proteinase inhibitors in blood, a function of their relative affinities and concentrations, has long been hypothesized to influence immune competency. The identification of proteinase-activated receptor responses in cells of the mononuclear phagocyte system suggests a potential explanation. The major serum proteinase inhibitor, alpha1proteinase inhibitor (alpha1PI, alpha1-antitrypsin), has been reported to increase in concentration during inflammation. Quantitative determination of serum alpha1PI has traditionally been performed nephelometrically; however, antigenically quantitated levels may not be representative of functional capacity. It has previously been observed that alpha1PI in serum exhibits bimodal behavior as the result of various concentrations of proteinase inhibitors, specifically alpha2macroglobulin (alpha2M) and inter-alpha-trypsin inhibitor, which compete in binding to a panel of serine proteinases. Consequently, it has not previously been possible to assign a numerical value for the specific activity of these competing proteinase inhibitors in serum. By applying known constants representing the association of proteinase inhibitors with porcine pancreatic elastase (PPE), the theoretical relationship between the functional and antigenic values for alpha1PI and alpha2M has been empirically derived allowing, for the first time, the calculation of their specific activities in serum. As predicted, the serum concentration of alpha1PI was found to be highly correlated with residual uninhibited PPE catalytic activity in healthy individuals, but not in individuals exhibiting fragmented or complexed alpha1PI. Using these techniques, both the antigenic and functional levels of alpha1PI were determined in sera from subjects with insulin-dependent diabetes mellitus (IDDM) who had been clinically diagnosed as having either periodontal disease or gingival health. Determination of quantitative levels by antigen-capture suggests that the IDDM subjects with periodontitis manifest dramatically increased levels of fragmented serum alpha1PI compared with their orally healthy counterparts or normal controls. In contrast, functional analysis of serum alpha1PI revealed no differences between the three subject populations. The elevated levels of antigenically determined serum alpha1PI reflect the inflammatory status of periodontal disease. These results support the importance of and provide methodology for determining the functionally active levels of alpha1PI allowing reexamination of changes detected during the acute phase of inflammation, replacement therapy, and longitudinal studies in relevant disease processes including malignancy and diabetes.


Radiotherapy potentiates the therapeutic efficacy of intratumoral dendritic cell administration.
We examined whether radiotherapy (RT) could enhance the efficacy of dendritic cell (DC)-based immunotherapy of cancer. Mice bearing s.c. D5 melanoma or MCA 205 sarcoma tumors were treated with intratumoral (i.t.) injections of bone marrow-derived unpulsed DCs in combination with local fractionated tumor irradiation. DC administration alone slightly inhibited D5 tumor growth and had no effect on MCA 205. RT alone caused a modest inhibition of both tumors. DC administration combined with RT inhibited D5 and MCA 205 tumor growth in an additive and synergistic manner, respectively. In both tumor models, RT intensified the antitumor efficacy of DC administration independent of apoptosis or necrosis within the tumor mass. Combination treatment of i.t. DCs plus RT was superior to s.c. injections of tumor lysate-pulsed DCs plus interleukin 2 in inhibiting D5 tumor growth and prolonging survival of mice. Splenocytes from mice treated with i.t. DCs plus RT contained significantly more tumor-specific, IFN-gamma-secreting T cells compared with control groups. Moreover, adoptive transfer of these splenocytes mediated significant tumor regression in mice bearing established pulmonary metastases. Combined treatment followed by resection of residual s.c. tumor conferred protective immunity against a subsequent i.v. tumor challenge. Furthermore, i.t. DC plus RT treatment of s.c. tumor in mice bearing concomitant pulmonary metastases resulted in a significant reduction of lung tumors. i.t. DC administration combined with RT induces a potent local and systemic antitumor response in tumor-bearing mice. This novel regimen may be beneficial in the treatment of human cancers.


Pathophysiology of the respiratory system related to anesthesia.
The pathophysiology of the respiratory system can be viewed by simply evaluating the status of a functional residual capacity (FRC). More specifically, patients with airways that are characterized as extremely compliant or "floppy" will have an increased FRC, which is the hallmark of chronic obstructive pulmonary disease. Patients with noncompliant, "stiff" lungs suffer from a form of restrictive disease with a resultant reduction in the FRC. Hence, the implications for anesthesia care focus on the FRC; that is, raising the FRC in the restrictive disease patient and normalizing or preventing further increase in the FRC in the patient with chronic obstructive pulmonary disease.


A gene coding for the uric acid-xanthine permease of Aspergillus nidulans: inactivational cloning, characterization, and sequence of a cis-acting mutation.
In Aspergillus nidulans, integration of transforming sequences can proceed through recombination with homologous sequences or at heterologous sites in the genome. In a strain with a large deletion in the gene coding for acetamidase (amdS), a plasmid carrying this gene integrates into and inactivates uapA, the putative structural gene for uric acid-xanthine permease, with a frequency of 0.3%. The integration event occurs 3' to the open reading frame of amdS. A 10-nucleotide sequence which occurs in this region is also found within the open reading frame of uapA. We have taken advantage of this integration event to clone the permease gene and to characterize a cis-acting mutation, uap-100, as a duplication of 139 bp located in the upstream region of uapA. Northern and dot blot analyses confirmed earlier results measuring the uptake of uric acid: the transcription of the uapA gene is inducible and the uap-100 mutation results in a bypass of the need for induction while having an 8-fold up-promoter effect under inducing conditions.


Identification in extracts from AR4-2J cells of inositol 1,4,5-trisphosphate by its susceptibility to inositol 1,4,5-trisphosphate 3-kinase and 5-phosphatase.
The identity of 3H-labelled material ascribed to Ins(1,4,5)P3 in resting or bombesin-stimulated myo-[3H]inositol-labelled AR4-2J cells was investigated by determining its ability to serve as substrate for partially purified Ins(1,4,5)P3/Ins(1,3,4,5)-P4 5-phosphatase and Ins(1,4,5)P3 3-kinase. This 3H-labelled material was metabolized by these two enzymes at rates which were indistinguishable from those for an internal [32P]Ins(1,4,5)P3 standard, establishing its identity as authentic Ins(1,4,5)P3. In addition, and in contrast with findings in earlier studies utilizing substance P as an agonist, prolonged stimulation with bombesin resulted in an increase in an InsP4 which was degraded by Ins(1,4,5)P3/Ins(1,3,4,5)P4 5-phosphatase. These findings serve to confirm the previous estimate of Horstman, Takemura & Putney [(1988) J. Biol. Chem. 263, 15297-15303] for the intracellular concentrations of Ins(1,4,5)P3 in resting (2 microM) and agonist-stimulated (25 microM) AR4-2J cells. The implications of these findings for the physiological regulation of intracellular Ca2+ through this intracellular messenger are discussed.


