Radiofrequency ablation (RFA): development of a flow model for bovine livers for extensive bench testing.
To develop a flow model for bovine livers for extensive bench testing of technical improvements or procedure-related developments of radiofrequency ablation excluding animal experiments. The perfusion of bovine livers directly from the slaughterhouse was simulated in a liver perfusion tank developed for the experimental work. The liver perfusion medium used was a Tyrode solution prepared in accordance with physiologic criteria (as for liver transplants) which was oxygenated by an oxygenator and heated to 36.5 degrees C. Portal vein circulation was regulated via a flow- and pressure-controlled pump and arterial circulation using a dialysis machine. Flow rate and pressure were adjusted as for the physiology of a human liver converted to bovine liver conditions. The fluid discharged from the liver was returned into the perfusion system through the vena cava. Extendable precision swivel arms with the radiofrequency probe attached were mounted on the liver perfusion tank. RFA was conducted with the RF3000 generator and a 2 cm LeVeen needle (Boston Scientific, Ratingen, Germany) in a three-dimensional grid for precise localization of the generated thermolesions. Four bovine livers weighing 8.4 +/- 0.4 kg each were prepared, connected to the perfusion system, and consecutively perfused for the experiments. Mean arterial flow was 569 +/- 43 ml/min, arterial pressure 120 mmHg, portovenous flow 1440 +/- 305 ml/min, and portal pressure 10 mmHg. Macroscopic evaluation after the experiments revealed no thrombi within the hepatic vessels. A total of 136 RF thermolesions were generated with an average number of 34 per liver. Mean RF duration was 2:59 +/- 2:01 min:sec with an average baseline impedance of 28.2 +/- 3.4 ohms. The mean diameter of the thermolesions along the puncture channel was 22.98 +/- 4.34 mm and perpendicular to the channel was 23.27 +/- 4.82 mm. Extracorporeal perfusion of bovine livers with consecutive standardized RF ablation was feasible. The bovine liver flow model seems to allow extensive, standardized evaluation of technical or procedure-related developments of RF systems.


"What if" should precede "whether" and "how" in the social conversation around human germline gene editing.
Given the potential large ethical and societal implications of human germline gene editing (HGGE) the urgent need for public and stakeholder engagement (PSE) has been repeatedly expressed. In this short communication, we aim to provide directions for broad and inclusive PSE by emphasizing the importance of futures literacy, which is a skill to imagine diverse and multiple futures and to use these as lenses to look at the present anew. By first addressing "what if" questions in PSE, different futures come into focus and limitations that arise when starting with the "whether" or "how" questions about HGGE can be avoided. Futures literacy can also aid in the goal of societal alignment, as "what if" questions can be answered in many different ways, thereby opening up the conversation to explore a multitude of values and needs of various publics. Broad and inclusive PSE on HGGE starts with asking the right questions.


[Gene TAENIATA is a novel negative regulator of the Arabidopsis thaliana homeobox genes KNAT1, KNAT2, KNAT6, and STM].
Mutant Arabidopsis thaliana taeniata (tae) plants are characterized by an altered morphology of leaves and the inflorescence. At the beginning of flowering, the inflorescence produces fertile flowers morphologically intermediate between a shoot and a flower. The recessive mutation tae also causes the formation of ectopic meristems and shoot rosettes on leaves. The expressivity of the mutant characters depend on the temperature and photoperiod. Analysis of the activity of KNOX class I genes in the leaves of the tae mutant has demonstrated the expression of genes KNAT2 and STM and an increase in the expression of genes KNAT1 and KNAT6 compared to wild-type leaves. These data indicate that the TAE gene negatively regulates the KNAT1, KNAT2, KNAT6, and STM genes.


Italian consensus recommendations for a biomarker-based aetiological diagnosis in mild cognitive impairment patients.
Biomarkers support the aetiological diagnosis of neurocognitive disorders in vivo. Incomplete evidence is available to drive clinical decisions; available diagnostic algorithms are generic and not very helpful in clinical practice. The aim was to develop a biomarker-based diagnostic algorithm for mild cognitive impairment patients, leveraging on knowledge from recognized national experts. With a Delphi procedure, experienced clinicians making variable use of biomarkers in clinical practice and representing five Italian scientific societies (neurology - Società Italiana di Neurologia per le Demenze; neuroradiology - Associazione Italiana di Neuroradiologia; biochemistry - Società Italiana di Biochimica Clinica; psychogeriatrics - Associazione Italiana di Psicogeriatria; nuclear medicine - Associazione Italiana di Medicina Nucleare) defined the theoretical framework, relevant literature, the diagnostic issues to be addressed and the diagnostic algorithm. An N-1 majority defined consensus achievement. The panellists chose the 2011 National Institute on Aging and Alzheimer's Association diagnostic criteria as the reference theoretical framework and defined the algorithm in seven Delphi rounds. The algorithm includes baseline clinical and cognitive assessment, blood examination, and magnetic resonance imaging with exclusionary and inclusionary roles; dopamine transporter single-photon emission computed tomography (if no/unclear parkinsonism) or metaiodobenzylguanidine cardiac scintigraphy for suspected dementia with Lewy bodies with clear parkinsonism (round VII, votes (yes-no-abstained): 3-1-1); 18 F-fluorodeoxyglucose positron emission tomography for suspected frontotemporal lobar degeneration and low diagnostic confidence of Alzheimer's disease (round VII, 4-0-1); cerebrospinal fluid for suspected Alzheimer's disease (round IV, 4-1-0); and amyloid positron emission tomography if cerebrospinal fluid was not possible/accepted (round V, 4-1-0) or inconclusive (round VI, 5-0-0). These consensus recommendations can guide clinicians in the biomarker-based aetiological diagnosis of mild cognitive impairment, whilst guidelines cannot be defined with evidence-to-decision procedures due to incomplete evidence.


ZrB₂-CNTs Nanocomposites Fabricated by Spark Plasma Sintering.
ZrB₂-based nanocomposites with and without carbon nanotubes (CNTs) as reinforcement were prepared at 1600 °C by spark plasma sintering. The effects of CNTs on the microstructure and mechanical properties of nano-ZrB₂ matrix composites were studied. The results indicated that adding CNTs can inhibit the abnormal grain growth of ZrB₂ grains and improve the fracture toughness of the composites. The toughness mechanisms were crack deflection, crack bridging, debonding, and pull-out of CNTs. The experimental results of the nanograined ZrB₂-CNTs composites were compared with those of the micro-grained ZrB₂-CNTs composites. Due to the small size and surface effects, the nanograined ZrB₂-CNTs composites exhibited stronger mechanical properties: the hardness, flexural strength and fracture toughness were 18.7 ± 0.2 GPa, 1016 ± 75 MPa, and 8.5 ± 0.4 MPa·m1/2, respectively.


The effects of physical exercise on the serum iron profile in spontaneously hypertensive rats.
The purpose of this study was to evaluate the profile of serum iron in spontaneously hypertensive rats after an aerobic physical exercise. To accomplish this, 12 normotensive Wistar rats and 12 spontaneously hypertensive rats were distributed into "physical exercise" and "no physical exercise" groups. The animals in the physical exercise group underwent to an aerobic exercise for a total of 4 weeks. Blood was collected for the analysis of iron. Our results indicate that rats of the physical exercise group had significantly lower serum iron levels after the aerobic exercise protocol compared to the spontaneously hypertensive rats no physical exercise group (F ((3,16)) = 4.4915, p < 0.01). No significant difference was found between no physical exercise groups. The results indicated that the difference in iron may be due to an increased demand for iron, prompted by chronic physical exercise. In addition, erythrocytosis has been associated with increased blood pressure in spontaneously hypertensive rats, suggesting that iron reduction may be related to decreased blood pressure in these animals.


The elevated gene expression level of the A(2B) adenosine receptor is associated with hyperglycemia in women with gestational diabetes mellitus.
Adenosine receptors denoted by A1 , A2A , A2B , and A3 and encoded by ADORA1, ADORA2A, ADORA2B, and ADORA3 genes, respectively, are adenosine-activated G-protein-coupled receptors that play an important role in obesity and type 2 diabetes mellitus. However, little is known about their significance in gestational diabetes mellitus (GDM). The purpose of this study was to investigate whether there are changes in leukocyte AR expression in GDM patients and whether these alterations are linked to well-known diabetic genes. Leukocytes were isolated from the blood of normal glucose tolerant (NGT; n = 35) and GDM (n = 82) pregnant women, and expression of ARs was determined by a semi-quantitative polymerase chain reaction (PCR). Univariate correlation analysis was performed to investigate associations between expression of ARs and anthropometric and metabolic parameters of patients. Furthermore, the identification of diabetic genes linked to significantly differentiated leukocyte adenosine receptors expression in GDM women was also carried out with the use of the human diabetes RT(2) profiler PCR arrays. ADORA2B mRNA expression was significantly higher in GDM versus NGT pregnant women (p < 0.05), and positively correlated with the glucose level at 1-h 75-g oral glucose tolerance test (OGTT; r = 0.21, p = 0.044). Nineteen diabetic genes linked to leukocyte ADORA2B overexpression associated with hyperglycemia in GDM women were also identified. Maternal leukocyte ADORA2B overexpression is associated with hyperglycemia in GDM subjects, and it is accompanied by complex alterations in the expression of diabetes-related genes involved in insulin action, carbohydrate and lipid metabolism, oxidative stress, and inflammation.


A Direct Aspiration, First Pass Technique (ADAPT) versus Stent Retrievers for Acute Stroke Therapy: An Observational Comparative Study.
Mechanical thrombectomy with stent retrievers is now the standard therapy for selected patients with ischemic stroke. The technique of A Direct Aspiration, First Pass Technique for the Endovascular Treatment of Stroke (ADAPT) appears promising with a high rate of recanalization. We compared ADAPT versus stent retrievers (the Solitaire device) for efficacy and safety as a front-line endovascular procedure. We analyzed 243 consecutive patients with large intracranial artery occlusions of the anterior circulation, treated within 6 hours with mechanical thrombectomy by either ADAPT or the Solitaire stent. Th primary outcome was complete recanalization (modified TICI ≥ 2b); secondary outcomes included complication rates and procedural and clinical outcomes. From November 2012 to June 2014, 119 patients were treated with stent retriever (Solitaire FR) and 124 by using the ADAPT with Penumbra reperfusion catheters. The median baseline NIHSS score was the same for both groups (Solitaire, 17 [interquartile range, 11-21] versus ADAPT, 17 [interquartile range, 12-21]). Time from groin puncture to recanalization (Solitaire, 50 minutes [range, 25-80 minutes] versus ADAPT, 45 minutes [range, 27-70 minutes], P = .42) did not differ significantly. However, compared with the Solitaire group, patients treated with ADAPT achieved higher final recanalization rates (82.3% versus 68.9%; adjusted relative risk, 1.18; 95% CI, 1.02-1.37; P = .022), though differences in clinical outcomes between the cohorts were not significant. Use of an adjunctive device was more frequent in the ADAPT group (45.2% versus 13.5%, P < .0001). The rate of embolization in new territories or symptomatic hemorrhage did not differ significantly between the 2 groups. Front-line ADAPT achieved higher recanalization rates than the Solitaire device. Further randomized controlled trials are warranted to define the best strategy for mechanical thrombectomy.


