Efficacy and Tolerability of ALK/MET Combinations in Patients With ALK-Rearranged Lung Cancer With Acquired MET Amplification: A Retrospective Analysis.
MET amplification is a potentially actionable resistance mechanism in ALK-rearranged (ALK+) lung cancer. Studies describing treatment outcomes of this molecular subgroup are lacking. We assembled a cohort of patients with ALK+ lung cancer and acquired MET amplification (identified by tissue or plasma) who received regimens targeting both ALK and MET. Efficacy and safety were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 and Common Terminology Criteria for Adverse Events version 4.03, respectively. A total of 12 patients were included in the series. MET amplification was detected after a median of 1.5 (range 1-5) lines of therapy. Four distinct regimens were implemented to address MET amplification: crizotinib (n = 2), lorlatinib plus crizotinib (n = 6), alectinib plus capmatinib (n = 3), and alectinib plus crizotinib (n = 1). Partial responses were observed in five (42%) of 12 patients, including patients who received crizotinib (n = one of two), lorlatinib plus crizotinib (n = three of six), and alectinib plus capmatinib (n = one of three). Primary progression was observed in four patients (33%). Grades 1 to 2 peripheral edema, occurring in seven (58%) patients, was found with both crizotinib and capmatinib. One patient required dose reduction of capmatinib plus alectinib for persistent grade 2 edema. Across the regimens, one patient discontinued therapy for toxicity, specifically neurocognitive toxicity from lorlatinib plus crizotinib. At progression on ALK+ MET therapy, potential resistance mechanisms included MET copy number changes and ALK kinase domain mutations. Combined ALK and MET inhibition is associated with moderate antitumor activity in patients with ALK+ NSCLC with concurrent MET amplification. Prospective studies are indicated to confirm activity and identify individuals most likely to benefit from the treatment.


Early pregnancies among middle school students: Attribution of blame and the feelings of responsibility among teachers and parents.
Globally, 15% of adolescents give birth before turning 18, leading to considerable personal, social, and medical impacts on adolescents and to the general society. This study aimed at exploring and comparing three psychological attributes (i.e., empathetic concern, feelings of responsibility, and attribution of blame) between parents and teachers for the phenomena. 672 teachers (54% females) and 690 parents (53% female) participated in the study. The results indicated a significant mean difference between parents and teachers on empathy (t = 5.735, p < 0.001), attribution of blame (t = 6.902, p < 0.001), and feelings of responsibility (t = 1.727, p < 0.001). Except for attribution of blame, parents' mean scores of other variables were higher than that of teachers. Teachers' higher attribution of blame to pregnant adolescents and lower empathetic concern raises a prominent concern over students' healthy environment at school. Understanding social feelings about responsibilities over adolescents' general health is very essential, especially for fighting against the problem of early pregnancy.


The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors.
Approximately 20% of grade II and most grade III gliomas fluoresce after 5-aminolevulinic acid (5-ALA) application. Conversely, approximately 30% of nonenhancing gliomas are actually high grade. The aim of this study was to identify preoperative factors (ie, age, enhancement, 18F-fluoroethyl tyrosine positron emission tomography [F-FET PET] uptake ratios) for predicting fluorescence in gliomas without typical glioblastomas imaging features and to determine whether fluorescence will allow prediction of tumor grade or molecular characteristics. Patients harboring gliomas without typical glioblastoma imaging features were given 5-ALA. Fluorescence was recorded intraoperatively, and biopsy specimens collected from fluorescing tissue. World Health Organization (WHO) grade, Ki-67/MIB-1 index, IDH1 (R132H) mutation status, O-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and 1p/19q co-deletion status were assessed. Predictive factors for fluorescence were derived from preoperative magnetic resonance imaging and F-FET PET. Classification and regression tree analysis and receiver-operating-characteristic curves were generated for defining predictors. Of 166 tumors, 82 were diagnosed as WHO grade II, 76 as grade III, and 8 as glioblastomas grade IV. Contrast enhancement, tumor volume, and F-FET PET uptake ratio >1.85 predicted fluorescence. Fluorescence correlated with WHO grade (P < .001) and Ki-67/MIB-1 index (P < .001), but not with MGMT promoter methylation status, IDH1 mutation status, or 1p19q co-deletion status. The Ki-67/MIB-1 index in fluorescing grade III gliomas was higher than in nonfluorescing tumors, whereas in fluorescing and nonfluorescing grade II tumors, no differences were noted. Age, tumor volume, and F-FET PET uptake are factors predicting 5-ALA-induced fluorescence in gliomas without typical glioblastoma imaging features. Fluorescence was associated with an increased Ki-67/MIB-1 index and high-grade pathology. Whether fluorescence in grade II gliomas identifies a subtype with worse prognosis remains to be determined.


Cognitive behavior therapy for eating disorders versus normalization of eating behavior.
We examine the science and evidence supporting cognitive behavior therapy (CBT) for the treatment of bulimia nervosa and other eating disorders. Recent trials focusing on the abnormal cognitive and emotional aspects of bulimia have reported a remission rate of about 45%, and a relapse rate of about 30% within one year. However, an early CBT trial that emphasized the normalization of eating behavior had a better outcome than treatment that focused on cognitive intervention. In support of this finding, another treatment, that restores a normal eating behavior using mealtime feedback, has an estimated remission rate of about 75% and a relapse rate of about 10% over five years. Moreover, when eating behavior was normalized, cognitive and emotional abnormalities were resolved at remission without cognitive therapy. The critical aspect of the CBT treatment of bulimia nervosa therefore may actually have been the normalization of eating behavior.


Characterization and chemical modulation of p62/SQSTM1/Sequestosome-1 as an autophagic N-recognin.
In the Arg/N-degron pathway, single N-terminal (Nt) residues function as N-degrons recognized by UBR box-containing N-recognins that induce substrate ubiquitination and proteasomal degradation. Recent studies led to the discovery of the autophagic Arg/N-degron pathway, in which the autophagic receptor p62/SQSTM1/Sequestosome-1 acts as an N-recognin that binds the Nt-Arg and other destabilizing residues as N-degrons. Upon binding to Nt-Arg, p62 undergoes self-polymerization associated with its cargoes, accelerating the macroautophagic delivery of p62-cargo complexes to autophagosomes leading to degradation by lysosomal hydrolases. This autophagic mechanism is emerging as an important pathway that modulates the lysosomal degradation of various biomaterial ranging from protein aggregates and subcellular organelles to invading pathogens. Chemical mimics of the physiological N-degrons were developed to exert therapeutic efficacy in pathophysiological processes associated with neurodegeneration and other related diseases. Here, we describe the methods to monitor the activities of p62 in a dual role as an N-recognin and an autophagic receptor. The topic includes self-polymerization (for cargo condensation), its interaction with LC3 on autophagic membranes (for cargo targeting), and the degradation of p62-cargo complexes by lysosomal hydrolases. We also discuss the development and use of small molecule mimics of N-degrons that modulate p62-dependent macroautophagy in biological and pathophysiological processes.


Primary thrombophilia in Mexico: a prospective study.
A group of 102 Mexican Mestizo patients with appropriate clinical features suggestive of primary thrombophilia was prospectively studied. Thirty-nine percent of them had activated protein C resistance, but only four patients displayed the factor V Leiden mutation. Five percent of the individuals were found to be protein C deficient, whereas 2% had protein S deficiency. No cases of abnormalities in antithrombin III, plasminogen, tissue-type plasminogen activator or plasminogen activator inhibitor were found. The low prevalence of the activated protein C resistance genotype, probably stemming from the genetic admixture of the Mexican Mestizo group is noteworthy.