[Nicotinic acid metabolism in patients with non-coronarogenic heart diseases].
To study the supply with nicotinic acid, 74 patients with rheumatic fever of varying degree and circulatory disorders, 10 patients with infectious-allergic myocarditis, 15 with tonsilogenous myocardiodystrophy were examined. Seventy normal subjects served as control. The supply with vitamin PP was evaluated from the blood content of NAD, NADP and N'-methylnicotinamide and its excretion with urine. All the patients with myocarditis and rheumatic fever demonstrated a decrease in the nicotinic acid supply which became more marked as the degree of rheumatic fever rose and circulatory failure supervened. In patients with tonsilogenous myocardiodystrophy , the disturbance of the vitamin supply was less overt.


Implementation of an individual patient prospective database of hospital births in Sri Lanka and its use for improving quality of care.
This study was aimed at piloting a prospective individual patient database on hospital deliveries in Colombo, Sri Lanka, and at exploring its use for developing recommendations for improving quality of care (QoC). Observational study. De Soysa Maternity Hospital, the largest referral hospital for maternity care in Sri Lanka. From July 2015 to June 2017, 150 variables were collected for each delivery using a standardised form and entered into a database. Data were analysed every 8 months, and the results made available to local staff. Outcomes of the study included: technical problems; data completeness; data accuracy; key database findings; and use of data. 7504 deliveries were recorded. No technical problem was reported. Data completeness exceeded that of other existing hospital recording systems. Less than 1% data were missing for maternal variables and less than 3% for newborn variables. Mistakes in data collection and entry occurred in 0.01% and 0.09% of maternal and newborn data, respectively. Key QoC indicators identified in comparison with international standards were: relatively low maternal mortality (0.053%); relatively high maternal near-miss cases (3.4%); high rate of induction of labour (24.6%), caesarean section (30.0%) and episiotomy (56.1%); relatively high rate of preterm births (9.4%); low birthweight rate (16.5%); stillbirth (0.97%); and of total deaths in newborn (1.98%). Based on key indicators identified, a list of recommendations was developed, including the use checklists to standardise case management, training, clinical audits and more information for patients. A list of lessons learnt with the implementation of the data collection system was also drawn. The study shows that the implemented system of data collection can produce a large quantity of reliable information. Most importantly, this experience provides an example on how database findings can be used for discussing hospital practices, identifying gaps and to agree on recommendations for improving QoC.


Opiate withdrawal symptoms in response to 10-day and 21-day methadone withdrawal programmes.
This study investigates and compares the responses of 132 opiate addicts to a 10-day or a 21-day in-patient oral methadone withdrawal regime. For both groups, symptom severity (on the Opiate Withdrawal Scale) steadily increased through the methadone withdrawal phase, and peaked near the point of completion of the prescribed drug, declining slowly thereafter. Patients on the 10-day programme reported significantly higher peak withdrawal scores than those on the 21-day programme. Although the proportions who completed detoxification were similar, there was a significantly higher drop-out rate immediately after detoxification for the 10-day group. The possible benefits and handicaps of the two withdrawal schedules are considered and recommendations are proposed for further refinement of the present widely adopted approach.


Biodegradable polymer-coated versus durable polymer-coated sirolimus-eluting stents: the final 5-year outcomes of the I-LOVE-IT 2 trial.
This analysis presents the final five-year results of the I-LOVE-IT 2 trial, a non-inferiority study comparing a biodegradable polymer (BP) sirolimus-eluting stent (SES) with a durable polymer (DP) SES in patients with coronary artery disease. Overall, 2,737 Chinese patients eligible for coronary stenting were treated with BP-SES or DP-SES in a 2:1 ratio. Patients who were randomised to the BP-SES group were additionally re-randomised to receive either six-month or 12-month dual antiplatelet therapy (DAPT) in a 1:1 ratio. The primary endpoint was 12-month target lesion failure (TLF: cardiac death, target vessel myocardial infarction (MI), or clinically indicated target lesion revascularisation). At five years, the overall follow-up rate was 90.8%, and the cumulative incidence of TLF as the primary endpoint was similar between BP-SES and DP-SES (hazard ratio [HR] 1.01, 95% confidence interval [CI]: 0.79 to 1.28), as was that for the patient-oriented composite endpoint (PoCE: all-cause death, all MI and any revascularisation) (HR 1.03, 95% CI: 0.86 to 1.23), or definite/probable stent thrombosis (ST) (HR 0.91, 95% CI: 0.70 to 1.77). Cumulative events were also similar between the six-month DAPT and 12-month DAPT groups after BP-SES implantation. I-LOVE-IT 2 showed that the five-year safety and efficacy of BP-SES and DP-SES were similar, as were those between six months and 12 months of DAPT after BP-SES implantation.


Oral cavity and oropharyngeal cancer incidence trends and disparities in the United States: 2000-2010.
Changes in the incidence of oral cancer based on anatomic location and demographic factors over time have been reported in the United States. The purpose of this study was to use recent data to examine oral cancer incidence trends and disparities by demographic factors and anatomic location. Surveillance, Epidemiology, and End Results (SEER) incidence data from 2000 to 2010 were used to characterize and analyze oral cancer incidence trends by anatomic region and subsite, age at diagnosis, gender, race/ethnicity, and stage at diagnosis. Poisson regression was used to compare incidence risk by select demographic factors. About 75,468 incident oral cancer cases were diagnosed from 2000 to 2010. The tonsil was the most frequently diagnosed anatomic subsite (23.1%) and the subsite with the greatest contribution to the overall, age-standardized cumulative incidence rate of 8.4 cases per 100,000 (95% confidence interval (CI): 8.3, 8.4). An increasing incidence trend was observed for cancers in the oropharyngeal region, in contrast to a decreasing trend seen in the oral cavity region. In the Poisson regression model, all race/ethnicity groups showed a lower incidence risk relative to whites for oral cavity and oropharyngeal cancer, and white males displayed the highest incidence rate of all race/ethnicity-gender groups during the study period (14.1 per 100,000; 95% CI: 14.0, 14.2). This study's epidemiological findings are especially important for oral health care providers, patient education, and the identification of risk profiles associated with oral cancer. The distinct epidemiological trends of oral cavity and oropharyngeal cancers dictate that oral cancer can no longer be viewed as a discrete entity. Oral health providers should have a strong understanding of the different risk factors associated with oral cavity and oropharyngeal cancers and educate their patients accordingly.