A mass spectrometry study of tirapazamine and its metabolites. insights into the mechanism of metabolic transformations and the characterization of reaction intermediates.
Tandem mass spectrometry methods were used to study the sites of protonation and for identification of 3-amino-1,2,4-benzotriazine 1,4-dioxide (1, tirapazamine), and its metabolites (3-amino-1,2,4-benzotriazine 1-oxide (3), 3-amino-1,2,4-benzotriazine 4-oxide (4), 3-amino-1,2,4-benzotriazine (5), and a related isomer 3-amino-1,2,4-benzotriazine 2-oxide (6). Fragmentation pathways of 3 and 5 indicated the 4-N-atom as the most likely site of protonation. Among the N-oxides studied, the 4-oxide (4) showed the highest degree of protonation at the oxygen atom. The differences in collision-induced dissociation of isomeric protonated 1-, 2- and 4-oxides allowed for their identification by LC/MS/MS. Gas phase and liquid phase protonation of tirapazamine occurred exclusively at the oxygen in the 4-position. A loss of OH radical from these ions (2(+)) resulted in ionized 3. Neutralization-reionization mass spectrometry (NR MS) experiments demonstrated the stability of the neutral analogue of protonated tirapazamine in the gas phase in the micro s time-frame. A significant portion of the neutral tirapazamine radicals (2) dissociated by loss of hydroxyl radical during the NR MS event, which indicates that previously proposed mechanisms for redox-activated DNA damage are reasonable. The activation energy for loss of hydroxyl radical from activated tirapazamine (2) was estimated to be approximately 14 kcal mol(-1). Stable neutral analogues of [3 + H](+) and [5 + H](+) ions were also generated in the course of NR MS experiments. Structures of these radicals were assigned to the molecules having an extra hydrogen atom at one of the ring N-atoms. Quantum chemical calculations of protonated 1, 3, 4 and 5 and the corresponding neutrals were performed to assist in the interpretation of experimental results and to help identify their structures.


Chlamydia pneumoniae and coronary artery disease: controversial results of serological studies.
I have read with great interest the article published by Carratelli et al. Briefly they have reported increased levels of inflammatory markers and elevated titers of IgG and IgA of C. pneumoniae by using both ELISA and MIF method. There are several factors which may underly the controversial results of seroepidemiological studies. I have commented on the report of Carratelli et al. regarding some of these factors.


Insect egg morphology: evolution, development, and ecology.
The insect egg can be viewed through many lenses: it is the single-celled developmental stage, a resource investment in the next generation, an unusually large and complex cell type, and the protective vessel for embryonic development. In this review, I describe the morphological diversity of insect eggs and then identify recent advances in understanding the patterns of egg evolution, the cellular mechanisms underlying egg development, and notable aspects of egg ecology. I also suggest areas for particularly promising future research on insect egg morphology; these topics touch upon diverse areas such as tissue morphogenesis, life history evolution, organismal scaling, cellular secretion, and oviposition ecology.


Human endometrial epithelial cells modulate the activation of gelatinase a by stromal cells.
Metalloproteinases (MMPs) are central effectors in endometrial physiology. Their production is tightly regulated by ovarian steroids and cytokines. Using zymography, we investigated MMP-2 production by human endometrial cells treated with estradiol-17beta + progesterone (E(2)+P) and by various key cytokines in endometrial physiology (IL-1beta, LIF, TGF-beta, and TNF-alpha). No gelatinase activity was detected in the culture media of epithelial cells. In basal conditions, stromal cells produced the pro form of MMP-2. MMP-2 production/activation was not directly affected by cytokine treatment. Interestingly, activated MMP-2 was only detected after treatment of stromal cells with culture medium from epithelial cells. Cytokine treatment of epithelial cells increased the capacity of conditioned medium to stimulate stromal cells to activate MMP-2. As the tissue inhibitor of MMP-2 (TIMP-2) is a regulator of gelatinase A activity, its concentration was measured by ELISA. TIMP-2 production by stromal cells was not affected by cytokines or by epithelial cell-conditioned medium. These results strongly suggest that regulation of stromal MMP-2 activation involves soluble factor(s) derived from the epithelial compartment.


Characterization of functional roles of DRY motif in the 2nd intracellular loop of dopamine D2 and D3 receptors.
Dopamine D(2)R and D(3)R (D(2)R, D(3)R) show very high sequence homology and employ virtually identical signaling pathways even though D(2)R is 2 approximately 5 times more active. Among the structural motifs identified, a triplet sequence, Asp-Arg-Tyr (DRY motif), plays critical roles in the determination of receptor conformations for signaling and intracellular trafficking of G protein-coupled receptors by forming intramolecular interactions. Thus, it is possible that different signaling efficiencies of D(2)R and D(3)R might be caused by the receptor activation levels stabilized by their own DRY motifs. In this study, the Arg and Asp residues of D(2)R and D(3)R were mutated, and resulting changes in their signaling and intracellular trafficking properties were comparatively studied. Mutation of the Arg residues of D(2)R and D(3)R abolished their signaling but differently affected their intracellular localizations. The wildtype and R132H-D(2)R were expressed mainly on the plasma membrane. On the other hand, compared with the wildtype D(3)R, a substantial amount of R128H-D(3)R was localized intracellularly. The expression of receptor proteins on the plasma membrane and their signaling efficiencies were more drastically affected by the mutation of the Asp residue of D(3)R than D(2)R. Therefore, it was concluded that the different levels of conformational strain exerted by the DRY motif might partly determine the quantitative differences in the signaling efficiencies between D(2)R and D(3)R.


The structure of a transcribing T7 RNA polymerase in transition from initiation to elongation.
Structural studies of the T7 bacteriophage DNA-dependent RNA polymerase (T7 RNAP) have shown that the conformation of the amino-terminal domain changes substantially between the initiation and elongation phases of transcription, but how this transition is achieved remains unclear. We report crystal structures of T7 RNAP bound to promoter DNA containing either a 7- or an 8-nucleotide (nt) RNA transcript that illuminate intermediate states along the transition pathway. The amino-terminal domain comprises the C-helix subdomain and the promoter binding domain (PBD), which consists of two segments separated by subdomain H. The structures of the intermediate complex reveal that the PBD and the bound promoter rotate by approximately 45 degrees upon synthesis of an 8-nt RNA transcript. This allows the promoter contacts to be maintained while the active site is expanded to accommodate a growing heteroduplex. The C-helix subdomain moves modestly toward its elongation conformation, whereas subdomain H remains in its initiation- rather than its elongation-phase location, more than 70 angstroms away.


Significance of serum miR-29a in the occurrence and progression of diabetic nephropathy: A cross-sectional study.
Diabetic nephropathy (DN), a common microvascular complication of type 2 diabetes mellitus (T2DM), is an important factor causing chronic kidney disease. However, the relationship between miR-29a and DN remains unknown. Therefore, a cross-sectional study was conducted to identify a potential molecular biomarker for DN prevention and management by detecting the serum miR-29a levels. The serum miR-29a levels were measured in 360 subjects (180 T2DM patients and 180 healthy controls) using quantitative reverse transcription PCR (qRT-PCR), and other conventional indicators were measured and analysed. A binary logistic regression was used to evaluate the DN risk factors; a receiver operating characteristic (ROC) curve was applied to analyse the diagnostic efficacy of miR-29a for DN, and a Spearman's rank correlation analysis was used to evaluate the correlation between serum miR-29a and cystatin C. The serum miR-29 levels in the T2DM patients were higher than those in the healthy subjects and significantly increased with the progression of DN (p < 0.05). Serum miR-29a and cystatin C are independent predictors of the occurrence of DN. Compared with a single indicator, the combination of serum miR-29a and cystatin C has better DN diagnostic performance. In addition, the serum miR-29a levels were positively correlated with cystatin C in the patients with DN (r = 0.521, p < 0.001). The expression of serum miR-29a was significantly associated with the occurrence and progression of DN and is expected to become a potential biomarker for the diagnosis of DN.


Factors associated with survival of patients with advanced lung cancer and long travel distances.
Patients with advanced cancer sometimes travel to locations that have the treatment that they need. We explored the prognostic factors of survival in patients with advanced lung cancer who travel long distances in Taiwan. We obtained data from the National Taiwan University Hospital (NTUH) Integrated Medical Database. Patients who received a diagnosis of stage IV lung cancer from 2010 to 2019 and were treated in NTUH and its Hsinchu and Yunlin branches were enrolled. Factors associated with survival were analyzed using a Cox hazard regression model. In total, 6178 patients with stage IV lung cancer were enrolled. Young age, female sex, smaller primary tumor size, better performance, and non-squamous cell non-small cell histology were independently associated with longer survival. Treatment in medical centers and long travel distances (>50 km) were associated with longer survival in the univariate analysis but not in the multivariate analysis (hazard ratio [HR]: 1.04, p = 0.361; HR: 0.99, p = 0.775, respectively). Participation in clinical trials was associated with longer survival in the univariate (HR: 0.53, p < 0.001) and multivariate analyses (HR: 0.62, p < 0.001). For the 1144 patients in the Hsinchu area, enrolment in clinical trials was an independent prognostic factor (HR: 0.72, p = 0.040), whereas treatment in medical centers was not (HR: 0.95, p = 0.635). Long travel distances and treatment in medical centers were not independently associated with survival for patients with advanced lung cancer. Enrolment in clinical trials was an independent prognostic factor.