Factors influencing oral cancer screening preferences in patients attending Tertiary Care University Oral Health Clinic.
Understanding factors that influence patients' preferences towards oral cancer (OC) screening is imperative to provide high-quality evidence-based OC screening interventions that can be targeted for population-level uptake. This study determined adult patients' knowledge and awareness of OC, and how health behaviours influenced their preferences towards OC screening. This cross-sectional study used a 42-point questionnaire, between February and May 2020 using a combination of in-person and telephone interviews. Chi-square test and multiple logistic regression analysis were applied to confounding factors that returned statistical significance against OC knowledge and awareness. Significance of P < 0.05 was accepted. Sixty-eight (38.6%) participants out of a total 176 had good knowledge of OC and 89 (50.6%) had good awareness. A total of 31.8% reported preference for OC screening by a general dental practitioner (GDP) over a general medical practitioner (GMP). Majority (72.7%) reported acceptance of OC screening at their next GDP visit. Ages 56-70 (OR = 0.357, 95% CI) and previous smokers (OR = 0.336, 95% CI) significantly influenced screening preferences. Knowledge of risk factors did not significantly influence OC screening preferences (χ2 = 3.178, P = 0.075). Significant gaps in OC knowledge, screening and role of GDPs exist with smoking history and age influencing OC screening preferences.


Therapeutic uses of heparin beyond its traditional role as an anticoagulant.
A number of physiological effects have been ascribed to heparin since its discovery almost 80 years ago, many of which are independent from its first-described and best- characterized activity as an anticoagulant. Heparin and heparan sulphate are believed to possess many biological activities that include the ability to modulate embryonic development, neurite outgrowth, tissue homeostasis, wound healing, metastasis, cell differentation, cell proliferation and inflammation. In this review, David Tyrell, Stephen Kilfeather and Clive Page examine some of the activities of heparin (and heparin derivatives) beyond its effects as an anticoagulant, and discuss the therapeutic potential of this old, but certainly not antiquated, drug.


Following the Rules Set by Accreditation Agencies and Governing Bodies to Maintain In-Compliance Status: Applying Critical Thinking Skills When Evaluating the Need for Change in the Clinical Laboratory.
Maintaining an in-compliance clinical laboratory takes continuous awareness and review of standards, regulations, and best practices. A strong quality assurance program and well informed leaders who maintain professional networks can aid in this necessary task. This article will discuss a process that laboratories can follow to interpret, understand, and comply with the rules and standards set by laboratory accreditation bodies.


Clinical Course of Cerebral Venous Thrombosis in Adult Acute Lymphoblastic Leukemia.
Venous thromboembolism (VTE) is a frequent complication in patients with acute lymphoblastic leukemia (ALL). A significant proportion of patients develop cerebral venous thrombosis (CVT). To investigate risk factors for and the clinical course of CVT in ALL patients, we describe all cases of CVT which occurred in a well-defined cohort of 240 adults, treated for newly diagnosed ALL in the HOVON (Dutch-Belgian Hemato-Oncology Cooperative Group)-37 study. We conducted a nested case-control study to explore the relevance of early symptoms and risk factors for CVT in ALL patients. Nine of 240 patients developed CVT (4%). CVT occurred during or shortly after L-asparaginase therapy (in 8 cases) and shortly after intrathecal methotrexate injections (in all cases) during cycle I of remission induction treatment. CVT was associated with prior headache and seizures. In 5 of 9 patients with CVT, headache before the diagnosis of CVT occurred within 3 days after lumbar puncture and initially had a postural character. CVT is relatively common in adult ALL patients. Our data suggest that CVT in adult ALL patients results from the additive effects of multiple risk factors, with a particular role for asparaginase and the effects of lumbar punctures for intrathecal therapy.


Inhibition of prostaglandin-H-synthase by o-phenylphenol and its metabolites.
Chronic administration of o-phenylphenol (OPP) is known to induce urinary bladder tumours in the Fischer rat. The underlying toxic mechanism is poorly understood. Recently, arachidonic acid (ARA)-dependent, prostaglandin-H-synthase (PHS)-catalysed metabolic activation of the OPP metabolite phenylhydroquinone (PHQ) to a genotoxic species was suggested to be involved in OPP toxicity. To investigate this hypothesis in more detail, we have studied the effects of OPP and its metabolites on PHS. When microsomal PHS from ovine seminal vesicles (OSV) was used as enzyme source, both OPP, PHQ, and 2-phenyl-1,4-benzoquinone (PBQ) inhibited PHS-cyclooxygenase. The inhibitory potency was inversely related to the ARA concentration in the assay; at 7 microM ARA IC50-values were: 13 microM (OPP), 17 microM (PHQ), and 190 microM (PBQ). In cells cultured from OSV, which express high PHS activity, 40 microM OPP almost completely suppressed prostaglandin formation. Studies with microsomal PHS demonstrated that PHQ was an excellent substrate for PHS-peroxidase; both ARA and hydrogen peroxide supported oxidation to PBQ. OPP was only a poor substrate for PHS, but inhibited the ARA-mediated and to a lesser extent also the hydrogen peroxide-mediated in vitro oxidation of PHQ. Moreover, PHQ at up to moderately cytotoxic concentrations (50 microM) did not induce micronuclei in OSV cell cultures. Taken together, our findings do not provide evidence for an ARA-dependent, PHS-catalysed formation of genotoxic species from PHQ. Moreover, it seems to be questionable whether such activation can effectively occur in vivo, since OPP and PHQ turned out to be efficient cyclooxygenase inhibitors, and high levels of OPP and PHQ were found at least in the urine of OPP-treated rats. On the other hand, inhibition of the formation of cytoprotective prostaglandins in the urogenital tract may play a crucial role in OPP-induced bladder carcinogenesis.


Platelet-associated immunoglobulins G, A and M are secreted during platelet activation: normal levels but defective secretion in grey platelet syndrome.
Platelet-associated (PA) IgG is known to be released from normal human platelets when they are stimulated by aggregating agents. We have studied whether PA-IgA and PA-IgM are also secreted during platelet activation or during blood collection and processing and whether their levels are related to those in serum. Processing of platelets from normal donors in the presence of secretion inhibitors prostaglandin E1 (PGE1) and theophylline increased levels of both surface and total PA-immunoglobulins (Ig) in intact and lysed platelets respectively, with increases being significant for surface PA-IgA and PA-IgM and total PA-IgM. About 50% of total PA-IgM, 40% PA-IgA and 20% PA-IgG was detectable on intact platelets. All three PA-Ig and PA-albumin were secreted in response to thrombin and this release was inhibited by PGE1. The platelet:serum ratio of each Ig and albumin were similar. In grey platelets deficient in alpha-granules, PA-Ig and PA-albumin levels were raised per platelet but when increased platelet size was taken into account PA-Ig were normal and PA-albumin just below normal. Although thrombin caused release of most of the small amounts of beta-thromboglobulin present, PA-Ig and PA-albumin were not released. This suggests that PA-Ig and albumin from plasma may enter a pool of secretory proteins in normal platelets, but in grey platelets they remain in some other site.


Compound IMB-Z inhibits hepatitis B virus replication through increasing APOBEC3G expression and incorporation into viral nucleocapsids.
As a host restriction factor, apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G) has been shown to suppress the replication of several viruses including hepatitis B virus (HBV). Recently, we reported that IMB-Z, a N-phenylbenzamide derivative, could inhibit Enterovirus 71 replication, and A3G mediated its antiviral activity. Whether IMB-Z exhibits an inhibitory effect on HBV replication has not been investigated. HBV DNA, pregenomic RNA (pgRNA), core protein, and capsid levels were determined by a qPCR assay or Southern blot, Northern blot, Western blot, and particle gel assay, respectively. Mutation analysis of HBV DNAs was conducted by a differential DNA denaturation PCR assay. A3G encapsidation into HBV nucleocapsids was examined by Western blot analysis after ultracentrifugation and a co-immunoprecipitation (IP) assay between HBV core and A3G proteins. In the present study, we found that IMB-Z could considerably inhibit HBV replication in HepAD38 cells. Interestingly, IMB-Z did not alter the HBV pgRNA production but could reduce the level of core protein, viral nucleocapsids, and core-associated DNA, as well as cccDNA intracellular amplification. Similar to the action of IMB-Z's inhibition of Enterovirus 71 replication, we found that IMB-Z's inhibition of HBV replication was associated with increased level of A3G. Mechanistically, we demonstrated that the inhibitory effect of IMB-Z is independent of the cytidine deaminase activity of A3G and is exerted by increasing its incorporation into viral nucleocapsids. Our results indicate that IMB-Z inhibits HBV through pharmacological induction A3G expression and incorporation into HBV nucleocapsids.