Impacts of Climate Change on Health and Health Services in Northern New South Wales, Australia: A Rapid Review.
Climate change is exposing populations to increasing temperatures and extreme weather events in many parts of Australia. To prepare for climate challenges, there is a growing need for Local Health Districts (LHDs) to identify potential health impacts in their region and strengthen the capacity of the health system to respond accordingly. This rapid review summarised existing evidence and research gaps on the impact of climate change on health and health services in Northern New South Wales (NSW)-a 'hotspot' for climate disaster declarations. We systematically searched online databases and selected 11 peer-reviewed studies published between 2012-2022 for the Northern NSW region. The most explored health outcome was mental health in the aftermath of floods and droughts, followed by increased healthcare utilisation due to respiratory, cardiovascular and mortality outcomes associated with bushfire smoke or heat waves. Future research directions were recommended to understand: the compounding impacts of extreme events on health and the health system, local data needs that can better inform models that predict future health risks and healthcare utilisation for the region, and the needs of vulnerable populations that require a whole-of-system response during the different phases of disasters. In conclusion, the review provided climate change and health research directions the LHD may undertake to inform future adaptation and mitigation policies and strategies relevant to their region.


Cutaneous vascular fibrinolytic activity in the local Shwartzman reaction.
A fibrin slide test was utilized to study cutaneous vascular plasminogen activator activity in normal rabbit, rat, monkey, and human skin and in rabbit skin following development of the local Shwartzman reaction and after substituting epsilon-aminocaproic acid for the preparatory injection of endotoxin in the local Shwartzman reaction. Cutaneous vascular plasminogen activator activity was also studied in rats after attempted induction of the local Shwartzman reaction following inhibition of fibrinolysis with epsilon-aminocaproic acid and/or pregnancy. Plasminogen activator activity was detected in vessels of normal rat, monkey, and human skin but was absent in skin from normal rabbits and rabbits with the local Shwartzman reaction. Intradermal injection of epsilon-aminocaproic acid failed to prepare for the local Shwartzman reaction. In the rat, which has greater cutaneous vascular plasminogen activator activity than the rabbit, inhibition of vascular activator with epsilon-aminocaproic acid and/or pregnancy failed to prepare for the local Shwartzman reaction. These studies indicate that although the markedly diminished level of cutaneous vascular plasminogen activator in the rabbit may be important in the pathogenesis of the local Shwatzman reaction, factors other than inhibition of fibrinolysis are also necessary for preparation of the reaction.


d-chiro-Inositol Ribophostin: A Highly Potent Agonist of d-myo-Inositol 1,4,5-Trisphosphate Receptors: Synthesis and Biological Activities.
Analogues of the Ca2+-releasing intracellular messenger d-myo-inositol 1,4,5-trisphosphate [1, Ins(1,4,5)P3] are important synthetic targets. Replacement of the α-glucopyranosyl motif in the natural product mimic adenophostin 2 by d-chiro-inositol in d-chiro-inositol adenophostin 4 increased the potency. Similar modification of the non-nucleotide Ins(1,4,5)P3 mimic ribophostin 6 may increase the activity. d-chiro-Inositol ribophostin 10 was synthesized by coupling as building blocks suitably protected ribose 12 with l-(+)-3-O-trifluoromethylsulfonyl-6-O-p-methoxybenzyl-1,2:4,5-di-O-isopropylidene-myo-inositol 11. Separable diastereoisomeric 3-O-camphanate esters of (±)-6-O-p-methoxy-benzyl-1,2:4,5-di-O-isopropylidene-myo-inositol allowed the preparation of 11. Selective trans-isopropylidene deprotection in coupled 13, then monobenzylation gave separable regioisomers 15 and 16. p-Methoxybenzyl group deprotection of 16, phosphitylation/oxidation, then deprotection afforded 10, which was a full agonist in Ca2+-release assays; its potency and binding affinity for Ins(1,4,5)P3R were similar to those of adenophostin. Both 4 and 10 elicited a store-operated Ca2+ current ICRAC in patch-clamped cells, unlike Ins(1,4,5)P3 consistent with resistance to metabolism. d-chiro-Inositol ribophostin is the most potent small-molecule Ins(1,4,5)P3 receptor agonist without a nucleobase yet synthesized.


An MDR-EGFP gene fusion allows for direct cellular localization, function and stability assessment of P-glycoprotein.
In cancer and AIDS, overexpression of the MDR1 gene has important implications in the design of chemotherapy protocols because of the ability of its product, the ATP-dependent drug efflux pump P-glycoprotein (Pgp), to confer selective advantage to tumor and HIV-infected cells in the form of multidrug resistance. To study Pgp expression and physiology, we designed a translational fusion between the MDR1 and enhanced green fluorescent protein (EGFP) genes. The chimeric protein, Pgp-EGFP, was concentrated mainly in the plasma membrane and in the Golgi when expressed in drug-sensitive KB-3-1 cells. Doxorubicin, daunorubicin and rhodamine-123 efflux assays confirmed function of the chimeric pump. Also, at the single-cell level, an inverse relationship between Pgp-EGFP expression and nuclear doxorubicin accumulation was demonstrated. Polarized Pgp expression on the apical cell surface was confirmed by transfection of the MDR-EGFP fusion gene into MDCK cells. However, after colchicine selection, Pgp-EGFP was also detectable in the lateral domain of the transfected MDCK monolayers. These results indicate that drug selection affects not only expression, but cellular localization of Pgp. Furthermore, using a tet-based inducible expression system for Pgp-EGFP, we confirmed the stable nature of Pgp (t(1/2 total Pgp-EGFP) = 2.2 days), but revealed that surface-Pgp acquires extra stability as an active pump (t(1/2 surface Pgp-EGFP) = 3.7 days).