Evidence for gene flow via seed dispersal from crop to wild relatives in Beta vulgaris (Chenopodiaceae): consequences for the release of genetically modified crop species with weedy lineages.
Gene flow and introgression from cultivated to wild plant populations have important evolutionary and ecological consequences and require detailed investigations for risk assessments of transgene escape into natural ecosystems. Sugar beets (Beta vulgaris ssp. vulgaris) are of particular concern because: (i) they are cross-compatible with their wild relatives (the sea beet, B. vulgaris ssp. maritima); (ii) crop-to-wild gene flow is likely to occur via weedy lineages resulting from hybridization events and locally infesting fields. Using a chloroplastic marker and a set of nuclear microsatellite loci, the occurrence of crop-to-wild gene flow was investigated in the French sugar beet production area within a 'contact-zone' in between coastal wild populations and sugar beet fields. The results did not reveal large pollen dispersal from weed to wild beets. However, several pieces of evidence clearly show an escape of weedy lineages from fields via seed flow. Since most studies involving the assessment of transgene escape from crops to wild outcrossing relatives generally focused only on pollen dispersal, this last result was unexpected: it points out the key role of a long-lived seed bank and highlights support for transgene escape via man-mediated long-distance dispersal events.


Electrochemically Active In Situ Crystalline Lithium-Organic Thin Films by ALD/MLD.
Intercalated metal-organic framework (iMOF) type electrochemically active aromatic metal carboxylates are intriguing material candidates for various energy storage devices and microelectronics. In this work, we grow in situ crystalline thin films of such materials through atomic/molecular layer deposition (ALD/MLD); the remarkable benefit of this approach is the possibility to evaluate their electrochemical properties in a simple cell configuration without any additives. Five organic linkers are investigated in combination with lithium: terephthalic acid (TPA), 3,5-pyridinedicarboxylic acid (PDC), 2,6-naphthalenedicarboxylic acid (NDC), 4,4'-biphenyldicarboxylic acid (BPDC), and 4,4'-azobenzenedicarboxylic acid (AZO). In particular, the electrochemical activity of Li-PDC and the crystal structure of Li-AZO are addressed here for the first time. We believe that the in situ gas-phase thin-film deposition is a crucial requirement to benefit from the iMOF-type electrode materials in, e.g., microelectronics and wearable devices.


Serum pancreatic oncofetal antigen: its clinical usefulness for screening pancreatic cancer in combination with tests for other tumor markers.
Screening for pancreatic cancer was carried out by serum pancreatic oncofetal antigen (POA) tests in 440 out-patients with abdominal complaints, with concomitant assay of carcinoembryonic antigen, alpha-fetoprotein and ferritin. POA was positive in 13 patients, of whom 3 cases of pancreatic cancer, and 4 of other malignant diseases were diagnosed while the remaining 6 were non-malignant. Of these out-patients, 5 cases were finally diagnosed as having pancreatic cancer by further examinations. Of these 5 patients, POA was negative in 2, of whom one was positive for CEA and AFP. Accordingly, when POA test was applied concomitantly with the other 3 marker tests, the detection rate of pancreatic cancer was elevated to 4/5. Twenty-three patients were found to have malignant diseases and 20 of them were positive for at least one of the 4 markers tested. These results suggest that serum POA assay is useful for screening the pancreatic cancer, especially when the other tumor markers are assayed concomitantly.


The underlying mode of action for lung tumors in a tiered approach to the assessment of inhaled cobalt compounds.
A mode of action (MOA) for cobalt substances based on the "International Programme on Chemical Safety Conceptual Framework for Evaluating a MOA for Chemical Carcinogenesis" is presented. The data recorded therein were generated in a tiered testing program described in the preceding papers of this special issue, as well as data from the public domain. The following parameters were included in the evaluation: solubility of cobalt substances in artificial lung fluids (bioelution), in vitro biomarkers for cytotoxicity, reactive oxygen species and hypoxia mimicry, inhalation toxicity following acute exposure and repeated dose inhalation effects. Two distinct groups of cobalt substances emerged: substances inducing all effects across the MOA form one group, associated with the adverse outcome of lung cancer in rodents upon chronic exposure. Another group of cobalt substances induces no or very limited effects in the in vitro and acute testing. Higher tier testing with a representative of this group, tricobalt tetraoxide, showed a response resembling rat lung overload following exposure to high concentrations of poorly soluble particles. Based on the fundamental differences in the lower tier toxicological profile, cobalt substances with an unknown hazard profile can be assigned to either group based on lower tier testing alone.


Seismomorphogenesis: a novel approach to acclimatization of tissue culture regenerated plants.
Plantlets under in vitro conditions transferred to ex vivo conditions are exposed to biotic and abiotic stresses. Furthermore, in vitro regenerated plants are typically frail and sometimes difficult to handle subsequently increasing their risk to damage and disease; hence acclimatization of these plantlets is the most important step in tissue culture techniques. An experiment was conducted under in vitro conditions to study the effects of shaking duration (twice daily at 6:00 a.m. and 9:00 p.m. for 2, 4, 8, and 16 min at 250 rpm for 14 days) on Sansevieria trifasciata L. as a model plant. Results showed that shaking improved handling, total plant height, and leaf characteristics of the model plant. Forty-eight hours after 14 days of shaking treatments with increasing shaking time, leaf length decreased but proline content of leaf increased. However, 6 months after starting the experiment different results were observed. In explants that received 16 min of shaking treatment, leaf length and area and photosynthesis rate were increased compared with control plantlets. Six months after starting the experiment, control plantlets had 12.5 % mortality; however, no mortality was observed in other treated explants. The results demonstrated that shaking improved the explants' root length and number and as a simple, cost-effective, and non-chemical novel approach may be substituted for other prevalent acclimatization techniques used for tissue culture regenerated plantlets. Further studies with sensitive plants are needed to establish this hypothesis.


Role of T cells in the pathogenesis of systemic lupus erythematous: Focus on immunometabolism dysfunctions.
Evidence demonstrates that T cells are implicated in developing SLE, and each of them dominantly uses distinct metabolic pathways. Indeed, intracellular enzymes and availability of specific nutrients orchestrate fate of T cells and lead to differentiation of regulatory T cells (Treg), memory T cells, helper T cells, and effector T cells. The function of T cells in inflammatory and autoimmune responses is determined by metabolic processes and activity of their enzymes. Several studies were conducted to determine metabolic abnormalities in SLE patients and clarify how these modifications could control the functions of the involved T cells. Metabolic pathways such as glycolysis, mitochondrial pathways, oxidative stress, mTOR pathway, fatty acid and amino acid metabolisms are dysregulated in SLE T cells. Moreover, immunosuppressive drugs used in treating autoimmune diseases, including SLE, could affect immunometabolism. Developing drugs to regulate autoreactive T cell metabolism could be a promising therapeutic approach for SLE treatment. Accordingly, increased knowledge about metabolic processes paves the way to understanding SLE pathogenesis better and introduces novel therapeutic options for SLE treatment. Although monotherapy with metabolic pathways modulators might not be sufficient to prevent autoimmune disease, they may be an ideal adjuvant to reduce administration doses of immunosuppressive drugs, thus reducing drug-associated adverse effects. This review summarized emerging data about T cells that are involved in SLE pathogenesis, focusing on immunometabolism dysregulation and how these modifications could affect the disease development.


Advances in endovascular neuro-oncology: endovascular selective intra-arterial (ESIA) infusion of targeted biologic therapy for brain tumors.
Malignant gliomas continue to have a poor clinical outcome with available therapies. In the past few years, new targeted biologic therapies have been studied, with promising results. However, owing to problems with ineffective IV delivery of these newer agents, an alternative, more direct delivery mechanism is needed. Simultaneously, advancements in neuroendovascular technology have allowed endovascular selective intra-arterial approaches to delivery. This method has the potential to increase drug delivery and selectively target tumor vasculature. To review the history of IA therapy for brain tumors, prior failures and successes, the emergence of new technologies and therapies, and the future direction of this young field. A comprehensive literature search of two databases (PubMed, Ovid Medline) was performed for several terms including 'brain tumor', 'glioma', and 'endovascular intra-arterial'. Forty-five relevant articles were identified via a systematic review following PRISMA guidelines. Additional relevant articles were selected for further in-depth review. Emphasis was given to articles discussing selective intra-arterial intracranial delivery using microcatheters. Endovascular intra-arterial therapy with chemotherapy has had mixed results, with currently active trials using temozolomide, cetuximab, and bevacizumab. Prior attempts at IA chemotherapy with older-generation medications did not surpass the efficacy of IV administration. Advances in neuro-oncology have brought to the forefront new targeted biologic therapies. In this review, we discuss the emerging field of endovascular neuro-oncology, a field that applies modern neuroendovascular techniques to the delivery of new therapeutic agents to brain tumors. The development of targeted therapies for brain tumors has been concurrent with the development of microcatheter technology, which has made superselective distal intracranial arterial access feasible and safe.


Concentration of caesium-137, cobalt-60 and potassium-40 in some wild and edible plants around the nuclear power plant in Bulgaria.
The activities of 137Cs, 60Co and 40K were determined in samples of wild (Taraxacum officinale, Plantago lanceolata and Populus nigra 'Italica') and edible (vegetable, corn, fruit) plants as well as soil collected from the 30 km safety zone of the Bulgarian NPP "Kozloduy" and comparisons with earlier measurements and analyses of samples from other regions and with literature values were performed. The derived transfer factors for 137Cs and 40K from soil to plants ranged between 0.002 and 0.009 for 137Cs, and between 0.09 and 0.35 for 40K. The individual effective dose (calculated from the present results and data on the activity of other foodstuffs and from information about dietary habits) comprises 4.5% of the annual dose limit.


Synthesis, biological evaluation, and structure-activity relationships of 2-[2-(benzoylamino)benzoylamino]benzoic acid analogues as inhibitors of adenovirus replication.
2-[2-Benzoylamino)benzoylamino]benzoic acid (1) was previously identified as a potent and nontoxic antiadenoviral compound (Antimicrob. Agents Chemother. 2010, 54, 3871). Here, the potency of 1 was improved over three generations of compounds. We found that the ortho, ortho substituent pattern and the presence of the carboxylic acid of 1 are favorable for this class of compounds and that the direction of the amide bonds (as in 1) is obligatory. Some variability in the N-terminal moiety was tolerated, but benzamides appear to be preferred. The substituents on the middle and C-terminal rings were varied, resulting in two potent inhibitors, 35g and 35j, with EC(50) = 0.6 μM and low cell toxicity.