Radiosynthesis and initial characterization of a PDE10A specific PET tracer [18F]AMG 580 in non-human primates.
Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important second messengers for neurotransmission. Inhibition of PDE10A has been identified as a potential target for treatment of various neuropsychiatric disorders. To assist drug development, we have identified a selective PDE10A positron emission tomography (PET) tracer, AMG 580. We describe here the radiosynthesis of [(18)F]AMG 580 and in vitro and in vivo characterization results. The potency and selectivity were determined by in vitro assay using [(3)H]AMG 580 and baboon brain tissues. [(18)F]AMG 580 was prepared by a 1-step [(18)F]fluorination procedure. Dynamic brain PET scans were performed in non-human primates. Regions-of-interest were defined on individuals' MRIs and transferred to the co-registered PET images. Data were analyzed using two tissue compartment analysis (2TC), Logan graphical (Logan) analysis with metabolite-corrected input function and the simplified reference tissue model (SRTM) method. A PDE10A inhibitor and unlabeled AMG 580 were used to demonstrate the PDE10A specificity. KD was estimated by Scatchard analysis of high and low affinity PET scans. AMG 580 has an in vitro KD of 71.9 pM. Autoradiography showed specific uptake in striatum. Mean activity of 121 ± 18 MBq was used in PET studies. In Rhesus, the baseline BPND for putamen and caudate was 3.38 and 2.34, respectively, via 2TC, and 3.16, 2.34 via Logan, and 2.92, and 2.01 via SRTM. A dose dependent decrease of BPND was observed by the pre-treatment with a PDE10A inhibitor. In baboons, 0.24 mg/kg dose of AMG 580 resulted in about 70% decrease of BPND. The in vivo KD of [(18)F]AMG 580 was estimated to be around 0.44 nM in baboons. [(18)F]AMG 580 is a selective and potent PDE10A PET tracer with excellent specific striatal binding in non-human primates. It warrants further evaluation in humans.


Highly fluorescent dendrimers containing stilbene, and 4-styrylstilbene with resorcinarene cores: synthesis and optical properties.
Dendron conjugated branches of stilbene and 4-styrylstilbene groups have been attached to resor-cinarene cores. A noticeable effect in solution for all dendrimers was observed in the fluorescence quantum yield. The optical properties do not change with concentration in solution. The optical properties of thin films are identical to those of the solutions indicating the absence of intermolecular interactions. The dendrimers were characterized by 1H, 13C NMR, FTIR, UV-Vis, fluorescence spectroscopy, MALDI-TOF or FAB+ mass spectrometry, and elemental analysis.


An evaluation of commercial kits for creatine phosphokinase assay.
1. The evaluation of seven colorimetric and twelve kinetic or ultra-violet (UV) creatine phosphokinase (CPK) kit methods for their reliability as a diagnostic tool in clinical laboratories has revealed that over 35% of such commercial products readily available in Canada do not yield reliable results. 2. Six out of seven colorimetric kits failed to meet the criteria of minimum reliability as did one of the twelve UV kinetic kits.


Ultrasonographic features of splenic hemangiosarcoma in dogs: 18 cases (1980-1986).
The medical records of 18 dogs in which ultrasonography was useful in making a diagnosis of splenic hemangiosarcoma were reviewed. Splenic ultrasonography revealed masses with echo patterns that ranged from anechoic fluid to hyperechoic tissue. In 7 dogs, metastasis was detected ultrasonographically as anechoic to hypoechoic lesions in the liver.


Performance of Existing and Novel Symptom- and Antigen Testing-Based COVID-19 Case Definitions in a Community Setting.
Point-of-care antigen tests are an important tool for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection, yet are less clinically sensitive than real-time reverse-transcription polymerase chain reaction (RT-PCR), affecting their efficacy as screening procedures. Our goal in this analysis was to see whether we could improve this sensitivity by considering antigen test results in combination with other relevant information, namely exposure status and reported symptoms. In November 2020, we collected 3,419 paired upper respiratory specimens tested by RT-PCR and the Abbott BinaxNOW (Abbott Laboratories, Abbott Park, Illinois) antigen test at 2 community testing sites in Pima County, Arizona. We used symptom, exposure, and antigen-testing data to evaluate the sensitivity and specificity of various symptom definitions in predicting RT-PCR positivity. Our analysis yielded 6 novel multisymptom case definitions with and without antigen test results, the best of which overall achieved a Youden's J index of 0.66, as compared with 0.53 for antigen testing alone. Using a random forest as a guide, we show that this definition, along with our others, does not lose the ability to generalize well to new data despite achieving optimal performance in our sample. Our methodology is broadly applicable, and our code is publicly available to aid public health practitioners in developing or fine-tuning their own case definitions.


The relationship between indoor and outdoor Snellen visual acuity in cataract patients.
One hundred six cataractous eyes of 78 patients were evaluated to examine the relationship between indoor and outdoor Snellen visual acuity. While 81 of all cataractous eyes (76.4%) had Snellen visual acuities of 20/40 or better when tested indoors, only 33 eyes (31.2%) had 20/40 or better Snellen visual acuities when tested outdoors facing the sun. When tested indoors, only three eyes (2.8%) had Snellen visual acuities worse than 20/80, while 31 eyes (29.2%) had outdoor Snellen visual acuities worse than 20/80. Ten eyes (9.4%) had outdoor Snellen visual acuities worse than 20/200. Seventy-four eyes (69.8%) had outdoor visual acuities that were at least two Snellen lines worse than those measured indoors and 23 eyes (21.7%) had outdoor visual acuities that were at least five Snellen lines worse. The median difference between indoor and outdoor visual acuity was three Snellen lines. The need for increased precision in the ability to assess outdoor "real world" vision while in the ophthalmologist's examination room is discussed. Clearly, indoor Snellen visual acuity alone is insufficient to evaluate functional visual impairment in cataract patients.


Reasons for alcohol use by female heavy, moderate, and occasional social drinkers.
Subjective and behavioral reasons for drinking alcohol were elicited from 26 female social drinkers for 3 points in time by means of standardized questionnaire items selected from the Alcohol Use Inventory and the Alcoholic Stages Index. The 26 women resided for 35 days on a clinical research unit and could consume alcohol on 21 days. On the first study day subjects recalled subjective and behavioral reasons for drinking for the 21 days immediately prior to admission to the study and the 21 days of greatest alcohol consumption during the previous year. On the day after the end of the alcohol acquisition phase of the study, subjects responded to questions about their reasons for alcohol consumption during 21 days on the research unit. Each subject was classified as a heavy, moderate, or occasional drinker on the basis of observed alcohol intake. The heavy, moderate, and occasional drinkers differed significantly in history of alcohol use, and differences in questionnaire response patterns were reported for all 3 time intervals. In contrast to moderate and occasional drinkers, heavy social drinkers had significantly elevated questionnaire item scores for the 21 days of heaviest alcohol consumption during the past year and for the 21 days immediately prior to the study. However, both heavy drinkers and occasional social drinkers had significantly elevated scores for the 21-day alcohol acquisition phase on the research unit. Scores for moderate social drinkers were similar for each of the 3-time intervals.