Emerging Immunotherapies for Cancer and Their Potential for Application in Pediatric Oncology.
After decades of basic research, immune-based therapeutics for the treatment of cancer are showing evidence of efficacy in clinical trials; several immunotherapeutics already incorporated into standard treatment regimens. Intensive research is underway to improve the efficacy of immunotherapeutics and to expand the application of immunotherapy to a wider array of cancers. The therapeutic options that comprise immunotherapy for cancer are vast and span monoclonal antibodies, tumor vaccines, adoptive cellular therapies, as well as therapies aimed at reversing immunosuppression and enhancing immune reactivity globally and/or locally within the tumor microenvironment. In pediatric cancer, monoclonal antibodies have demonstrated efficacy in hematologic malignancies, and neuroblastoma and bispecific antibodies that activate resident T cells, as well as adoptive cell therapy, have shown recent exciting results for the treatment of acute lymphoblastic leukemia in childhood. This review discusses the basic principles of tumor immunology driving clinical development of new immunotherapies, describes immunotherapeutics with demonstrated efficacy and several currently in clinical trials, and highlight agents that seem to be most promising for the treatment of pediatric cancer.


[Does hyponatremia predict post-transurethral resection of the prostate syndrome?].
The florid post-TUR syndrome observed in one of our patients prompted us to conduct a prospective study on 100 males undergoing TUR to determine the natremia levels that could herald the presentation of this syndrome. Several parameters were evaluated, including pre- and post-operative serum sodium levels, total volume of irrigant used, and the weight of the resected prostate. Although the natremia levels dropped significantly in 4 patients, only the patient who had motivated this study developed symptoms and evidently no conclusions can be drawn on the basis of a single observation.


Molecular basis of ribotype variation in the seventh pandemic clone and its O139 variant of Vibrio cholerae.
Ribotyping has been widely used to characterise the seventh pandemic clone including South American and O139 variants which appeared in 1991 and 1992 respectively. To reveal the molecular basis of ribotype variation we analysed the rrn operons and their flanking regions. All but one variation detected by BglI, the most discriminatory enzyme, was found to be due to changes within the rrn operons, resulting from recombination between operons. The recombinants are detected because of the presence of a BglI site in the 16S gene in three of the nine rrn operons and/or changes of intergenic spacer types of which four variants were identified. As the frequency of rrn recombination is high, ribotyping becomes a less useful tool for evolutionary studies and long term monitoring of the pathogenic clones of Vibrio cholerae as variation could undergo precise reversion by the same recombination event.


How muscles recover from paresis and atrophy after intramuscular injection of botulinum toxin A: Study in juvenile rats.
Botulinum toxin A (BoNT-A) is a potent biological toxin widely used for the management of skeletal muscle spasticity or dynamic joint contracture. Intramuscular injection of BoNT-A causes muscle denervation, paresis, and atrophy. This clinical effect of botulinum toxin A lasts 3 to 6 months, and injected muscle eventually regains muscle mass and recovers muscle function. The goal of the present study was to characterize the molecular and cellular mechanisms leading to neuromuscular junction (NMJ) regeneration and skeletal muscle functional recovery after BoNT-A injection. Fifty-six 1-month-old Sprague-Dawley rats were used. Botulinum toxin A was injected into the left gastrocnemius muscle at a dosage of 6 units/kg body weight. An equivalent volume of saline was injected into the right gastrocnemius muscle to serve as control. The gastrocnemius muscle samples were harvested from both hind limbs at 3 days, 7 days, 15 days, 30 days, 60 days, 90 days, 180 days, and 360 days after administration of toxin. In addition, the gastrocnemius muscles from 1-month-old rats with no injections were harvested to serve as uninjected control group. Muscle samples were processed and mRNA was extracted. Real-time polymerase chain reaction (PCR) and gene microarray technology were used to identify key molecules involved in NMJ stabilization and muscle functional recovery. More than 28,000 rat genes were analyzed and approximately 9000 genes are expressed in the rat gastrocnemius muscle. Seven days following BoNT-A injection, 105 genes were upregulated and 59 genes were downregulated. Key molecules involved in neuromuscular junction (NMJ) stabilization and muscle functional recovery were identified and their time course of gene expression following BoNT-A injection were characterized. This animal study demonstrates that following intramuscular injection of BoNT-A, there is a sequence of cellular events that eventually leads to NMJ stabilization, remodeling, and myogenesis and muscle functional recovery. This recovery process is divided into two stages (aneural and neural) and that the IGF-1 signaling pathway play a central role in the process.


Recognizing diversity in coral symbiotic dinoflagellate communities.
A detailed understanding of how diversity in endosymbiotic dinoflagellate communities maps onto the physiological range of coral hosts is critical to predicting how coral reef ecosystems will respond to climate change. Species-level taxonomy of the dinoflagellate genus Symbiodinium has been predominantly examined using the internal transcribed spacer (ITS) region of the nuclear ribosomal array (rDNA ITS2) and downstream screening for dominant types using denaturing gradient gel electrophoresis (DGGE). Here, ITS2 diversity in the communities of Symbiodinium harboured by two Hawaiian coral species was explored using direct sequencing of clone libraries. We resolved sixfold to eightfold greater diversity per coral species than previously reported, the majority of which corresponds to a novel and distinct phylogenetic lineage. We evaluated how these sequences migrate in DGGE and demonstrate that this method does not effectively resolve this diversity. We conclude that the Porites spp. examined here harbour diverse assemblages of novel Symbiodinium types and that cloning and sequencing is an effective methodological approach for resolving the complexity of endosymbiotic dinoflagellate communities harboured by reef corals.


Variation in the mating system of Vincetoxicum hirundinaria (Asclepiadaceae) in peripherial island populations.
Self-fertility may be selected for in small and isolated plant populations of normally outcrossing species. In addition, adaptations for self-fertility are likely to arise in island populations and in populations that are located at the border of the species range. The mating system of Vincetoxicum hirundinaria (Asclepiadaceae) is examined in island populations that are located at the northern border of the species range. Pollination experiments were conducted under glasshouse conditions with plants from four populations. The frequencies of self-fertile individuals were relatively high and did not differ among populations. Cross-pollination resulted in higher fruit set than self-pollination. However, fruit-set from self-pollination and cross-pollination did not differ in the self-fertile individuals. Interestingly, the proportion of aborted fruits was on average higher following cross-pollination than following self-pollination. No differences were observed in seed number or seed mass between self- and cross-pollinated fruits. Pollen tube growth following self- and cross-pollinations was indistinguishable. The results of this study revealed that V. hirundinaria possess a mixed-mating system in the studied island populations. Evidence was also provided for a late-acting self-incompatibility system commonly observed in Asclepiadaceae. No clear signs of inbreeding depression were observed in the early stages of development.