Molecular mechanisms of extinction of liver-specific functions in mouse hepatoma rat fibroblast hybrids: extinction of alpha-fetoprotein gene.
Somatic cell hybrids formed by the fusion of mouse hepatoma (BWTG3) and rat fibroblast (JF1) cells exhibit the extinction of mouse AFP gene expression. Analysis of HindIII digests clearly shows that both mouse and rat AFP genes are present in the hybrids. DNA-RNA hybridization data show that AFP mRNA is virtually absent in the somatic cell hybrids. Our studies indicate, therefore, that extinction of mouse AFP gene expression in somatic cell hybrids (BJ01, BJ50, and BJ140) occurs in the presence of the rat genes and that the mechanism of extinction involves processes that result in the loss of AFP mRNA. We propose that the mechanism may involve either the inhibition of transcription or an inhibition of the processing of the mRNA transcript.


Substance use disorders. Difficulties in diagnoses.
Patients attempt, consciously or unconsciously, to minimize or disguise their substance use, in part to preserve shreds of self-respect, avoid guilt and shame, and avoid the real or imagined criticism of others. It is ironic that substance users not only use the substance to gain access to pleasant events or escape or avoid unpleasant events, but also to deny, minimize, or disguise that very use for the same reasons.


Construction of a nomogram to predict overall survival for patients with M1 stage of colorectal cancer: A retrospective cohort study.
The M1 stage of colorectal cancer (CRC) has a poor prognosis. The aim of this study is to develop a reliable tool for the prediction for CRC patients with M1 stage, thus assisting the strategy of clinical diagnosis and treatment. CRC patient information collected in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015 was extracted and evaluated. Multivariate analysis with Cox proportional hazards regression identified risk factors that predicted overall survival (OS) and the results were used to construct a nomogram to predict 3-, and 5-year OS in CRC patients with M1 stage. The Kaplan-Meier curve was plotted to evaluate OS differences. A total of 19,796 patients from the SEER database were included for analysis. All patients were randomly allocated to 2 cohorts, the training cohort (n = 13,860) and the validation cohort (n = 5936). Patients' age at diagnosis; gender; race; tumor site; tumor grade; T and N stage; brain, lung, bone, and liver metastasis status; marital status; and therapy were associated with survival in the multivariate models. All these factors were incorporated to construct a nomogram. Additionally, we divide all 19,796 patients into high-risk group and low-risk group according to our nomogram, and plotted Kaplan-Meier curve. The result indicated that patients with higher risk had worse survival outcomes. Our predictive model has the potential to provide an individualized risk estimate of survival in CRC patients with M1 stage.


Role of pretreatment type and microbial mechanisms on enhancing volatile fatty acids production during anaerobic fermentation of refinery waste activated sludge.
This study compared the effects of alkaline, thermal, thermal-peroxymonosulfate (PMS), and alkyl polyglucose (APG) pretreatments on volatile fatty acids (VFAs) production from refinery waste activated sludge (RWAS), including VFAs yield, composition, organics components, microbial communities, and the potential improvement of mechanisms. All pretreatments effectively enhanced the bioconversion of RWAS and consequently promoted the hydrolysis process, which inhibited the methanogenesis process. However, the release of lignin/carboxyl-rich alicyclic molecules (CRAM)-like compounds and tannin substances in Thermal-PMS and APG groups significantly influenced the acidogenesis and acetogenesis processes. Among all pretreatments, alkaline pretreatment showed the highest VFAs yield of 95.06 mg/g volatile solids (VS) and VS removal of 17%. This result could be associated with the enrichment of functional hydrolytic-acidification bacteria, such as Planococcus and Soehngenia, and increased metabolism of amino acids, carbohydrates, and nucleotides. By considering an economical and efficient perspective, this study recommended the alkaline pretreatment for the anaerobic fermentation of RWAS.


A YAG laser technique to facilitate removal of posterior chamber intraocular lenses from the capsular bag.
A technique is presented which facilitates repositioning or removal of a decentered capsular bag-fixated posterior chamber intraocular lens. The anterior lens capsule in front of the encapsulated haptic loop is disrupted with the YAG laser. This frees the loop from the capsular bag so a dialing maneuver will not stress the posterior capsule or zonule.


Prognostic significance of oncofetal antigens in patients with ovarian cancer.
The prognostic significance of elevated oncofetal antigens, namely carcinoembryonic antigen (CEA), alphafetoprotein (AFP), and beta subunit of human chorionic gonadotrophin (beta HCG) were studied in 39 patients with cancer of the ovary. At low cut-off levels, (CEA greater than 2.5 micrograms/l, AFP greater than 5 micrograms/l, and beta HCG greater than 3 IU/l) the median survival was 21 months in patients with one or more positive markers compared to greater than 43 months in patients without markers. At high cut-off points (namely CEA greater than 10 micrograms/l, AFP greater than 10 micrograms/l and beta HCG greater than 10 IU/l), the median survival of patients having one or more positive markers was 10 months compared to greater than 46 months in patients with no markers. Using linear regression and Logrank analysis, the difference between the observed and expected death rate was significant (P less than 0.05 at low cut-off levels, and less than 0.01 at high cut-off levels). These results indicate that patients who have one or more positive oncofetal markers on presentation are likely to have a significantly worse prognosis than patients without markers. Moreover, higher levels of oncofetal markers are associated with correspondingly worse prognosis.


Performance Characteristics of a Dual-Sided Position-Sensitive Sparse-Sensor Detector for Gamma-ray Imaging.
We characterize the performance of a dualsided position-sensitive sparse sensor (DS-PS3) array detector for positron emission tomography (PET). The DS-PS3 detector is designed as a high performance, cost effective PET detector for organ-specific imaging systems (e.g., brain, breast, etc.). Two sparse 4-by-4 arrays of silicon photomultipliers (18.5% SiPM fill-factor) coupled through segmented light guide are used to readout a 15-by-15 array of 2-mm-pitch, 20-mm-long LSYO crystals. Uniform flood data were used for crystal identification, depth determination, and position-dependent energy resolution. Intrinsic-spatial and depth-of-interaction (DOI) resolutions were determined by stepping a collimated gamma-ray source over the front and side, respectively. We measured an average intrinsic spatial resolution of 2.14 ± 0.07 mm full width at half maximum (FWHM). DOI FWHM resolution varied from 2.2 mm for crystals over sensors to 5.3 mm for crystals between sensors. Average DOI resolution was 3.6 ± 0.8 mm FHWM. Average energy resolution for the detector module was 16.6% with a range of 11.3% to 25.8%. We have demonstrated use of a dual-sided sparse sensor arrays to enable low-cost high-performance decoding of three-dimensional positioning within a PET detector using an 18.5% sensor fill-factor.


The effects of donepezil on phencyclidine-induced cognitive deficits in a mouse model of schizophrenia.
Donepezil is the first-line of treatment for Alzheimer's disease (AD), which improves cognitive impairment effectively, but whether it has an impact on cognitive impairment in schizophrenia remains unknown. In this study, we evaluated the effects and mechanisms of donepezil on schizophrenia-like cognitive deficits induced by phencyclidine (PCP). The cognitive deficits model of schizophrenia was established by injecting PCP into mice. Risperidone, an atypical antipsychotic drug, served as positive control drug. Three behavioral tests including novel object recognition (NOR) test, Morris Water Maze (MWM) and passive avoidance (PA) test were performed to evaluate the effect of donepezil on PCP-induced cognitive deficits. Furthermore, the content of BDNF and NGF in the hippocampus and cortex of mice was determined using ELISA. Expressions of p-GSK-3β/GSK-3β, p-Akt/Akt, Bcl-2/Bax and Caspase-3 in the hippocampus and cortex were detected by Western blot. Results revealed that donepezil has a protective effect on PCP-induced cognitive dysfunction. Moreover, donepezil can also improve PCP-induced schizophrenia-like cognitive deficits by inhibiting neuronal apoptosis and regulating synaptic plasticity, which was possible through the up-regulation of p-Akt, p-GSK-3β, Bcl-2 and the down-regulation of Bax, Caspase-3. The results indicated that donepezil might exhibit a beneficial effect on the treatment of cognitive dysfunction in schizophrenia.


Learning from the challenges of undertaking an evaluation of a multi-partner housing support initiative delivered within a hospital setting.
We present learning from a mixed-methods evaluation of a housing support initiative for hospital inpatients. A mixed-methods process evaluation. A social housing provider delivered a housing support service in two hospitals (mental health unit and general hospital). Healthcare providers, the social housing provider and academic researchers designed and undertook a co-produced, mixed-methods process evaluation of the intervention. The evaluation included questionnaires, semi-structured interviews, analysis of routinely collected data and economic analysis. Despite commitment from the partners, the evaluation faced challenges. We reflect on the lessons learnt within our discussion paper. Despite the commitment of the partners, we faced several challenges.We took an iterative approach to the design and processes of the evaluation to respond to arising challenges. Recruitment of service-users was more difficult than anticipated, requiring additional staff resources. Given the small-scale nature of the intervention, and the quality of data recorded in hospital records, the planned economic analysis was not feasible. Positive factors facilitating evaluation included involvement of staff delivering the intervention, as well as managers. Being able to offer payment to partner organisations for staff time also facilitated ongoing engagement. Multi-partner evaluations are useful, however, researchers and partners need to be prepared to take an iterative, resource intensive approach. Both availability and quality of routine data, and the resources required to support data collection, may limit feasibility of specific methods when evaluating small-scale cross-sector initiatives. Thus, this necessitates a flexible approach to design and analysis.


Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection.
The mechanism by which pancreatic ductal adenocarcinoma (PDA) cells escape immune detection and survive in lymph nodes is poorly understood. One possible mechanism by which PDA cells can escape immune detection is through upregulation of indoleamine 2,3-dioxygenase (IDO), an enzyme that can starve T lymphocytes of tryptophan. Seventeen cases of PDA were evaluated by immunohistochemistry for expression of IDO in tumor cells and the number of Forkhead box p3-expressing regulatory T cells. To validate IDO protein expression, Western blot analysis for IDO was performed on primary pancreatic cancer cell-line protein lysates. Upregulation of IDO in metastatic PDA cells was associated with an increased number of regulatory T cells. Cytoplasmic IDO expression was present in all tumors (primary and metastatic) from patients with lymph node metastases. Intensity of staining was stronger in the corresponding metastatic foci when compared with the primary tumor. Three nonmetastatic PDAs were negative or only focally positive for IDO. Additionally, IDO expression in PDA was independent of tumor histologic grade. Forkhead box p3 regulatory T cells were increased in lymph nodes containing metastatic tumor cells expressing IDO. Using Western blot and reverse transcriptase polymerase chain reaction analysis, we validated that IDO expression in pancreatic cancer cells is induced by interferon-gamma as reported previously. These data support the notion that metastatic PDA cells select for overexpression of IDO to evade immunologic detection. Future studies will define whether IDO expression in PDA patients with lymph node-positive metastases correlates with decreased survival. In addition, inhibition of IDO in PDA patients can be useful to enhance immunotherapeutic strategies.