Genomic- and protein-based approaches for connectin (titin) identification in the ascidian Ciona intestinalis.
Determining the complete primary structure of large proteins is difficult because of the large sequence size and low sequence homology among animals, as is the case with connectin (titin)-like proteins in invertebrate muscles. Conventionally, large proteins have been investigated using immuno-screenings and plaque hybridization screenings that require significant time and labor. Recently, however, the genomic sequences of various invertebrates have been determined, leading to changes in the strategies used to elucidate the complete primary structures of large proteins. In this paper, we describe our methods for determining the sequences of large proteins by elucidating the primary structure of connectin from the ascidian Ciona intestinalis as an example. We searched for genes that encode connectin-like proteins in the C. intestinalis genome using the BLAST search program. Subsequently, we identified some domains present in connectin and connectin-like proteins, such as immunoglobulin (Ig), fibronectin type 3 (Fn) and kinase domains in C. intestinalis using the SMART program and manual estimation. The existence of these domains and the unique sequences between each domain were confirmed using RT-PCR. We also examined the localization of mRNA using whole-mount in situ hybridization (WISH) and protein expression using SDS-PAGE. These analyses indicate that the domain structure and molecular weight of ascidian connectin are similar to those of vertebrate connectin and that ascidian connectin is also expressed in heart muscle, similarly to vertebrate connectin. The methods described in this study can be used to determine the primary structures of large proteins, such as novel connectin-like proteins in invertebrates.


Highly Stretchable, Self-Healing, and Low Temperature Resistant Double Network Hydrogel Ionic Conductor as Flexible Sensor and Quasi-Solid Electrolyte.
With the rapid development of flexible energy storage and wearable strain sensing, conductive hydrogels are attracting attention as electrolyte materials for flexible strain sensors and flexible supercapacitors due to their excellent flexibility and wetting properties. In this work, antifreezing hydrogels with high stretchability, adhesion, and conductivity are designed and prepared by introducing phosphoric acid solutions into polyacrylamide and chitosan systems. The multifunctional hydrogel samples prepared by this method can be used as both quasi-solid electrolytes and wearable strain sensors. The hydrogel-based supercapacitor shows a charge/discharge efficiency of 99.67% and a capacitance retention of 98.85% after 10 000 cycles charge/discharge tests at -30 °C. The tiny characteristic heartbeat wave forms are detected by the hydrogel as a flexible strain sensor. It is foreseeable that PCP multifunctional hydrogel can be a promising flexible material for a new generation of flexible sensors and flexible energy storage devices in a certain range of temperatures.


Adverse effects of methylphenidate on the reproductive axis of adolescent female rats.
To examine the effects of chronic methylphenidate use on the reproductive axis of adolescent female rats. Controlled prospective study. University research laboratory. Twenty prepubertal female Sprague Dawley rats. Subcutaneous implantation of drug-filled Alzet minipumps (Durect Corporation, Cupertino, CA) for infusing methylphenidate (450 microg/d, treated) or physiological saline (control) for 4 weeks. Estrous cyclicity was checked from 3 weeks of pump implantation till the termination of the experiments. Animals were killed after 4 weeks of treatment. Estrous cyclicity, pituitary and peripheral FSH and LH, serum estrogen and progesterone, ovarian histology, and immunocytochemistry for localizing growth differentiation factor-9 and activin receptors-I. Compared with the control group, the treated animals exhibited the following: [1] poor vaginal opening and erratic estrous cyclicity; [2] undeveloped, disrupted, or prematurely luteinized ovarian follicles; [3] absence of growth differentiation factor-9 and of activin receptors I and IB in the oocyte; and [4] high levels of LH in the pituitary. Chronic methylphenidate administration during adolescence perturbs pubertal onset, adversely affects maturation of the female reproductive axis by retarding pituitary LH release, and adversely affects ovarian folliculogenesis. These novel findings may have significant clinical implications in evaluating the effects of methylphenidate abuse on adolescent health.


Lignin-based non-crosslinked nanocarriers: A promising delivery system of pesticide for development of sustainable agriculture.
Lignin sulfonate (LS), a waste material from the paper pulping, was modified with benzoic anhydride to obtain benzoylated lignin sulfonates of adjustable hydrophilicity (BLS). When BLS was combined with difenoconazole (Di), a broad-spectrum fungicide, lignin-based, non-crosslinked nanoparticles were obtained either by solvent exchange or solvent evaporation. When a mass ratio of 1:5 LS: benzoic anhydride was used, the Di release from Di@BLS5 after 1248 h was ca. 74 %, while a commercial difenoconazole microemulsion (Di ME) reached 100 % already after 96 h, proving the sustained release from the lignin nanocarriers. The formulation of Di in lignin-based nanocarriers also improved the UV stability and the foliar retention of Di compared to the commercial formulation of the fungicide. Bioactivity assay showed that Di@BLS5 exhibited high activities and duration against strawberry anthracnose (Colletotrichum gloeosporioides). Overall, the construction of fungicide delivery nano-platform using BLS via a simple non-crosslinked approach is a novel and promising way to develop new formulations for nanopesticide and the development of sustainable agriculture.


Soft nanobrush-directed multifunctional MOF nanoarrays.
Controlled growth of well-oriented metal-organic framework nanoarrays on requisite surfaces is of prominent significance for a broad range of applications such as catalysis, sensing, optics and electronics. Herein, we develop a highly flexible soft nanobrush-directed synthesis approach for precise in situ fabrication of MOF nanoarrays on diverse substrates. The soft nanobrushes are constructed via surface-initiated living crystallization-driven self-assembly and their active poly(2-vinylpyridine) corona captures abundant metal cations through coordination interactions. This allows the rapid heterogeneous growth of MOF nanoparticles and the subsequent formation of MIL-100 (Fe), HKUST-1 and CUT-8 (Cu) nanoarrays with tailored heights of 220~1100 nm on silicon wafer, Ni foam and ceramic tube. Auxiliary functional components including metal oxygen clusters and precious metal nanoparticles can be readily incorporated to finely fabricate hybrid structures with synergistic features. Remarkably, the MIL-100 (Fe) nanoarrays doped with Keggin H3PMo10V2O40 dramatically boost formaldehyde selectivity up to 92.8% in catalytic oxidation of methanol. Moreover, the HKUST-1 nanoarrays decorated with Pt nanoparticles show exceptional sensitivity to H2S with a ppb-level detection limit.


Psychosocial Screening and Assessment Practice within Cardiac Rehabilitation: A Survey of Cardiac Rehabilitation Coordinators in Australia.
Many cardiac rehabilitation (CR) guidelines and position statements recommend screening for psychosocial risk factors, although there is wide variation in the recommended factors and recommended screening tools. Little is known about screening in CR in Australia. Cardiac rehabilitation coordinators at the 314 CR programs operating across Australia, drawn from the 2014 Australian Directory of Cardiac Rehabilitation Services were invited to participate in an online survey. Of 165 complete responses, 157 (95%) CR coordinators indicated that they screened at entry with 132 (80%) screening on exit. At CR entry, programs screened for - depression (83%), anxiety (75%), stress (75%), and sleep disturbance (57%). The use of standardised instruments by those screening at entry varied from 89% for depression to only 9% for sleep disturbance. Organisational, resource and personal barriers inhibited the routine screening for many psychosocial factors. Surveys such as this are useful for monitoring the rate of adoption of guideline recommendations and identifying barriers to implementation. Findings can also inform discussions about what should be included in minimum data sets for CR programs, and the identification of brief screening tools that have been validated not just in the general population but in cardiac patients.