Prediction of early death after therapeutic hepatic arterial embolisation.
A consecutive series of 14 patients with hepatic malignant disease treated by palliative hepatic arterial embolisation was reviewed. Twelve patients had hepatic pain from their tumour and two were suffering from the carcinoid syndrome. Six patients died within four weeks of the procedure (group 1) and eight survived for at least 10 weeks (group 2). Factors were sought that might permit prediction of a high risk of early death (group 1). The pre-embolisation angiograms reviewed by a "blind" observer showed no differences in vascularity or tumour size between the groups and no difference in the extent of arterial occlusion after embolisation. The portal vein was patent in all patients. No significant difference was seen between the groups in the pre-embolisation biochemical values, with the exception of lower serum albumin concentrations and higher alkaline phosphatase activities in group 1. All those who died early had serum alkaline phosphatase activities of 45 KAU or above, while six of the eight who survived longer had activities below this value (p less than 0.02). These findings suggest that serum alkaline phosphatase activity of 45 KAU or more (normal range 3-13) might alone be a useful predictor of early death. Stepwise discriminant analysis using a weighted combination of serum alkaline phosphatase activity and albumin concentration predicted the outcome in all but one of the patients studied (p less than 0.002).


Induction of necrosis and apoptosis to KB cancer cells by sanguinarine is associated with reactive oxygen species production and mitochondrial membrane depolarization.
Sanguinarine is a benzopheanthridine alkaloid present in the root of Sanguinaria canadensis L. and Chellidonium majus L. In this study, sanguinarine (2 and 3 microM) exhibited cytotoxicity to KB cancer cells by decreasing MTT reduction to 83% and 52% of control after 24-h of exposure. Sanguinarine also inhibited the colony forming capacity (>52-58%) and growth of KB cancer cells at concentrations higher than 0.5-1 microM. Short-term exposure to sanguinarine (>0.5 microM) effectively suppressed the adhesion of KB cells to collagen and fibronectin (FN). Sanguinarine (2 and 3 microM) induced evident apoptosis as indicated by an increase in sub-G0/G1 populations, which was detected after 6-h of exposure. Only a slight increase in cells arresting in S-phase and G2/M was noted. Induction of KB cell apoptosis and necrosis by sanguinarine (2 and 3 microM) was further confirmed by Annexin V-PI dual staining flow cytometry and the presence of DNA fragmentation. The cytotoxicity by sanguinarine was accompanied by an increase in production of reactive oxygen species (ROS) and depolarization of mitochondrial membrane potential as indicated by single cell flow cytometric analysis of DCF and rhodamine fluorescence. NAC (1 and 3 mM) and catalase (2000 U/ml) prevented the sanguinarine-induced ROS production and cytotoxicity, whereas dimethylthiourea (DMT) showed no marked preventive effect. These results suggest that sanguinarine has anticarcinogenic properties with induction of ROS production and mitochondrial membrane depolarization, which mediate cancer cell death.


Announcing new members of the Advisory Editorial Board.
We on the Editorial Board of "Anaesthesiology Intensive Therapy" are committed to continuous improvement of the quality of our journal, and thus we are excited that two excellent clinician-scientists have joined us in this endeavour. It is our great honour to announce that Doctor Thomas Kander of Lund University (Sweden) and Doctor Dan Drzymal-ski of Tufts Medical Center (Boston, Massachusetts) have become members of the Advisory Editorial Board of "Anaesthesio-logy Intensive Therapy".


Investigation of the Feasibility of an Intervention to Manage Fall Risk in Wheeled Mobility Device Users with Multiple Sclerosis.
Falls are a common concern for wheeled mobility device users with multiple sclerosis (MS); however, no evidence-based fall prevention programs have been developed to meet the specific needs of the population. We examine the preliminary feasibility of a fall management intervention in wheeled mobility device users with MS. Study participants were exposed to an intervention program targeting risk factors for falls, including transfer skills and seated postural control. The feasibility of the program was evaluated by assessing participant perspectives, cost, recruitment rates, study adherence, participant retention, safety, and the ability to collect primary and secondary outcomes, including fall frequency, concerns about falling, transfer quality, and seated postural control. 16 wheeled mobility device users completed the program, which was found to be feasible and was positively evaluated by participants. No adverse events were experienced. After exposure to the intervention, fall frequency significantly decreased (P < .001) and transfer quality (P = .001) and seated postural control (P = .002) significantly improved. No significant differences were found regarding concerns about falling (P = .728). This study examined the feasibility of an intervention program to manage fall risk in wheeled mobility device users with MS. The program was found to be feasible, and preliminary results showed the intervention to be effective in decreasing fall frequency. Additional testing is needed to further examine the efficacy and long-term impact of the intervention.


Relation of calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women. The Iowa Women's Health Study.
To investigate whether a high intake of calcium, vitamin D, or dairy products may protect against colon cancer, the authors analyzed data from a prospective cohort study of 35,216 Iowa women aged 55-69 years without a history of cancer who completed a dietary questionnaire in 1986. Through 1990, 212 incident cases of colon cancer were documented. Adjusted for age, intakes of calcium and vitamin D were significantly inversely associated with the risk of colon cancer. The relative risks for the highest quintile of intake as compared with the lowest were 0.52 (95% confidence interval (CI) 0.33-0.82) for calcium and 0.54 (95% CI 0.35-0.84) for vitamin D. After multivariate adjustment, the trends were no longer statistically significant and the relative risks for the highest versus the lowest quintiles of calcium and vitamin D intakes were attenuated: 0.68 (95% CI 0.41-1.11) for calcium and 0.73 (95% CI 0.45-1.18) for vitamin D. Although the multivariate-adjusted findings did not reach statistical significance at p < or = 0.05, when considered in the context of the whole body of literature on this subject, they are consistent with a possible role for calcium or vitamin D in modestly reducing colon cancer risk.


kappa-Carrageenan as a carrier in affinity precipitation of yeast alcohol dehydrogenase.
kappa-Carrageenan is a non-toxic polymer from seaweeds, which becomes reversibly insoluble upon the addition of K(+). Its conjugate with the dye, Cibacron Blue 3GA, was used to purify alcohol dehydrogenase from crude yeast extract by affinity precipitation. Response surface methodology was used to optimize conditions for affinity precipitation of the enzyme with the polymer-dye conjugate. Recovery of 58% of the enzyme activity with 13.6-fold purification was obtained.