Enhancing the design and utilization of asthma action plans through community-based participatory research in an urban African American community.
Across the U.S., large inequities in asthma prevalence and outcomes persist, disproportionately affecting low-income, minoritized children. West Louisville is particularly impacted by these inequities due to a complex interplay of socioeconomic, historical, and industrial processes. Additionally, low health literacy and mistrust in healthcare exacerbate poor asthma self-management. To engage community members and health professionals to address childhood asthma management in a marginalized community experiencing significant health inequities. Although prior asthma knowledge was not required, the majority of our community advisory council (CAC) members either had asthma or cared for children/grandchildren with asthma. Through facilitated decision-making using the Boot Camp Translation approach, the CAC chose to focus on improving asthma self-management in their community through enhancing the design and utilization of asthma action plans (AAPs). Upon adding inhaler images to a user-friendly AAP, the CAC developed and implemented a provider incentive program and a health communication campaign to promote the Tool's utilization. Evaluation of the intervention consisted of a short questionnaire measuring relevant patient demographics and campaign knowledge, and phone interviews with providers to gather feedback on the incentive and Tool design. Over the short two-month intervention, a total of 8 practices with 28 providers used 153 Tools to provide asthma self-management counseling. The majority of providers preferred the enhanced Tool to other AAPs they had used. Inhaler images facilitating improved communication regarding asthma medications. Using a participatory approach, a community preferred intervention targeting barriers to effective asthma control increased provider utilization and community awareness of AAPs and bridged a communication gap between patients and providers. Leveraging community members' (including patients/caregivers) and health professionals' expertise led to the development of an enhanced patient-education tool and an effective provider incentive program with the potential to improve childhood asthma management in marginalized populations.


Prediction of acute neurovascular syndromes with prehospital clinical features witnessed by bystanders.
The prompt recognition of an acute neurovascular syndrome by the patient or a bystander witnessing the event can directly influence outcome. We aimed to study the predictive value of the medical history and clinical features recognized by the patients' bystanders to preclassify acute stroke syndromes in prehospital settings. We analyzed 369 patients: 209 (56.6%) with acute ischemic stroke (AIS), 107 (29.0%) with intracerebral hemorrhage (ICH), and 53 (14.4%) with subarachnoid hemorrhage (SAH). All patients had neuroimaging as diagnostic gold standard. We constructed clinical prediction rules (CPRs) with features recognized by the bystanders witnessing the stroke onset to classify the acute neurovascular syndromes before final arrival to the emergency room (ER). In all, 83.2% cases were referred from other centers, and only 16.8% (17.2% in AIS, 15% in ICH, and 18.9% in SAH) had direct ER arrival. The time to first assessment in ≤ 3 h occurred in 72.4% (73.7%, 73.8%, and 64.2%, respectively), and final ER arrival in ≤ 3 h occurred in 26.8% (32.1%, 15.9%, and 28.3%, respectively). Clinical features referred by witnesses had low positive predictive values (PPVs) for stroke type prediction. Language or speech disorder + focal motor deficit showed 63.3% PPV, and 77.0% negative predictive value (NPV) for predicting AIS. Focal motor deficit + history of hypertension had 35.9% PPV and 78.8% NPV for ICH. Headache alone had 27.9% PPV and 95.3% NPV for SAH. In multivariate analyses, seizures, focal motor deficit, and hypertension increased the probability of a time to first assessment in ≤ 3 h, while obesity was inversely associated. Final ER arrival was determined by age and a direct ER arrival without previous referrals. CPRs constructed with the witnesses' narrative had only adequate NPVs in the prehospital classification of acute neurovascular syndromes, before neuroimaging confirmation.


Morphological evidence for the ability of eosinophils to damage antibody-coated schistosomula.
Schistosomula of Schistosoma mansoni were incubated with preparations from human peripheral blood containing up to 98% eosinophils, in the presence or absence of anti-schistosomular antibody. It was found that there was a correlation between damage to the schistosomula, as judged by phase-contrast microscopy, and release of 51chromium from labelled organisms. The proportion of schistosomula showing damage did not increase over the times tested (two to six hours), but the release of chromium was progressive over the same period. This suggested that the chromium within damaged schistosomula was not all released immediately after the initial damage. A small proportion of the schistosomula appeared not to be susceptible to antibody-dependent, eosinophil-mediated damage. Antibody alone, in the absence of eosinophils, did not have any detectable damaging effect. Electron microscopy showed that, in the presence of antibody, the interaction between eosinophils and schistosomula, which results in damage to the schistosomula, is initiated by an intimate contact between the eosinophils and the schistosomular surface.


Smoking and tetramer tryptase accelerate intervertebral disc degeneration by inducing METTL14-mediated DIXDC1 m6 modification.
Although cigarette smoking (CS) and low back pain (LBP) are common worldwide, their correlations and the mechanisms of action remain unclear. We have shown that excessive activation of mast cells (MCs) and their proteases play key roles in CS-associated diseases, like asthma, chronic obstructive pulmonary disease (COPD), blood coagulation, and lung cancer. Previous studies have also shown that MCs and their proteases induce degenerative musculoskeletal disease. By using a custom-designed smoke-exposure mouse system, we demonstrated that CS results in intervertebral disc (IVD) degeneration and release of MC-restricted tetramer tryptases (TTs) in the IVDs. TTs were found to regulate the expression of methyltransferase 14 (METTL14) at the epigenetic level by inducing N6-methyladenosine (m6A) deposition in the 3' untranslated region (UTR) of the transcript that encodes dishevelled-axin (DIX) domain-containing 1 (DIXDC1). That reaction increases the mRNA stability and expression of Dixdc1. DIXDC1 functionally interacts with disrupted in schizophrenia 1 (DISC1) to accelerate the degeneration and senescence of nucleus pulposus (NP) cells by activating a canonical Wnt pathway. Our study demonstrates the association between CS, MC-derived TTs, and LBP. These findings raise the possibility that METTL14-medicated DIXDC1 m6A modification could serve as a potential therapeutic target to block the development of degeneration of the NP in LBP patients.


Asymmetric dimethylarginine levels in preeclampsia - Systematic review and meta-analysis.
Preeclampsia (PE) is the leading cause of maternal and perinatal mortality around the world. The impaired function of fetal-placental vasculature is a key factor in PE. Several studies have investigated the connection between PE and endothelial dysfunction. Also, many authors have examined the changes in asymmetric dimethylarginine (ADMA) as a prominent marker of endothelial dysfunction. Our study aim is to review and analyse the connections between PE and ADMA levels. To obtain data we performed a comprehensive literature search in Pubmed, Embase and Web of Science. Standardized mean differences were used to estimate the differences in ADMA levels. The quantitative analysis included 10 studies reporting a total number of 631 PE and 498 healthy pregnant individuals. We found significantly higher ADMA levels in PE patients compared to controls, when comparing the ADMA levels of the patients to the ADMA levels of the controls (z = 5.93, p < 0.001). This difference was present regardless of the measurement method. Regarding the onset of PE, we found significantly higher ADMA levels in patients suffering from early-onset PE when comparing the ADMA levels of the early-onset PE patients to that of the controls (z = 2.82, p = 0.005). However, we did not find such difference when we compared late-onset PE patients' ADMA levels to controls. ADMA is significantly higher in PE patients than in the controls. Elevated ADMA levels can play a major role in the development of PE, but more research is needed to clarify the connection between the two.


Environmental decentralization and green development: the mediating role of industrial upgrading.
Green development is a comprehensive concept incorporating environmental protection, playing a vital role in industrial upgrading and economic transformation. Under the current national status of political centralization and fiscal decentralization, decentralized environmental governance exerts a noticeable impact on green development (GTFP). The direct, mediating mechanism, and the spillover effects of environmental decentralization (ED) on GTFP are examined according to 30 Chinese areas dataset from 2005 to 2019. We reveal that a significant negative impact of ED on GTFP. The mediating effect of industrial upgrading is found during impact of ED on GTFP process. Furthermore, with the rising ED of surrounding areas, the GTFP of its region will be weakened. Meanwhile, an overall negative spillover effect of ED on the GTFP of neighboring areas is confirmed. ED in eastern and central China negatively impact GTFP, and such impact in the western area is insignificant. The spillover effects are also heterogeneous.


Electronic excitations of biomolecules studied by quantum chemistry.
Significant methodological advances have been made over the past ten years in developing reliable quantum chemical methods for the treatment of electronically excited states. These methods can nowadays be used routinely by the experienced researcher to accurately compute excitation spectra of medium-sized organic molecules; results have been reported for several popular photobiological systems, including green fluorescent protein. First steps are currently being taken to account for the solvochromic shifts of chromophore excitations caused by particular protein environments and to dynamically simulate photochemical reactions in the excited states.


Gamma knife radiosurgery for clinically persistent acromegaly.
Gamma knife radiosurgery (GKRS) is an important additional strategy for unresected clinically active pituitary adenomas. Radiosurgery for acromegaly aims to achieve tumor growth control and endocrine remission, potentially obviating the need for lifetime medication suppression therapy. Forty patients with clinically active acromegaly underwent GKRS between 1988 and 2009. Thirty-four patients had undergone prior surgical resection. The median follow-up interval was 72 months (range 24-145). Endocrine remission was defined as growth hormones (GH) level <2.5 ng/ml and a normal insulin-like growth factor 1 (IGF-1) level (age and sex adjusted) off growth hormone inhibiting drugs for at least 3 months. Endocrine control was defined as normal GH and IGF-1 levels on suppression medication. Endocrine remission was achieved in 19 (47.5 %) patients and endocrine control in four additional (10.0 %) patients. Patients with lower IGF-1 level and with tumors that were less invasive of the cavernous sinus before GKRS were associated with better GH remission rates. Imaging-defined local tumor control was achieved in 39 (97.5 %) patients (27 had tumor regression). One patient with delayed tumor progression underwent a second GKRS procedure. Three other patients had repeat GKRS because of persistently elevated and clinically symptomatic GH and IGF-1 levels. Sixteen (40.0 %) patients eventually developed a new pituitary axis deficiency at a median onset of 36 months after radiosurgery. No patient developed new visual dysfunction. Gamma knife radiosurgery, which is most often applied in clinically symptomatic acromegaly persistent after initial microsurgery, was most effective when the tumor was less invasive of the cavernous sinus and when patients had lower IGF-1 levels before GKRS. Almost one half of the patients no longer required long term medication suppression.