Molecular cloning and heterologous expression analysis of JrVTE1 gene from walnut (Juglans regia).
Tocopherol cyclase (VTE1) plays a key role in promoting the production of γ-tocopherol and improving total tocopherol content in photosynthetic organisms. Walnut is an important source of tocopherols in the human diet, and γ-tocopherol is the major tocopherol compound in walnut kernels. In this study, a full-length cDNA of the VTE1 gene was isolated from walnut using RT-PCR and RACE, and designated as JrVTE1. The full-length cDNA of the JrVTE1 gene contained a 1353-bp open-reading frame encoding a 451-amino-acid protein with a calculated molecular weight of 49.5 kDa. The deduced JrVTE1 protein had a considerable homology with other plant VTE1s and belonged to the tocopherol cyclase family. Functional characterization of JrVTE1 by heterologous expression was carried out in E. coli BL21 (DE3) and microshoot lines of the fruit trees jujube (Zizyphus jujuba var. spinosa) and pear (Pyrus communis) cultivar 'Old Home'. JrVTE1 in E. coli expressed as a 50 kDa protein, as expected. One or two copies of the transferred JrVTE1 gene were detected in the genomes of representative transgenic lines (from the initial transgenic plants) of jujube and pear by gel blots analysis. Over-expression of JrVTE1 in jujube and pear resulted in an accumulation of tocopherol and a shift in tocopherol composition in leaf, root and stem tissues. In the transgenic jujube, the total tocopherol content increased by 29.8 μg/g in the stems of line J3, 43.7 and 22.5 μg/g in the roots and leaves of line J1, respectively, whereas in the transgenic pear it increased by 47.3 μg/g in the leaf of line P3, and 16.7 and 10.4 μg/g in roots and stems of line P9, respectively. In the examined tissues of transgenic plants, the highest accumulation rate was the γ-tocopherol. These results indicate that JrVTE1 is one of the rate-limiting enzymes for tocopherol production and could be used to improve the tocopherol content of tree crops through genetic engineering.


Chronic tick-borne encephalitis virus antigenemia: possible pathogenesis pathways.
Study of the proliferative potential and immunophenotype of lymphocytes and cytokine-producing capacity of mononuclear cells in patients with chronic tick-borne encephalitis virus antigenemia showed changes in T cell lymphoproliferative response, relative content of T cells and T helper inductors, immunoregulatory index, and imbalance in the production of immunoregulatory Th1 and Th2 cytokines.


[Problems of luxations and fractures of the mandible. A global summarizing overview].
A general synthesis of the diagnostic and therapeutic problems related with the mandibular contusions, luxations and fractures is proposed. Emphasis is laid on the evolution of treatment methods, particularly on the various osteosynthesis developed for the last twenty years.


Nup88 mRNA overexpression is associated with high aggressiveness of breast cancer.
The nuclear pore complex protein Nup88 is overexpressed in tumor cells. Immunohistochemical studies have shown that this overexpression is linked to higher aggressiveness of colorectal carcinoma and to enhanced metastatic potential of melanoma cells. However, the antibodies so far developed against Nup88 have the drawback of recognizing a number of other, up to now unspecified antigens besides Nup88. For this reason, we devised the present study on Nup88 expression at the mRNA level. RNA was extracted from fresh tumor tissue corresponding to 122 breast cancer patients. Nup88 mRNA expression was measured by means of differential RT-PCR, standardizing against a constitutive internal control gene (beta-actin). The results were dichotomized into "high" and "low" expression levels, using the median value as cut-off. High Nup88 mRNA expression levels correlated significantly with ductal and tubular histology (p = 0.012), histologic and nuclear grade 3 of tumors (p < 0.001), absence of hormone receptor expression (p < 0.001), expression of the c-erb-B2 oncogene (p < 0.001), expression of mutant p53 protein (p < 0.001), high proliferation (defined by Ki67 labeling index >20%, p < 0.001), DNA aneuploidy (p < 0.001) as well as the most important ominous clinical prognostic factor, axillary node invasion (p < 0.001). We also found an inverse correlation (p < 0.001) with expression of the H-MAM (mammaglobin) gene, a marker of low biologic and clinical aggressiveness of breast cancer. All of these factors, without exception, define a highly aggressive tumor phenotype. These findings appear to be specific to Nup88 and not to nuclear pore proteins in general. Indeed, analysis of Nup107 (which is a limiting component of the nuclear pore complex) under the same conditions in the same tumors did not yield comparable results.


Concurrent validity of palpation and musculoskeletal ultrasound in evaluating the fascia of individuals with and without myofascial pain syndrome.
Palpation evaluates the fascia, a three-dimensional web of connective tissues. We propose altered fascia system displacement in patients with myofascial pain syndrome. This study determined the concurrent validity of palpation and musculoskeletal ultrasound (MSUS) videos played on Windows Media Player 10 (WMP) when evaluating the direction of the fascia system's displacement at the end of the cervical active range of motion (AROM). This cross-sectional study used palpation as index test and MSUS videos on WMP as reference test. First, three physical therapists palpated right and left shoulders for each cervical AROM. Second, during cervical AROM, PT-Sonographer recorded the fascia system displacement. Third, using the WMP, the physical therapists evaluated the direction of skin, superficial and deep fascia displacements at the end of cervical AROM. MedCalc Version 19.5.3 determined the "exact" Clopper-Pearson Interval (CPI). We found strong accuracy between palpation and MSUS videos on WMP when determining the direction of skin displacement during cervical flexion and extension (CPI= 78.56 to 96.89). There was moderate agreement between palpation and MSUS videos on WMP when determining the direction of the skin, superficial fascia, and deep fascia displacements during cervical lateral flexion and rotation (CPI= 42.25 to 64.13). Skin palpation during cervical flexion and extension may be useful in evaluating patients with myofascial pain syndrome (MPS). It is unclear what fascia system was evaluated when shoulders were palpated at the end of cervical lateral flexion and rotation. Palpation as diagnostic tool for MPS was not investigated.


Non-invasive in situ Visualization of the Murine Cranial Vasculature.
Understanding physiologic and pathologic central nervous system function depends on our ability to map the entire in situ cranial vasculature and neurovascular interfaces. To accomplish this, we developed a non-invasive workflow to visualize murine cranial vasculature via polymer casting of vessels, iterative sample processing and micro-computed tomography, and automatic deformable image registration, feature extraction, and visualization. This methodology is applicable to any tissue and allows rapid exploration of normal and altered pathologic states.


Method and its Composition for encapsulation, stabilization, and delivery of siRNA in Anionic polymeric nanoplex: An In vitro- In vivo Assessment.
Small interfering RNA (siRNA) are synthetic RNA duplex designed to specifically knockdown the abnormal gene to treat a disease at cellular and molecular levels. In spite of their high potency, specificity, and therapeutic potential, the full-fledged utility of siRNA is predominantly limited to in vitro set-up. Till date, Onpattro is the only USFDA approved siRNA therapeutics available in the clinic. The lack of a reliable in vivo siRNA delivery carrier remains a foremost obstacle towards the clinical translation of siRNA therapeutics. To address the obstacles associated with siRNA delivery, we tested a dendrimer-templated polymeric approach involving a USFDA approved carrier (albumin) for in vitro as well as in vivo delivery of siRNA. The developed approach is simple in application, enhances the serum stability, avoids in vivo RNase-degradation and mediates cytosolic delivery of siRNA following the endosomal escape process. The successful in vitro and in vivo delivery of siRNA, as well as targeted gene knockdown potential, was demonstrated by HDAC4 inhibition in vitro diabetic nephropathy (DN) podocyte model as well as in vivo DN C57BL/6 mice model. The developed approach has been tested using HDAC4 siRNA as a model therapeutics, while the application can also be extended to other gene therapeutics including micro RNA (miRNA), plasmids oligonucleotides, etc.


Clinical Outcomes of Percutaneous Fontan Stenting in Adults.
Fontan pathway stenosis is a well-known complication after palliation. Percutaneous stenting is effective for angiographic/hemodynamic relief of Fontan obstruction, but its clinical impact in adults remains unknown. This was a retrospective cohort of 26 adults undergoing percutaneous stenting for Fontan obstruction from 2014 to 2022. Procedural details, functional capacity, and liver parameters were reviewed at baseline and during follow-up. Median age was 22.5 years (interquartile range [IQR] 19-28.8 y); 69% were male. After stenting, Fontan gradient significantly decreased (2.0 ± 1.9 vs 0 [IQR 0-1] mm Hg; P < 0.005), and minimal Fontan diameter increased (11.3 ± 2.9 vs 19.3 [IQR 17-20] mm; P < 0.001). One patient developed acute kidney injury periprocedurally. During a follow-up of 2.1 years (IQR 0.6-3.7 y), 1 patient had thrombosis of the Fontan stent and 2 underwent elective Fontan re-stenting. New York Heart Association functional class improved in 50% of symptomatic patients. Changes in functional aerobic capacity on exercise testing were directly related to pre-stenting Fontan gradient (n = 7; r = 0.80; P = 0.03) and inversely related to pre-stenting minimal Fontan diameter (r = -0.79; P = 0.02). Thrombocytopenia (platelet count < 150 109/L) was present in 42.3% of patients before and in 32% after the procedure (P = 0.08); splenomegaly (spleen size > 13 cm) was present in 58.3% and 58.8% (P = 0.57), respectively. Liver fibrosis (aspartate transaminase to platelet ratio index and Fibrosis-4) scores were unchanged after the procedure compared with baseline. Percutaneous stenting in adults is safe and effective in relieving Fontan obstruction, resulting in subjective improvement in functional capacity in some. A subset of patients demonstrated improvement in markers of portal hypertension, suggesting that Fontan stenting could improve Fontan-associated liver disease in select individuals.