Interventions to prevent hypothermia at birth in preterm and/or low birthweight infants.
Keeping vulnerable preterm infants warm is problematic even when recommended routine thermal care guidelines are followed in the delivery suite. To assess efficacy and safety of interventions designed for prevention of hypothermia in preterm and/or low birthweight infants applied within 10 minutes after birth in the delivery suite compared with routine thermal care. We used the standard search strategy of the Cochrane Neonatal Review Group (CNRG). The review was updated in October 2009. Trials using randomised or quasi-randomised allocations to test a specific intervention designed to prevent hypothermia, (apart from 'routine' thermal care) applied within 10 minutes after birth in the delivery suite to infants of < 37 weeks' gestational age or birthweight </= 2500 g. We used the methods of the CNRG for data collection and analysis. 1) Barriers to heat loss [5 studies; plastic wrap or bag (3), plastic cap (1), stockinet cap (1)]:Plastic wraps or bags were effective in reducing heat losses in infants < 28 weeks' gestation (4 studies, n = 223; WMD 0.68 degrees C; 95% CI 0.45, 0.91), but not in infants between 28 to 31 week's gestation. Plastic caps were effective in reducing heat losses in infants < 29 weeks' gestation (1 study, n = 64; MD 0.80 degrees C; 95% CI 0.41, 1.19). There was insufficient evidence to suggest that either plastic wraps or plastic caps reduce the risk of death within hospital stay. There was no evidence of significant differences in other clinical outcomes for either the plastic wrap/bag or the plastic cap comparisons. Stockinet caps were not effective in reducing heat losses.2) External heat sources [2 studies; skin-to-skin (1), transwarmer mattress (1)]:Skin-to-skin care (SSC) was shown to be effective in reducing the risk of hypothermia when compared to conventional incubator care for infants (1 study, n = 31; RR 0.09; 95% CI 0.01, 0.64). The transwarmer mattress reduced the incidence of hypothermia on admission to NICU in VLBW infants (1 study, n = 24; RR 0.30; 95% CI 0.11, 0.83). Plastic wraps or bags, plastic caps, SSC and transwarmer mattresses all keep preterm infants warmer leading to higher temperatures on admission to neonatal units and less hypothermia. However, the small numbers of infants and studies and the absence of long-term follow-up mean that firm recommendations for clinical practice cannot be given.


Identification of plasma microRNAs as new potential biomarkers with high diagnostic power in human cutaneous melanoma.
Melanoma is a devastating disease with few therapeutic options in the advanced stage and with the urgent need of reliable biomarkers for early detection. In this context, circulating microRNAs are raising great interest as diagnostic biomarkers. We analyzed the expression profiles of 21 selected microRNAs in plasma samples from melanoma patients and healthy donors to identify potential diagnostic biomarkers. Data analysis was performed using global mean normalization and NormFinder algorithm. Linear regression followed by receiver operating characteristic analyses was carried out to evaluate whether selected plasma miRNAs were able to discriminate between cases and controls. We found five microRNAs that were differently expressed among cases and controls after Bonferroni correction for multiple testing. Specifically, miR-15b-5p, miR-149-3p, and miR-150-5p were up-regulated in plasma of melanoma patients compared with healthy controls, while miR-193a-3p and miR-524-5p were down-regulated. Receiver operating characteristic analyses of these selected microRNAs provided area under the receiver operating characteristic curve values ranging from 0.80 to 0.95. Diagnostic value of microRNAs is improved when considering the combination of miR-149-3p, miR-150-5p, and miR-193a-3p. The triple classifier had a high capacity to discriminate between melanoma patients and healthy controls, making it suitable to be used in early melanoma diagnosis.


Clinicopathologic correlation of xenon arc and argon laser photocoagulation. Procedure in human diabetic eyes.
Xenon arc and argon laser lesions applied as scatter treatment to two diabetic patients were studied clinically and histopathologically. Seventy-one burns were grouped as very severe, severe, and moderately severe, according to pigmentation and diameter of the retinal scar. All lesions except half of the moderately severe ones showed full-thickness retinal involvement. In very severe xenon burns, whether xenon or argon, only proliferated retinal pigment epithelium provided a thin retinal scar, corresponding to an ophthalmoscopic appearance of "bare sclera". In the center of severe and moderately severe lesions, both glial cells and pigment epithelium bridged the retinal defect, forming a thick pigmented scar that contained pigment-laden macrophages. Rephotocoagulation over such thick scars may be less hazardous than is generally assumed. Nonvascular preretinal membranes were frequently present over very severe xenon lesions but rarely over very severe argon burns.


A Prospective, Single-Arm, Multicenter Trial of Catheter-Directed Mechanical Thrombectomy for Intermediate-Risk Acute Pulmonary Embolism: The FLARE Study.
The aim of this study was to evaluate the safety and effectiveness of percutaneous mechanical thrombectomy using the FlowTriever System (Inari Medical, Irvine, California) in a prospective trial of patients with acute intermediate-risk pulmonary embolism (PE). Catheter-directed thrombolysis has been shown to improve right ventricular (RV) function in patients with PE. However, catheter-directed thrombolysis increases bleeding risk and many patients with PE have relative and absolute contraindications to thrombolysis. Patients with symptomatic, computed tomography-documented PE and RV/left ventricular (LV) ratios ≥0.9 were eligible for enrollment. The primary effectiveness endpoint was core laboratory-assessed change in RV/LV ratio. The primary safety endpoint comprised device-related death, major bleeding, treatment-related clinical deterioration, pulmonary vascular injury, or cardiac injury within 48 h of thrombectomy. From April 2016 to October 2017, 106 patients were treated with the FlowTriever System at 18 U.S. sites. Two patients (1.9%) received adjunctive thrombolytics and were analyzed separately. Mean procedural time was 94 min; mean intensive care unit stay was 1.5 days. Forty-three patients (41.3%) did not require any intensive care unit stay. At 48 h post-procedure, average RV/LV ratio reduction was 0.38 (25.1%; p < 0.0001). Four patients (3.8%) experienced 6 major adverse events, with 1 patient (1.0%) experiencing major bleeding. One patient (1.0%) died, of undiagnosed breast cancer, through 30-day follow-up. Percutaneous mechanical thrombectomy with the FlowTriever System appears safe and effective in patients with acute intermediate-risk PE, with significant improvement in RV/LV ratio and minimal major bleeding. Potential advantages include immediate thrombus removal, absence of thrombolytic complications, and reduced need for post-procedural critical care.