Visual working memory depends on attentional filtering.
Working memory holds information actively being used in cognitive performance. Two important aspects of working memory are how many items it can hold, and how efficiently it can be used. Recently, Vogel and colleagues used event-related brain potentials to show that these two things are related. People who could remember more objects from a spatial array also more efficiently excluded irrelevant objects. The results raise important questions about what aspect of working memory is most fundamental.


Palatability of British trees to insects: constitutive and induced defences.
Undamaged foliage of sixteen species of broadleaved trees was assessed for background (constitutive) palatability using larvae of Spodoptera littoralis (Lepidoptera) in laboratory bioassays. Palatability (dry weight consumed in 48 h) varied significantly between species and exhibited a four-fold range. Leaves of fifteen species were damaged artificially in the field and offered with control (undamaged) leaves to Spodoptera after 48 h and two weeks on the tree. Leaves adjacent to the damaged ones were similarly tested. Ten species exhibited significant (P<0.02) wound induced declines in palatability; damaged and adjacent foliage was involved. Although there was no significant relationship between the trees' constitutive palatability and the number of invertebrate herbivore species they support, this previously-demonstrated relationship closely approached significance when the species showing wound-induced effects were excluded from the regression. These results are discussed within the limitations of laboratory bioassays and the possible field consequences are briefly considered.


A simple substitute for a missing segment of the proximal anterior urethra.
We describe 2 patients with an absent segment of the bulbomembranous urethra, in 1 of whom the defect extended from the triangular ligament to the scrotal area. A simple method to restore continuity is presented, which is applicable to a wide variety of conditions resulting in the absence of a long segment of the bulbomembranous urethra.


Nitrofurantoin, sulfamethizole and cephalexin urinary concentration in unequally functioning pyelonephritic kidneys.
Nitrofurantoin, sulfamethizole and cephalexin peak urinary drug concentrations were studied in patients and non-human primates with unequally functioning pyelonephritic kidneys. The peak urinary drug concentration of the poorly functioning kidney in comparison to the better kidney was greater than its percentage relative blood flow or creatinine clearance but variable in its relationship to creatinine concentration, osmolality and sodium concentration. Although for each unit of creatinine clearance the poorly functioning kidney had a higher peak urinary drug concentration than the better functioning kidney, for each kidney the peak urinary drug concentration seemed to be directly proportional to the creatinine clearance, the drug dosage and the renal mechanisms of drug excretion. Nitrofurantoin in the usual recommended dosage did not reach minimal inhibitory urinary drug concentration below a unilateral creatinine clearance of 20 ml. per minute. Whereas, sulfamethizole and cephalexin reached peak urinary drug concentrations greater than the minimal inhibitory concentration at the lowest studied unilateral creatinine clearance of 4 and 11 ml. per minute, respectively.


Association between antidepressants and breast/ovarian cancer.
Women are more vulnerable to the development of major depressive disorder (MDD) than men. Although several epidemiological studies have investigated the association between antidepressants and the risk of developing cancer, different methodologies were applied and as a result most of the results were inconsistent. A recent study by Cosgrove and colleagues at Harvard University investigated the relationship between prescriptions for antidepressants and breast/ovarian cancer, to determine whether such medications are associated with the development of cancer. This paper discusses the relationship between the use of antidepressants and breast/ovarian cancer risk in the context of the potential limitations and significance of this recent research. Clinicians might need to be vigilant when treating female patients who require antidepressants, particularly those with other clinical risk factors in relation to breast/ovarian cancer; although more data will be necessary to evaluate the exact association between antidepressants and the development of such cancers.


Characterization of sequence-dependent synergy between ZD1839 ("Iressa") and oxaliplatin.
ZD1839 ("Iressa"), a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is currently undergoing preclinical and clinical evaluation in several solid tumors. The present study aimed to assess the effect of ZD1839 in combination with oxaliplatin in the colon cancer cell lines HT-29 and LoVo. For in vitro chemosensitivity testing, cells were treated with serial dilutions of each drug sequentially at a fixed ratio of doses that corresponded to 1/20, 1/10, 1/5, 1/2, 1, 1.5 and 2 times the individual IC(50) values. Oxaliplatin followed by ZD1839 produced a synergistic effect. In contrast, oxaliplatin following ZD1839 exhibited an additive effect at best. Mass spectrometry examination revealed that ZD1839 modestly enhanced cellular oxaliplatin accumulation and platinum-DNA (Pt-DNA) adducts (P>0.05). In additional studies, high-performance liquid chromatography revealed that oxaliplatin had no effect on ZD1839 accumulation. In contrast, ZD1839 markedly inhibited removal of Pt-DNA adducts (P<0.05). With oxaliplatin treatment (1 day) followed by ZD1839 (1 day), then incubation with drug-free medium (1 day), 90% of Pt-DNA adducts remained. Apoptosis examination revealed that oxaliplatin-induced apoptosis was prolonged by sequential oxaliplatin followed by ZD1839 treatment compared with oxaliplatin alone. Further experiments revealed that ZD1839 decreased cellular gamma-glutamyltransferase activity. The above observations provide a mechanistic explanation for the synergy of oxaliplatin followed by ZD1839, and suggest that this treatment combination warrants further preclinical and clinical investigation.


Inflammation of the neck.
In the evaluation of a large series of infectious processes in the cervical region, certain diagnostic sonographic patterns have been established, which prove very helpful in differentiating the various stages and the extension of inflammatory processes. The advantages of sonographic imaging are demonstrated.


Visible-light photocatalytic degradation of water-soluble polyvinyl alcohol in aqueous solution by Cu2O@TiO2: Optimization of conditions, mechanisms and toxicity analysis.
Polyvinyl alcohol (PVA), a water-soluble synthetic polymer, is one of the most prevalent non-native polyvinyl alcohols found in the environment. Due to its inherent invisibility, its potential for causing severe environmental pollution is often underestimated. To achieve efficient degradation of PVA in wastewater, a Cu2O@TiO2 composite was synthesized through the modification of titanium dioxide with cuprous oxide, and its photocatalytic degradation of PVA was investigated. The Cu2O@TiO2 composite, supported by titanium dioxide, facilitated photocarrier separation and demonstrated high photocatalytic efficiency. Under alkaline conditions, the composite exhibited a 98% degradation efficiency for PVA solutions and a 58.7% PVA mineralization efficiency. Radical capture experiments and electron paramagnetic resonance (EPR) analyses revealed that superoxide radicals primarily drive the degradation process within the reaction system. Throughout the degradation process, PVA macromolecules are broken down into smaller molecules, including ethanol, and compounds containing aldehyde, ketone, and carboxylic acid functional groups. Although the intermediate products exhibit reduced toxicity compared to PVA, they still pose certain toxic hazards. Consequently, further research is necessary to minimize the environmental impact of these degradation products.


Cryotherapy for retinopathy of prematurity to prevent retrolental fibroplasia.
This report analyses the results of cryotherapy in 22 eyes with severe retinopathy of prematurity (acute retrolental fibroplasia) and compares the results with data from other sources on untreated eyes. The evolution of the indications for and methods of treatment, the results of treatment, and related features are discussed. The need for a common terminology and classification of the disease is emphasized.


Spectroscopy and laser operation of Sm(3+)-doped lithium lutetium tetrafluoride (LiLuF(4)) and strontium hexaaluminate (SrAl(12)O(19)).
We report on laser operation in the orange and red spectral range in samarium (Sm(3+))-doped fluoride and oxide crystals at 300 K. Sm(3+)-doped LiLuF(4) (LLF) and SrAl(12)O(19) (SRA) crystals were grown by the Czochralski-technique and utilized for spectroscopic investigations and laser experiments. The spin-forbidden transitions of Sm(3+)exhibit low cross sections the order of 10(-21) cm(2), but high radiative upper state lifetimes of several ms in both crystal systems. Under 2ω-OPSL-pumping at 480 nm, orange laser operation was achieved with Sm:LLF and Sm,Mg:SRA at lasing wavelengths of 606 nm and 593 nm, respectively. Furthermore laser oscillation was demonstrated at 648 nm in the red and 703 nm in the deep red spectral range with Sm:LLF and Sm,Mg:SRA, respectively. Output power levels of several 10 mW were obtained at slope efficiencies of up to 15 %. Most of the realized lasers were operating in a strongly modulated or even self-pulsing regime.


Plasma amino acid pattern in burn subjects: influence of septicemia.
A comparison of plasma amino acid levels was made between two groups of burn subjects, septic and non-septic. On day 4 after injury, results do not show any differences between patients who later went on to develop sepsis on day 7 and those who remained non-septic. Similarly, no differences between these two groups were discernable on day 7. Thus metabolic variations induced by septicemia do not seem to modify the usual burn-induced amino acid variations; consequently, plasma amino acid determination in burn patients do not appear to predict septicemia.


Clinical trials in radiology and data sharing: results from a survey of the European Society of Radiology (ESR) research committee.
To determine the current situation and future directions of clinical trials and data sharing in radiology. This survey was conducted between July and September 2018 among European heads of imaging departments and speakers at the Clinical Trials in Radiology sessions at ECR 2015-2018. The survey was approved by the ESR research committee, was administered online, and chi-square tests were used. The overall response rate was 29% (132/460). Responses were received from institutions in 29 countries. These institutions reported having conducted 429 trials, leading to 332 publications, of which 43% were first and 44% were last authorships by those institutions. For future trials, 98% of respondents (93/95) said they would be interested in sharing data, although only 34% had shared data already (23/68, p < 0.001). The major barriers to data sharing were data protection (78%, 74/95), ethical issues (49%, 47/95), and the lack of a data sharing platform (49%, 47/95). Of the respondents, 89% believed a platform would facilitate data sharing (85/95 vs. 10/95 did not, p < 0.001) and should offer easy data uploading (74%, 70/95), data safety (66%, 63/95), easy communication between providers and re-users (62%, 59/95), and data access policies (56%, 53/95). A considerable number of imaging trials are being performed and published by radiologists in Europe whilst data sharing is hardly taking place, despite great interest. This is most likely due to data protection and ethical issues, as well as the absence of a data sharing platform. • Radiologists have performed a considerable number of more than 400 imaging trials in the last 5 years. • Although only 34% of institutions had shared trial data already, 98% are interested in doing so. • Major data sharing barriers are ethics, data protection, and the absence of a sharing platform.