Heart rate regulation during cycle-ergometer exercise via event-driven biofeedback.
This paper is devoted to the problem of regulating the heart rate response along a predetermined reference profile, for cycle-ergometer exercises designed for training or cardio-respiratory rehabilitation. The controller designed in this study is a non-conventional, non-model-based, proportional, integral and derivative (PID) controller. The PID controller commands can be transmitted as biofeedback auditory commands, which can be heard and interpreted by the exercising subject to increase or reduce exercise intensity. However, in such a case, for the purposes of effectively communicating to the exercising subject a change in the required exercise intensity, the timing of this feedback signal relative to the position of the pedals becomes critical. A feedback signal delivered when the pedals are not in a suitable position to efficiently exert force may be ineffective and this may, in turn, lead to the cognitive disengagement of the user from the feedback controller. This note examines a novel form of control system which has been expressly designed for this project. The system is called an "actuator-based event-driven control system". The proposed control system was experimentally verified using 24 healthy male subjects who were randomly divided into two separate groups, along with cross-validation scheme. A statistical analysis was employed to test the generalisation of the PID tunes, derived based on the average transfer functions of the two groups, and it revealed that there were no significant differences between the mean values of root mean square of the tracking error of two groups (3.9 vs. 3.7 bpm, [Formula: see text]). Furthermore, the results of a second statistical hypothesis test showed that the proposed PID controller with novel synchronised biofeedback mechanism has better performance compared to a conventional PID controller with a fixed-rate biofeedback mechanism (Group 1: 3.9 vs. 5.0 bpm, Group 2: 3.7 vs. 4.4 bpm, [Formula: see text]).


Plant species effects on soil nutrients and chemistry in arid ecological zones.
The presence of vegetation strongly influences ecosystem function by controlling the distribution and transformation of nutrients across the landscape. The magnitude of vegetation effects on soil chemistry is largely dependent on the plant species and the background soil chemical properties of the site, but has not been well quantified along vegetation transects in the Great Basin. We studied the effects of plant canopy cover on soil chemistry within five different ecological zones, subalpine, montane, pinyon-juniper, sage/Mojave transition, and desert shrub, in the Great Basin of Nevada all with similar underlying geology. Although plant species differed in their effects on soil chemistry, the desert shrubs Sarcobatus vermiculatus, Atriplex spp., Coleogyne ramosissima, and Larrea tridentata typically exerted the most influence on soil chemistry, especially amounts of K(+) and total nitrogen, beneath their canopies. However, the extent to which vegetation affected soil nutrient status in any given location was not only highly dependent on the species present, and presumably the nutrient requirements and cycling patterns of the plant species, but also on the background soil characteristics (e.g., parent material, weathering rates, leaching) where plant species occurred. The results of this study indicate that the presence or absence of a plant species, especially desert shrubs, could significantly alter soil chemistry and subsequently ecosystem biogeochemistry and function.


Bioconjugation of peptides using advanced nanomaterials to examine their interactions in 3D printed flow-through device.
Peptide-peptide interactions are crucial in the living cell as they lead to the formation of the numerous types of complexes. In this study, synthetic peptides containing 11 of cysteines (α-domain of metallothionein (MT)) and sialic acid binding region (130-loop of hemagglutinin (HA)) were employed. The aim of the experiment was studying the interactions between MT and HA-derived peptides. For this purpose, fragments were tagged with cysteines at C-terminal part to serve as ligand sites for PbS and CuS quantum dots (QDs), and therefore these conjugates can be traced and quantified during wide spectrum of methods. As a platform for interaction, γ-Fe2O3 paramagnetic particles modified with tetraethyl orthosilicate and (3-aminopropyl)triethoxysilane (hydrodynamic diameter 30-40 nm) were utilized and MT/HA interactions were examined using multi-instrumental approach including electrochemistry, electrophoretic methods, and MALDI-TOF/TOF mass spectrometry. It was found that peptides enter mutual creation of complexes, which are based on some of nonbonded interactions. The higher willingness to interact was observed in MT-derived peptides toward immobilized HA. Finally, we designed and manufactured flow-through electrochemical 3D printed device (reservoir volume 150 μL) and utilized it for automated analysis of the HA/MT metal labels. Under the optimal conditions, (deposition time and flow rate 80 s and 1.6 mL/min for CuS and 120 s and 1.6 mL/min PbS, respectively), the results of peptide-conjugated QDs were comparable with atomic absorption spectrometry.


Effect of drying methods on the gastrointestinal fate and bioactivity of phytochemicals from cocoa pod husk: In vitro and in silico approaches.
Cocoa pod husk (CPH) contains many nutraceutical phytochemicals whose gastrointestinal fate and bioactivity can be affected by drying methods. Microwave (MW), forced-air drying (AF), and AF plus extrusion (AF-E) dried CPH samples were chemically characterized, and their phenolic and theobromine (THB) contents were evaluated under oral-gastric-intestinal (in vitro) and colonic fermentation (ex vivo). Absorption, distribution, metabolism, excretion, and toxicity (ADEMT) properties of CPH's small molecules were evaluated in silico. The chemical composition of CPH [mostly carbohydrates/insoluble dietary fiber], polyphenol [total polyphenols > condensed tannin (CT) > monomeric flavonoids] differed minimally among samples, except for THB content (AF/AF-E > MW) and antioxidant capacity (MW > AF/AF-E). Time- trend gastrointestinal (X3 behavior) and colonic bioaccessibility were AF/AF-E > MW, but phenolic acids, procyanidins, and THB fluctuated in a sample-specific fashion. In silico modeling showed that bioactives of CPH easily crossed the intestinal epithelium illustrating their bioaccessibility and, permeability. These bioactives can act as receptor ligands in a structure-dependent manner, suggesting their use as a functional ingredient.


Lifetime Carcinogenic Risk Proportions from Inhalation Exposures in Industrial and Non-Industrial Regions.
The aim of this work was to estimate the share of selected significant risk factors for respiratory cancer in the overall incidence of this disease and their comparison in two environmentally different burdened regions. A combination of a longitudinal cross-sectional population study with a US EPA health risk assessment methodology was used. The result of this procedure is the expression of lifelong carcinogenic risks and their contribution in the overall incidence of the disease. Compared to exposures to benzo[a]pyrene in the air and fibrogenic dust in the working air, several orders of magnitude higher share of the total incidence of respiratory cancer was found in radon exposures, for women 60% in the industrial area, respectively 100% in the non-industrial area, for men 24%, respectively 15%. The share of risks in workers exposed to fibrogenic dust was found to be 0.35% in the industrial area. For benzo[a]pyrene, the share of risks was below 1% and the share of other risk factors was in the monitored areas was up to 85%. The most significant share in the development of respiratory cancer in both monitored areas is represented by radon for women and other risk factors for men.