Cornea Full-field Displacement and Strain Measurement in Vivo Using Three-dimensional Digital Image Correlation.
Corneal biomechanics are becoming increasingly important for clinical evaluation and diagnosis, such as in refractive surgery, glaucoma, and keratoconus. We developed and used a new technique to measure the full-field displacement and strain of the cornea under elevated intraocular pressure in vivo. In this study, we propose a three-dimensional digital image correlation method for the determination of corneal biomechanical properties. Corneal deformation change on the rabbit eyeball was investigated under different inflation conditions with intraocular pressure levels of 2.3, 3.3, 5.3, and 6.9 kPa in vivo. The proposed method was able to measure the displacement of the corneal surface and to construct real-time full-field three-dimensional deformation vector fields and strain mapping. The results show that the strain distribution is not uniform on the corneal surface at each intraocular pressure level. Compression strains, rather than extensile strains, are dominant at the corneal apex region. This technique has the potential to be used as an assistive tool for the determination of corneal biomechanical properties in ophthalmologic investigations.


Cross-national variation in the subjective wellbeing of youth in low and middle income countries: The role of structural and micro-level factors.
Subjective wellbeing (i.e. life satisfaction and happiness) impacts youth's social, economic and political participation. Prior studies have documented cross-national variation in subjective wellbeing of adults but there is a lack of data on the prevalence and correlates of subjective wellbeing among youth in low and middle income countries. This paper utilizes data from an international dataset - Multiple Indicator Cluster Surveys to assess the influence of structural and micro-level factors on the subjective wellbeing of youth (ages 15 - 24) in 29 countries or regions in Eastern Europe, Latin America, Asia and Africa. We find that within countries, global life satisfaction and happiness are associated with age, education attainment, place of residence, marital status, household wealth and exposure to mass media. Significant interactions between age, gender and education are observed. However, none of the country level development indicators account for cross-national variation in youth's SWB although there is some indication that income inequities between countries may influence youth's SWB. The findings underscore the need for objective measures of subjective wellbeing to understand the conditions in LMICs.


Late somatic sequelae after treatment of childhood cancer in Slovenia.
This is a long-term follow-up clinical study of adolescents and adults, survivors of childhood cancer. We evaluate and analyze the late somatic sequelae of childhood cancer treatment. Many such studies are susceptible to a strong selection bias, i.e., they employ a limited non-systematic sample of patients, based on a clinical hospital that provided the cancer treatment or performed the follow-up. To address the issue of selection bias, we perform here an analysis of late sequelae on a systematic database of the entire population of the children treated for cancer in Slovenia. Due to the specifics of cancer treatment procedures in Slovenia, they have all been treated and followed-up in the same clinic. The data are based on the centralized registry of cancer patients in Slovenia and present a controlled and homogeneous collection. Late sequelae are evaluated following a modified CTCAE, i.e., the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0. We use survival analysis method to estimate the incidence of and risk for late sequelae, where the time variable is measured in years from the diagnosis date, while we follow the event of incidence of late sequelae scored other than none. Survival analysis is performed using Kaplan Meier estimator and Cox regression model. The incidence of mild, moderate, or severe late sequelae of childhood cancer treatment significantly decreased from 75% in the group of patients diagnosed before 1975 to 55% for those diagnosed after 1995. The Cox regression analysis of the risk factors for the incidence of late sequelae identifies three significant factors: treatment modalities, age at diagnosis, and primary diagnosis. The change of treatment modalities in terms of replacement of surgery and radiotherapy with chemotherapy is the main reason for the decrease of the incidence and the risk for late sequelae of childhood cancer treatment; treatment modalities including surgery significantly increase the risk ratio of late sequelae, while those based on chemotherapy only significantly decreases the risk. Risk of late sequelae increases with the diagnosis age: younger children are more susceptible to late effects of treatment. Finally, primary diagnosis significantly influences the risk for late sequelae, but mostly due to the dependency of the treatment modality on the primary diagnosis.


Ultrafast Anisotropy Decay Reveals Structure and Energy Transfer in Supramolecular Aggregates.
Chlorosomes from green bacteria perform the most efficient light capture and energy transfer, as observed among natural light-harvesting antennae. Hence, their unique functional properties inspire developments in artificial light-harvesting and molecular optoelectronics. We examine two distinct organizations of the molecular building blocks as proposed in the literature, demonstrating how these organizations alter light capture and energy transfer, which can serve as a mechanism that the bacteria utilize to adapt to changes in light conditions. Spectral simulations of polarization-resolved two-dimensional electronic spectra unravel how changes in the helicity of chlorosomal aggregates alter energy transfer. We show that ultrafast anisotropy decay presents a spectral signature that reveals contrasting energy pathways in different chlorosomes.


One century after the description of the "sign": Joseph Babinski and his contribution to neurosurgery.
One hundred years ago, in 1896, Joseph Babinski published a preliminary report on "réflexe cutané plantaire" (cutaneous plantar reflex), which became widely known as the Babinski sign. However, Babinski did not view the description of the sign as his major achievement. Instead, he considered his greatest contribution to medicine to be his having "... indiqué la voie à Martel et à Vincent" (pointed the way to Thierry de Martel and Clovis Vincent, founders of French neurosurgery). Several of Babinski's manuscripts deal with neurosurgical problems. In 1900, 1 year before Alfred Fröhlich's description, Babinski gave the first account of the adiposogenital syndrome and its relation to pituitary-hypothalamic disorder. Many other original contributions ensued. These include a report on the relief of papilledema by surgical decompression in 1901, the successful removal (in collaboration with de Martel) of an intracranial meningioma in 1909, the description (again with de Martel) of a cerebellopontine angle tumor treated by surgical excision with good result in 1925, and several manuscripts concerning diagnosis and treatment of compressive spinal cord lesions. Babinski's dream to establish a department of neurosurgery became a reality shortly after his death. The Hôpital de la Pitie in Paris, where Babinski did most of his work, established the first French department of neurosurgery chaired by Babinski's pupil, Vincent.