A phase II study of bevacizumab with modified OPTIMOX1 as first-line therapy for metastatic colorectal cancer: the TCOG-GI 0802 study.
Although bevacizumab plus FOLFOX is a standard treatment for metastatic colorectal cancer, oxaliplatin must be withdrawn in many patients because of cumulative neurotoxicity. We postulated that a reduced dose of oxaliplatin and modified treatment schedule would prolong the time to treatment failure and evaluated bevacizumab combined with a modified OPTIMOX1 regimen (mOPTIMOX1, oxaliplatin dose: 85 mg/m(2)). Eligible patients had a histologically confirmed diagnosis of metastatic colorectal cancer and a performance status of 0-1. Patients were excluded if they had grade 1 or higher peripheral sensory neuropathy or had previously received chemotherapy for metastatic colorectal cancer. Patients received bevacizumab plus mFOLFOX6 every 2 weeks for 6 cycles, followed by 12 cycles of a simplified biweekly regimen of leucovorin and fluorouracil (sLV5FU2) plus bevacizumab. Oxaliplatin was then reintroduced, and bevacizumab plus mFOLFOX6 was continued until progressive disease. The median duration of disease control was 11.7 months (95 % confidence interval [CI], 9.7-13.5 months). The median overall survival was 23.1 months (95 % CI, 18.8-27.9 months). The overall response rate according to both the RECIST and WHO criteria was 51.3 %. The most common grade 3 or 4 toxicities were neutropaenia (32.5 %), hypertension (17.5 %), leukocytopaenia, sensory neuropathy, and diarrhoea (10.0 %). There were no treatment-related deaths. Bevacizumab plus mFOLFOX6 was well tolerated, and patients could continue chemotherapy for longer than with conventional FOLFOX regimens. This regimen might be an effective treatment option for patients with metastatic colorectal cancer.


Transgenic model of smooth muscle cell cycle reentry: expression pattern of the collageneous matrix.
We have previously shown that genetically induced smooth muscle cell (SMC) cycle reentry in transgenic mouse models expressing the SV40 T antigen (TAg) resulted in adaptive arterial remodeling. The present investigation targeted the in vitro expression pattern of the collageneous matrix associated with TAg-induced SMC cycle modulation. SMC cultures were established from the transgenic model expressing temperature-sensitive TAg. This allowed inducible transgene expression at the permissive temperature of 33 degrees C compared with the restrictive temperature of 39.5 degrees C. To distinguish a transgene effect from a temperature effect, SMCs with constitutively expressed TAg were used as controls. Data were obtained using array technology, Northern blotting, reverse transcription polymerase chain reaction, and zymography. TAg-induced SMC cycle reentry resulted in significant down-regulation of matrix metalloproteinase (MMP)-3, whereas MMP-2, -9, and -11 were not influenced. In addition, SMC cycle reentry resulted in significantly increased RNA levels of procollagen alpha2(IV), procollagen alpha2(V), and procollagen alpha1(XI), whereas procollagen alpha1(III) and procollagen alpha1(VIII) were down-regulated. Studies of the RNA expression levels of granulocyte-macrophage colony-stimulating factor revealed an up-regulation of this proinflammatory and matrix-modulating cytokine. This transgenic model provides evidence that TAg-induced cell cycle reentry is associated with a complex modulation of the collageneous matrix. Factors identified in this in vitro study reveal a comprehensive expression pattern of candidates, which might allow the vessel to undergo adaptive arterial remodeling under in vivo conditions. Our results will give rise to further investigations to elaborate on this hypothesis and to improve understanding of the role of such factors in vascular diseases.


Two-century sediment records of atmospheric mercury variations in North China and their relations with regional and global emissions.
Sedimentary mercury (Hg) records from remote areas are significant for revealing historical variations of regional Hg and understanding the influence of regional and global Hg emissions. In this study, sediment cores were retrieved from two subalpine lakes in Shanxi Province in North China and employed to reconstruct atmospheric Hg variations over the last two centuries. The two records show similar anthropogenic Hg fluxes and evolution trends, corresponding with that they were affected mainly by regional atmospheric Hg deposition. Before ~1950, the records show negligible Hg pollution signals. Atmospheric Hg in the region had increased rapidly since the 1950s, lagged more than a half-century compared to the global Hg. This indicates that they were seldom affected by Hg emissions dominated by Europe and North America after the industrial revolution. The Hg increases since the 1950s in the two records corresponded well with rapid industrial developments in and around Shanxi Province after the founding of the China, implying the dominant contribution of domestic Hg emissions. By comparing other Hg records, we find that widespread increases in atmospheric Hg in China likely occurred post ~1950. This study rouses to re-examine historical variations in atmospheric Hg at various settings, which is significant to understanding global Hg cycling in the industrial era.


Successful treatment with alectinib after crizotinib-induced interstitial lung disease.
We herein report a case of a 46-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged stage IV lung adenocarcinoma who received the ALK inhibitor crizotinib as second-line therapy. On the 47th day following crizotinib initiation, a chest computed tomography scan revealed ground-glass opacities with a clinical manifestation of desaturation, although a partial response to treatment was detected. The diagnosis of crizotinib-induced interstitial lung disease (ILD) was confirmed, and crizotinib was discontinued, followed by the initiation of corticosteroid therapy. After improvement of ILD with corticosteroid therapy, alectinib was administered as salvage therapy, resulting in tumor shrinkage without any recurrence of ILD. To the best of our knowledge, this is the first report of successful alectinib treatment following crizotinib-induced ILD. Our results indicate that alectinib could be a promising alternative treatment option in patients with crizotinib-induced ILD.


A comparison of quality of life of early breast cancer patients treated with accelerated partial breast irradiation versus whole breast irradiation in China.
To compare quality of life (QoL) of early breast cancer patients treated with either accelerated partial breast irradiation (APBI) or whole breast irradiation (WBI) after breast-conserving therapy in China. The functional assessment of chronic illness therapy-Breast, traditional Chinese version 4 (FACT-B) instruments were given to 84 women (31 APBI and 53 WBI) who attended the radiotherapy clinic between July 2006 and May 2009 at Cancer Center of Sun Yat-sen University. Baseline characteristics and Karnofsky performance status scores were not different between the two groups. The median follow-up period in the APBI group was 29 versus 34 months in the WBI group. The APBI group scores in the physical domain, functional domain, social domain, and breast-specific concerns of FACT-B were 23.01 ± 3.91, 17.97 ± 4.99, 20.87 ± 4.80, and 22.55 ± 5.45, respectively, and were not significantly different from those of the WBI group (22.80 ± 3.50, 17.50 ± 4.40, 20.13 ± 5.31, 23.81 ± 4.65, respectively, P = 0.987, P = 0.476, P = 0.442, P = 0.330, respectively). However, the scores of the APBI group with respect to the emotional domains were lower compared to those of the WBI group (16.84 ± 3.86 vs. 19.47 ± 3.45, respectively, P = 0.002). Compared with women who underwent WBI, women treated with APBI were shown to have no significantly better QoL outcome, and yet had worse emotional response to their treatment.


Development and validation of a combined ferroptosis and immune prognostic signature for lung adenocarcinoma.
Studies have shown that the regulation of ferroptosis could be a new approach to cancer treatment and abnormal ferroptosis is closely associated with a dysregulated immune response. However, a combined signature with ferroptosis-related genes (FRGs) and immune-related genes (IRGs) is necessary to be constructed for predicting prognoses and guiding individualized precision therapy of lung adenocarcinoma (LUAD) patients. In this study, based on the Cancer Genome Atlas (TCGA) cohort, prognosis-related FRGs and IRGs were first identified and incorporated into the Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression model to generate a combined signature of ferroptosis- and immune-related genes (CSFI) values to predict the overall survivals (OSs) of LUAD patients. And patients with LUAD from the Gene Expression Omnibus (GEO) database were applied for the validation set. Nomogram was constructed based on multivariate Cox regression analysis. Subsequently, ferroptosis, immunity, and gene mutation status of patients between the CSFI-high and -low groups were compared. Additionally, the enrichment pathways in CSFI-high and -low groups were explored by Gene Ontology (GO), Kyoto Gene and Genome Encyclopedia (KEGG) and Gene Set Enrichment Analysis (GSEA) analyses. As a result, the CSFI-low group showed a good prognosis instead of the CSFI-high group. CSFI was identified to be an independent prognosis factor for LUAD. In general, there were ferroptosis- and immune-suppressive states in CSFI-high patients. Notably, the mutation frequencies of TP53 were higher in CSFI-high patients. In LUAD, CSFI which served as a novel classifier was offered for predicting the prognoses of patients and contributing to guiding personalized targeted therapy of patients. Therefore, based on these findings, it was believed that a synergistic treatment of ferroptosis and immunity would be more effective on LUAD patients with low CSFI values.


Incidence and clinical factors associated with ulceration in infantile hemangiomas.
Ulceration is an important complication in infantile hemangiomas (IHs). Prior to the use of β-blockers, the estimated incidence of this complication in a referral population was between 15% and 30%. The incidence and factors associated with ulceration have not been systematically studied since the emergence of β-blocker therapy. Examine the incidence and clinical predictors for ulceration in IHs. Retrospective study at tertiary referral centers. Compared with a previous large pre-propranolol cohort study, ulceration occurred at a significantly lower incidence of 11.4%. Clinical factors associated with ulceration included partial segmental morphology, location in the diaper area, and size greater than 5 cm. Higher risk of ulceration in Black patients was observed, suggesting barriers to care including delayed diagnosis and referral to specialty care. Retrospective design at tertiary referral centers. Compared with reports before the use of β-blockers became widespread, the incidence of ulceration in IHs has decreased. However, it continues to be a relatively frequent complication of IH.


Involvement of post-capillary venules in Behçet's disease: an electronmicroscopic study.
In Behçet's disease, severe pathological changes are observed in the post-capillary venules, indicating that the venous side of the circulation is generally involved. It is proposed that one of the initial pathological changes is multiplication of the basal lamina surrounding the post-capillary venule.


Therapeutic prospects to treat skeletal muscle wasting in COPD (chronic obstructive lung disease).
Chronic obstructive pulmonary disease (COPD) is an incurable group of lung diseases characterised by progressive airflow limitation and loss of lung function, which lead to profound disability. It is mostly caused by cigarette smoke. Although COPD is one of the most prevalent diseases worldwide and its incidence is increasing, current therapies do little to improve the condition. Much current research focuses on strategies to halt the accelerated rate of decline in lung function that occurs in the disease. However, as most symptoms occur when the lungs are already extensively and irreversibly damaged, it is uncertain whether an agent able to slow or halt decline in lung function would actually provide relief to COPD patients. As lung function worsens, systemic comorbidities contribute markedly to disability. Loss of lean body mass (skeletal muscle) has recently been identified as a major determinant of disability in COPD and an independent predictor of mortality. In contrast to lung structure damage, skeletal muscle retains regenerative capacity in COPD. In this review, we discuss mechanisms of wasting in COPD, focusing on therapeutic strategies that might improve the health and productive life expectancy of COPD patients by improving skeletal muscle mass and function. Single or combination approaches exploiting the suppression of procatabolic inflammatory mediators, inhibition of ubiquitin ligases, repletion of anabolic hormones and growth factors, inhibition of myoblast apoptosis, remediation of systemic oxidative stress and promotion of repair, and regeneration via stimulation of satellite cell differentiation hold considerable therapeutic promise.