miR-499 rs3746444 and miR-196a-2 rs11614913 Are Associated with the Risk of Glioma, but Not the Prognosis.
Previous studies of correlations of microRNA (miR)-499 rs3746444 and miR-196a-2 rs11614913 polymorphisms with glioma risk have yielded inconsistent results. In this study, relationships between these two polymorphisms and glioma risk and survival were evaluated. In total, 605 patients and 1,300 controls were genotyped. rs3746444 increased glioma risk in five genetic models (GA versus AA, odds ratio [OR], 95% confidence interval [CI] = 1.31 [1.05-1.66], p = 0.02; GG versus AA, OR [95% CI] = 10.70 [6.13-18.69], p < 0.0001; GA + GG versus AA, OR [95% CI] = 1.82 [1.47-2.24], p < 0.0001; GG versus AA + GA, OR [95% CI] = 9.99 [5.74-17.40], p < 0.0001; G versus A, OR [95% CI] = 2.18 [1.82-2.60], p < 0.0001). rs11614913 decreased glioma risk in a recessive model (OR [95% CI] = 0.79 [0.64-0.97], p = 0.03). No relationships between either SNP and survival were found. rs3746444 in the miR-499 seed region could affect target recognition. Bioinformatics analyses indicated that miR-499 rs3746444 is involved in various biological processes and pathways, including "cell adhesion molecule binding," "positive regulation of catabolic process," "NF-kappa B pathway," and "PI3K-Akt pathway," by targeting mRNAs. Our results suggested that miR-499 rs3746444 and miR-196a-2 rs11614913 have crucial roles in glioma susceptibility.


Myoepithelioma of soft tissue: A cytological-pathological correlation with literature review.
Myoepitheliomas of soft tissue are rare tumors with variable morphologic, immunohistochemical and molecular profiles and therefore are diagnostically challenging for pathologists. We report a case in a 60-year-old male with a painless slowly growing 3cm mass on left medial forefoot. Core biopsy of the mass showed a neoplastic proliferation of plasmacytoid tumor cells, consistent with myoepithelioma of soft tissue. Immunohistochemical stains demonstrated positivity of the tumor cells for cytokeratin AE1/AE3, CK18, S-100 protein and myosin heavy chain (SMMS-1), supporting the diagnosis. Fine-needle aspiration was performed intraoperatively before the resection of the mass. Air-dried Diff-Quik stained cytology slides showed singly scattered and loosely cohesive clusters of plasmacytoid and spindle cells with dense basophilic cytoplasm, distinct cytoplasmic borders, and round to oval mildly pleomorphic nuclei with smooth nuclear membrane. Scattered naked nuclei, binucleated tumor cells, as well as tumor cells with wispy elongated cytoplasm were also seen. Occasional clusters of cells were intimately associated with metachromatic fibrillary stromal material. Histologic examination of the resected tumor confirmed the diagnosis of myoepithelioma. Molecular studies showed absence of EWSR1 rearrangement. Cytological differential diagnosis, clinical, histological, immunohistochemical, and molecular features of soft tissue myoepitheliomas are discussed in this study.


Pharmacokinetics of a novel retinoid AGN 190168 and its metabolite AGN 190299 after intravenous administration of AGN 190168 to rats.
The pharmacokinetics of AGN 190168, a novel synthetic retinoid, and its major metabolite, AGN 190299, in rat blood after intravenous administration was investigated. Approximately 4.4 mg kg-1 (high dose) or 0.49 mg kg-1 (low dose) of AGN 190168 was administered to rats via the femoral vein. Blood was collected from the femoral artery at various time points during an 8 h period. Blood concentrations of AGN 190168 and AGN 190299 were determined by a specific and sensitive high-pressure liquid chromatographic (HPLC) method. AGN 190168 was rapidly metabolized in rats. The only detectable drug-related species in the blood was AGN 190299. Therefore, only pharmacokinetics of AGN 190299 were calculated. Elimination of AGN 190299 appeared to be non-linear after administration of the high dose, and linear after administration of the low dose. The maximum elimination rate (Vmax) and the concentration at half of the Vmax (km), as estimated by a Michaelis-Menten one-compartment model, were 7.58 +/- 2.42 micrograms min-1 (mean +/- SD) and 6.10 +/- 1.58 micrograms mL-1, respectively. The value of the area under the blood concentration time curve (AUC) was 9.54 +/- 1.68 micrograms h mL-1 after administration of the high dose and 0.594 +/- 0.095 micrograms h mL-1 after administration of the low dose. The clearance value was 7.79 +/- 1.20 mL min-1 kg-1 after the high dose, statistically significantly different from that after the low dose (p < 0.05), 14.0 +/- 2.2 mL min-1 kg-1. The terminal half-life (t1/2) was 1.25 +/- 0.74 h for the high-dose group and 0.95 +/- 0.16 h for the low-dose group. Study results demonstrate rapid systemic metabolism of AGN 190168 to AGN 190299, non-linear pharmacokinetics of AGN 190299 after the 4.4 mg kg-1 dose, and the lack of difference in disposition profiles between sexes after intravenous administration of AGN 190168 to rats.


Changes in the psychological defense mechanism and clinical features of patients with OCD - A four-year follow-up study.
The present study aims to (1) follow up with 4-year changes in the efficacy outcome, defense style questionnaire (DSQ) score, and clinical features of patients with obsessive-compulsive disorder (OCD) and (2) analyze the relationship between different levels of efficacy and changes in the patients' psychological defense mechanisms. The following data collection and 4-year follow-up were completed for 153 patients with OCD: (1) the treatment process, efficacy outcome, course of disease, and clinical features of OCD were collected using a self-made general information questionnaire and (2) the control method was used to analyze the changes in clinical symptoms (Yale-Brown obsessive compulsive scale [YBOCS], Hamilton anxiety score [HAMA], and Hamilton depression scale [HAMD]) in patients with OCD. Moreover, the changes in the psychological defense mechanism (measured by DSQ) and the relation between the prognosis and DSQ score were investigated. (1) The HAMA score (8.7 ± 4.8 points), HAMD score (12.0 ± 6.6 points) and YBOCS score (16.4 ± 8.4 points) were significantly lower during the follow-up than at the time of enrollment (p < 0.01). In the two DSQ evaluations, there were no significant differences in the factors, with the exception of a significant decrease in the use of "reaction formation" (t = 2.533, p = 0.015). The changes of mature defense factors in the significant efficacy group significantly increased (p < 0.01). Which was mainly manifested in the significant increase in the score of "sublimation" item, and the difference was extremely significant (t = -3.093, p = 0.006). An abnormal psychological defense mechanism plays an important role in OCD, and the use of a mature defense mechanism is significantly related to the treatment efficacy.


Phenothiazine effect on gastrointestinal tract function.
Clinical evidence indicates that phenothiazines, specifically chlorpromazine (CPZ), used extensively in the treatment of patients with mental and/or neurologic disorders produce an ileus characterized by pseudoobstruction with an extended barium transit time of eight to ten days. Postoperatively, these patients have a protracted ileus, lasting from ten to fourteen days. In our present study we investigated the mechanism of action by which phenothiazines block gastrointestinal tract function as well as the possible reversal of this effect by pharmacologic agents. Guinea pigs were injected intraperitoneally with CPZ at a dose of 30 mg/kg/day for five to seventeen days. This caused deleterious effects in the gastrointestinal tract, such as cessation of peristalsis of small intestine and colon, and marked distension of the cecum. In vitro pharmacologic studies were performed on the electrically stimulated longitudinal muscle-myenteric plexus of the guinea pigs. We found that phenothiazines interfered with the neuromuscular mechanism of the intestine, as exemplified by a lack of response to electrical current stimulation. The effect was protracted, lasting at least 24 hours. These effects were reversed by the administration of the anticholinesterase, physostigmine (PGM), provided the block was less than 80 per cent. The paralytic ileus produced was similar to that found in man.