Pharmacologic Inhibition of Ezrin-Radixin-Moesin Phosphorylation is a Novel Therapeutic Strategy in Rhabdomyosarcoma.
Intermediate and high-risk rhabdomyosarcoma (RMS) patients have poor prognosis with available treatment options, highlighting a clear unmet need for identification of novel therapeutic strategies. Ezrin-radixin-moesin (ERM) family members are membrane-cytoskeleton linker proteins with well-defined roles in tumor metastasis, growth, and survival. ERM protein activity is regulated by dynamic changes in the phosphorylation at a conserved threonine residue in their C-terminal actin-binding domain. Interestingly, ERM family member, ezrin, has elevated expression in the RMS tissue. Despite this, the translational scope of targeting ERM family proteins in these tumors through pharmacological inhibition has never been considered. This study investigates the inhibition of ERM phosphorylation using a small molecule pharmacophore NSC668394 as a potential strategy against RMS. Upon in vitro treatment with NSC668394, RMS cells exhibit a dose-dependent decrease in cell viability and proliferation, with induction of caspase-3 cleavage and apoptosis. siRNA-mediated knockdown of individual ERM protein expression revealed that each regulates RMS survival to a different degree. In vivo administration of NSC668394 in RMS xenografts causes significant decrease in tumor growth, with no adverse effect on body weight. Collectively, this study highlights the importance of the active conformation of ERM proteins in RMS progression and survival and supports pharmacologic inhibition of these proteins as a novel therapeutic approach.


A controlled trial of high dose interferon, alone and after prednisone withdrawal, in the treatment of chronic hepatitis B: long term follow up.
This study was designed to evaluate the safety and effectiveness of high dose interferon, with or without prednisone pretreatment, in patients with chronic hepatitis B. Patients were randomised to two treatment groups: group I (n = 26) received six weeks of prednisone followed by a two week, drug free period, and then 10 million units (MU) of interferon alfa-2b three times weekly subcutaneously for 16 weeks; group II (n = 24) were used as controls for 24 weeks and then treated with interferon. Loss of hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV)-DNA, with a return to normal alanine aminotransferase (ALT) activity, was seen in 16 of 26 group I patients (61.5%), in one group II patient (4.2%) during the control phase, and in 13 of 23 group II patients (56.5%) after interferon. Three of 26 (11.5%) in group I and one of 23 (4.3%) in group II eliminated the surface antigen (HBsAg). There were no statistically significant differences in response between groups I and II. Liver biopsies carried out in 20 patients showed that responders had a noticeable reduction in inflammation and disappearance of core antigen in liver tissue, changes not seen in non-responders. On long term follow up (four years), nine out of 28 responders (32.1%) eliminated HBsAg, and four initial non-responders had a late seroconversion.


The Agreement of the Nomogram Tool and Ultrasound Biomicroscopy Images in Calculating Ultrasound Cycloplasty Probe Model in Chinese Patients.
The aim of the study was to compare and explore the agreement between the nomogram tool and ultrasound biomicroscopy (UBM) images method to calculate the ultrasound cycloplasty (UCP) probe model in Chinese glaucoma patients. Retrospective analysis of Chinese glaucoma patients who visited Zhongshan Ophthalmic Center in Guangzhou from January to December 2019 and were eligible for UCP surgery. Visual acuity, intraocular pressure (IOP), ocular axial length (AL), and horizontal corneal diameter (white to white [WTW]) were measured. UBM images with clear ciliary body imaging and AL and WTW data were sent to trained personnel for probe model measurements. The data calculated by both methods were analyzed using unweighted and weighted κ statistics. The level of agreement refers to Landis and Koch's guideline for the strength of agreement indicated with weighted κ values. 1,061 eyes of 642 patients were involved, with a mean age of 61.66 ± 11.66 years. Their best-corrected visual acuity converted to logarithm of minimal-angle-of-resolution (logMAR) scores of -0.18-3.00 with a mean value of 0.69 ± 0.77. IOP was 22.0-60.0 mm Hg with a mean of 27.97 ± 5.66 mm Hg. The mean AL and WTW were 22.88 ± 1.33 (19.15-32.14) mm and 11.52 ± 0.49 (10.00-12.90) mm, respectively. The agreement between the two methods was fair (weighted κ = 0.299), matching in 62.86% of eyes (weighted κ = 0.299, κ = 0.264). The agreement in primary open angle glaucoma, acute primary angle-closure glaucoma, chronic primary angle-closure glaucoma, and secondary glaucoma patients was 60.85% (weighted κ = 0.336, κ = 0.301), 65.06% (weighted κ = 0.146, κ = 0.127), 62.26% (weighted κ = 0.204, κ = 0.184), and 57.97% (weighted κ = 0.332, κ = 0.280) of eyes, respectively. The agreement between UBM images and the nomogram tool to calculate the UCP probe model of Chinese patients is at a fair level. The nomogram tool prefers to use larger probes. Improvements to the nomogram tool, such as including data from more ethnic groups and being able to calculate separately for different types of glaucoma, are needed to improve accuracy. The inclusion of parameters or images from more directions of the eye may help measure probe models more accurately for both the nomogram tool and the UBM image measurement.


Fluorizoline Blocks the Interaction between Prohibitin-2 and γ-Glutamylcyclotransferase and Induces p21Waf1/Cip1 Expression in MCF7 Breast Cancer Cells.
Prohibitin-2 (PHB2) is a scaffold protein that has pleiotropic functions, which include interacting with γ-glutamylcyclotransferase (GGCT) in the cytoplasm and repressing the transcriptional activities of the p21Waf1/Cip (p21) gene in the nucleus. The cytotoxic drug fluorizoline binds to PHB1/2 and exerts antiproliferative actions on cancer cells. However, the precise mechanism underlying the antiproliferative effects of fluorizoline is not fully elucidated. In the present study, we first show that fluorizoline induces p21 expression in several human cancer cell lines, including MCF7 breast cancer cells. Treatment of MCF7 cells with fluorizoline suppressed proliferation and prevented cells from entering into the DNA synthesis phase. Knockdown of p21 rescued the suppressed proliferation, indicating that fluorizoline inhibited MCF7 cell growth via the induction of p21. Overexpression of PHB2 in MCF7 cells prevented the induction of p21 expression by fluorizoline and restored the antiproliferative effects and blockade of cell cycle progression. Moreover, treatment of MCF7 cells with fluorizoline inhibited the interaction between endogenous PHB2 and GGCT proteins and reduced the level of nuclear localization of PHB2 proteins. These results indicate that targeting PHB2 with fluorizoline induces the expression of p21 and consequently blocks proliferation of cancer cells. SIGNIFICANCE STATEMENT: This study shows that fluorizoline may be a promising novel anticancer drug candidate that induces p21 expression and blocks cell-cycle progression in human cancer cell lines. In addition, we show that fluorizoline inhibits the interaction between PHB2 and GGCT and reduces the nuclear localization of PHB2 proteins.