Spectroscopic detection and state preparation of a single praseodymium ion in a crystal.
The narrow optical transitions and long spin coherence times of rare earth ions in crystals make them desirable for a number of applications ranging from solid-state spectroscopy and laser physics to quantum information processing. However, investigations of these features have not been possible at the single-ion level. Here we show that the combination of cryogenic high-resolution laser spectroscopy with optical microscopy allows one to spectrally select individual praseodymium ions in yttrium orthosilicate. Furthermore, this spectral selectivity makes it possible to resolve neighbouring ions with a spatial precision of the order of 10 nm. In addition to elaborating on the essential experimental steps for achieving this long-sought goal, we demonstrate state preparation and read out of the three ground-state hyperfine levels, which are known to have lifetimes of the order of hundred seconds.


Morphological, hemodynamical and hemorheological changes of mature artificial saphenous arterio-venous shunts in the rat model.
Artificial femoral arterio-venous (AV) shunts are widely used in rodent models for studying shunt maturation and to optimize various surgical techniques. However, little is known about complex circulatory, microcirculatory, and hemorheological effects of end-to-side saphenous AV shunts. We aimed to study these parameters in mature AV shunts. Studying these questions in CD rats, end-to-side anastomoses were made between the left saphenous artery and vein. On the right-side the nonoperated saphenous vessels served as own control. Furthermore healthy control animals were also investigated. On the 8th to 12th postoperative week microcirculatory and blood flow measurements were performed and blood samples were taken both from the shunt's arterial and venous limbs and from the nonoperated side vessels. Hematological parameters, erythrocyte aggregation, and deformability were determined. The entire shunt and the control vessels were removed for histological examinations. The skin microcirculation on shunt side slightly increased on thigh and decreased on paws versus the nonoperated side. Blood flow measurements made directly on the vessels showed that arterial to venous blood flow rate ratio was 1.59 ± 0.29 on nonoperated side and 1.2 ± 0.13 on the shunt side, and 1.49 ± 0.05 in control animals. Erythrocyte aggregation and deformability worsened on the shunt side. Histologically increased number of smooth muscle elements and connective tissue were found in venous limb of the shunts. The artificial AV shunt between the saphenous artery and vein seems to be a suitable model for further functional-morphological and hemorheological examinations of hemodialysis in various states and diseases.


Deletion of the receptor MOM19 strongly impairs import of cleavable preproteins into Saccharomyces cerevisiae mitochondria.
The mitochondrial outer membrane proteins MOM19 and MOM72 are thought to function as import receptors for nuclear encoded preproteins. Different views exist about the importance of each receptor in the import of cleavable and noncleavable preproteins into mitochondria. Here we cloned and sequenced MOM19 from Saccharomyces cerevisiae and constructed a gene disruption mutant. Yeast cells lacking MOM19 were unable to grow on nonfermentable carbon sources and were slow in growing on a fermentable medium, while the growth of yeast cells lacking MOM72 (Mas70p) was much less impaired. delta MOM19 cells accumulated considerable amounts of mitochondrial preproteins in vivo. The import of cleavable preproteins into isolated delta MOM19 mitochondria was strongly inhibited, while import of the noncleavable ADP/ATP carrier and phosphate carrier was only slightly inhibited. The reciprocal situation was found for protein import into delta MOM72 mitochondria. In particular, import of the cleavable precursor of cytochrome c1 into delta MOM72 mitochondria was, in agreement with a previous report (Hines, V., and Schatz, G. (1993) J. Biol. Chem. 268, 449-454), found to be partially inhibited, yet a much stronger inhibition of import was seen into delta MOM19 mitochondria. The direct comparison of protein import into yeast mutants of either receptor yields a unifying hypothesis on mitochondrial preprotein targeting; both receptors have an overlapping specificity, and MOM19 plays a major role for cleavable preproteins. Interestingly, the primary sequence of MOM19 predicts the presence of a tetratricopeptide motif that was also found in MOM72, in the peroxisomal membrane protein PAS8/PAS10, and in several proteins involved in RNA synthesis or mitosis.


Determination of the toxicity of intravitreal minocycline in rabbit eyes.
To evaluate the retinal toxicity of intravitreal minocycline in rabbit eyes. Intravitreal injection of minocycline with concentrations of 1000, 500, 250, 125 and 62.5 μg in 0.1 ml was performed in 10 New Zealand albino rabbits. Each concentration was injected into two rabbit eyes. For each dose, normal saline was injected in one contralateral eye and the other fellow eye remained non-injected. Electrophysiologic testing was performed before and 4 weeks after injections. The eyes were enucleated 4 weeks after injections and examined using light microscopy. The clinical examination was unremarkable after injections. Electroretinography recordings were significantly affected at all doses in at least one of the a- or b-waves of photopic or scotopic responses. Histopathologic examination revealed marked atrophy and loss of integrity in all retinal layers in all minocycline injected eyes. Contralateral eyes were normal. In our study, intravitreal minocycline was toxic to the retina in albino rabbits even at a concentration of 62.5 µg/0.1 ml.


Uncertainties of calculated Cramér-Rao lower bounds: implications for quantitative MRS.
To investigate the uncertainties on relative Cramér-Rao lower bound (rCRB) estimates and demonstrate their biasing effects in MRS quantification. Simulations were performed to calculate the distribution of the computed rCRB (noted rCRB*) for several rCRB levels. One hundred thousand simulations per rCRB value were performed on simulated NMR signals containing either 1 signal (singlet) or 2 partially overlapping signals. False-positive and false-negative risks were compiled for different threshold levels. rCRB* distribution was experimentally checked on a deuterated water sample using a 9.4 Tesla vertical magnet. Simulations showed that (1) rCRB* distribution is asymmetrical, with a right-tailed distribution increasing the risk of accepting false-positive data (i.e., accepting an rCRB* value whereas the true rCRB value is higher than the threshold level) and (2) distribution broadness increases with increasing rCRB level. Simulations with overlapped peaks lead to more inaccuracy in the rCRB estimation. Probabilities of false detection increase with increasing threshold level. Analyzing results thanks to a CRB (or rCRB) based on experimental measurements might lead to misinterpretations. To exploit the rCRB* as rejection criteria, a conservative threshold level of 20% is recommended in order to limit the probability of false alarms.


Perturbed thymopoiesis in vitro in the absence of suppressor of cytokine signalling 1 and 3.
Cytokine signals are central to the differentiation of thymocytes and their stepwise progression through defined developmental stages. The intensity and duration of cytokine signals are regulated by the suppressor of cytokine signalling (SOCS) proteins. A clear role for SOCS1 during the later stages of thymopoiesis has been established, but little is known about its role during early thymopoiesis, nor the function of its closest relative, SOCS3. Here, we find that both SOCS1 and SOCS3 are expressed during early thymopoiesis, with expression coincident during the double negative (DN)2 and DN3 stages. We examined thymocyte differentiation in vitro by co-culture of SOCS-deficient bone marrow cells with OP9 cells expressing the Notch ligand Delta-like1 (OP9-DL1). Cells lacking SOCS1 were retarded at the DN3:DN4 transition and appeared unable to differentiate into double positive (DP) thymocytes. Cells lacking both SOCS1 and SOCS3 were more severely affected, and displayed an earlier block in T cell differentiation at DN2, the stage at which expression of SOCS1 and SOCS3 coincides. This indicates that, in addition to their specific roles, SOCS1 and SOCS3 share overlapping roles during thymopoiesis. This is the first demonstration of functional redundancy within the SOCS family, and has uncovered a vital role for SOCS1 and SOCS3 during two important checkpoints in early T cell development.


Repeated-batch operation for the synthesis of lactulose with β-galactosidase immobilized by aggregation and crosslinking.
Synthesis of lactulose under repeated-batch operation was done with cross-linked aggregates of Aspergillus oryzae β-galactosidase (CLAGs). The effect of the crosslinking agent to enzyme mass ratio and cross-linking time were first evaluated. Best results were obtained at 5.5gdeglutaraldehyde/g enzyme at 5h of cross-linking, obtaining a specific activity of 15,000IUg(-1), with 30% immobilization yield. CLAG was more stable than the free enzyme under non-reactive conditions with a half-life of 123h at 50°C and when operated in repeated-batch mode, yield and productivity was 3.8 and 4.3 times higher. Maximum number of batches was determined considering biocatalyst replacement at 50% residual activity. 98 and 27 batches could be performed under such criterion at fructose/lactose molar ratio of 4 and 20 respectively, reflecting that enzyme stability is strongly affected by the sugars distribution in the reaction medium.


Partial trisomy of the long arm of chromosome 1 in myelofibrosis and polycythemia vera.
We have identified partial trisomy 1q in 2 patients with different hematologic disorders. The first patient was a 55-year-old female with myelosclerosis and myeloid metaplasia diagnosed at age 38 years presenting with anemia, fatigue, bruising, fever, and splenomegaly. At age 56, she had 50--95% myeloblast cells and 95--100 nucleated RBC precursors per 100 WBC. Chromosome analysis of unstimulated leukocytes with Q, G, and C banding showed 46,XX,-6,+t(1;6) (q25;p22) in all metaphase cells. In vitro incorporation of Fe55 was demonstrated 90% of metaphases by autoradiography. The second patient, a 49-year-old male, was diagnosed as having polycythemia vera at age 30 during a regular checkup. He since developed hepatosplenomegaly. Chromosome analysis from a direct bone marrow preparation at age 44 and 45 showed grossly normal karyotypes. At age 49, his marrow by Q and G banding showed almost 100% of cells with 46,XY,-13,+t(1;13) (q12;p12). Eleven cases of trisomy of 1q have been reported in various hematologic disorders. It is apparent that partial trisomy 1q represents another nonrandom chromosomal abnormality, in addition to the most common nonrandom chromosomal aberrations, such as the Philadelphia chromosome, trisomy 8, trisomy 9, and monosomy 7 in hematologic disorders.