Novel CRISPR/Cas12a-based genetic diagnostic approach for SLC26A4 mutation-related hereditary hearing loss.
Hereditary hearing loss is a common defect of the auditory nervous system with high-incidence, seriously affecting the quality of life of the patients. The clinical manifestations of SLC26A4 mutation-related hearing loss are congenital sensorineural or mixed deafness. Sensitive and specific SLC26A4 mutation detection in the early clinical stage is key for the early indication of potential hearing loss in the lack of effective treatment. Using clustered regularly interspaced short palindromic repeats (CRISPR)-based nucleic acid detection technology, we designed a fast and sensitive detection system for SLC26A4 pathogenic mutations (c.919-2A > G, c.2168A > G and c.1229C > T). This recombinase-aided amplification-based detection system allows rapid target gene amplification and, in combination with the CRISPR-based nucleic acid testing (NAT) system, mutation site detection. Moreover, mismatches were introduced in CRISPR-derived RNA (crRNA) to increase signal differences between the wild-type genes and mutant genes. A total of 64 samples were examined using this approach and all results were verified using Sanger sequencing. The detection results were consistent with the polymerase chain reaction-Sanger sequencing results. Overall, this CRISPR-based NAT technology provides a sensitive and fast new approach for the detection of hereditary deafness and provides a crRNA optimization strategy for single-nucleotide polymorphism detection, which could be helpful for the clinical diagnosis of SLC26A4 mutation-related hereditary hearing loss.


Decoupling the adsorption mechanisms of arsenate at molecular level on modified cube-shaped sponge loaded superparamagnetic iron oxide nanoparticles.
In this study, a commercial cube-shaped open-celled cellulose sponge adsorbent was modified by in-situ co-precipitation of superparamagnetic iron oxide nanoparticles (SPION) and used to remove As(V) from aqueous solutions. Fe K-edge X-ray absorption spectroscopy (XAS) and TEM identified maghemite as the main iron phase of the SPION nanoparticles with an average size 13 nm. Batch adsorption experiments at 800 mg/L showed a 63% increase of adsorption capacity when loading 2.6 wt.% mass fraction of SPION in the cube-sponge. Experimental determination of the adsorption thermodynamic parameters indicated that the As(V) adsorption on the composite material is a spontaneous and exothermic process. As K-edge XAS results confirmed that the adsorption enhancement on the composite can be attributed to the nanoparticles loaded. In addition, adsorbed As(V) did not get reduced to more toxic As(III) and formed a binuclear corner-sharing complex with SPION. The advantageous cube-shape of the sponge-loaded SPION composite together with its high affinity and good adsorption capacity for As(V), good regeneration capability and the enhanced-diffusion attributed to its open-celled structure make this adsorbent a good candidate for industrial applications.


[The influence of postgraduate studies in Berlin on the research activity of Władysław Biegański].
The authors showed that Władysław Biegański's postgraduate studies in Berlin played a significant rule in his scientific activity. They also presented the impact of lectures of F.T. Frerichs, S. Henoch, F.K. Westphal and R. Virchow. His stay in Berlin was for Biegański an advantage, giving him the opportunity to improve his medical knowledge, encouraged him to scientific works and made him aware of significance of problems connected with the theory of medical studies.


Aspergillus and endobronchial abnormalities in lung transplant recipients.
To determine the relationship between aspergillus recovery from the airways of lung transplant recipients and the development of endobronchial abnormalities. Retrospective case series. Tertiary-care hospital. All patients who underwent lung transplantation between December 1991 and June 1999. The study cohort included 38 patients. The primary end point was the bronchoscopic identification of an endobronchial abnormality. Aspergillus was isolated from the lungs of nine patients (23.7%). Most of these isolates occurred early after transplantation (mean, 8 weeks). Endobronchial abnormalities arose in seven of the patients (18.4%) and manifested as either exuberant granulation tissue or stricture formation. Six of the 9 (66.6%) patients with aspergillus developed airway lesions, compared to 1 of the 29 patients (3.4%) without aspergillus (p = 0.0002). Endobronchial abnormalities were 19.3 times more likely to occur in patients in whom aspergillus had previously been isolated. As a screening test for the subsequent diagnosis of an airway complication, the recovery of aspergillus had a sensitivity and specificity of 85.7% and 90.3%, respectively. These aspergillus-related endobronchial abnormalities were clinically relevant as evidenced by a mean increase of 25.9% in the FEV(1) after bronchoscopic intervention. The early isolation of aspergillus from the airways of lung transplant recipients identifies patients at increased risk for the development of clinically significant endobronchial abnormalities.


'Healthcare Estates' to focus on reforms. Harrogate International Centre, 1-2 November 2005.
The Institute of Healthcare Engineering and Estate Management's (IHEEM) Healthcare Estates Conference and Exhibition is the leading national event for professionals in the field of estate planning, facilities management and healthcare engineering. According to IHEEM president Richard Nugent, the time is now right for estates and facilities professionals to seize the "once in a lifetime" opportunity to play their part increating a health service with facilities that are the envy of the world.


Comparison of Component-Resolved Diagnosis by Using Allergen Microarray With the Conventional Tests in Allergic Rhinitis Patients: The First Using in Korea.
The aim of this study was to evaluate the component-resolved diagnosis using a microarray allergen chip (Immuno Solid-phase Allergen Chip, ImmunoCAP ISAC) and to compare this new diagnostic tool with the established ImmunoCAP methods for allergen-specific IgE detection in allergic rhinitis patients. One hundred sixty-eight allergic rhinitis patients were included in this study. All the patients were diagnosed with allergic rhinitis according to their clinical symptoms, physical examination and a positive skin prick test. We analyzed their specific IgEs for house dust mites (Dermatophagoides farine [DF] and Dermatophagoides pteronyssinus [DP]), Alternaria alternata, birch, and mugwort using ImmunoCAP and ImmunoCAP ISAC in the same patient sample. We compared the sensitivity and correlation between the two tests. In cases of allergies to DP and DF, the sensitivity of the specific IgE was 80% and that of the allergen microarray was 78.9%. The correlation between the two tests was significant for both DP and DF (P<0.001). For the A. alternata, birch and mugwort allergens, the sensitivity of ImmunoCAP ISAC was slightly lower than that of ImmunoCAP. These results suggest that the allergen microarray chip method is a reliable new method to diagnose the components of an allergen in patients with allergic rhinitis sensitive to house dust mites. Further study about the utility of the allergen microarray is needed.


Multidimensional scaling locus of memristor and fractional order elements.
This paper combines the synergies of three mathematical and computational generalizations. The concepts of fractional calculus, memristor and information visualization extend the classical ideas of integro-differential calculus, electrical elements and data representation, respectively. The study embeds these notions in a common framework, with the objective of organizing and describing the "continuum" of fractional order elements (FOE). Each FOE is characterized by its behavior, either in the time or in the frequency domains, and the differences between the FOE are captured by a variety of distinct indices, such as the Arccosine, Canberra, Jaccard and Sørensen distances. The dissimilarity information is processed by the multidimensional scaling (MDS) computational algorithm to unravel possible clusters and to allow a direct pattern visualization. The MDS yields 3-dimensional loci organized according to the FOE characteristics both for linear and nonlinear elements. The new representation generalizes the standard Cartesian 2-dimensional periodic table of elements.


Microstructural integrity of the corpus callosum linked with neuropsychological performance in adolescents.
Diffusion tensor imaging (DTI) has revealed microstructural aspects of adolescent brain development, the cognitive correlates of which remain relatively uncharacterized. DTI was used to assess white matter microstructure in 18 typically developing adolescents (ages 16-18). Fractional anisotropy (FA) and mean diffusion (MD) were evaluated within the splenium and body of the corpus callosum in relation to cognitive performance. Visuospatial construction abilities were associated with white matter integrity in both the splenium and body of the corpus callosum, while only splenium integrity was associated with language and psychomotor function. Results suggest that, for typically developing adolescents, white matter coherence positively relates to visuospatial, psychomotor, and language skills. These findings may have implications for the cognitive functioning of clinical populations in which typical white matter development is altered.


Assessing the Moderating Effect of the End User in Consumer Behavior: The Acceptance of Technological Implants to Increase Innate Human Capacities.
Today, technological implants are being developed to increase innate human capacities, such as memory or calculation speed, and to endow us with new ones, such as the remote control of machines. This study's aim was two-fold: first, to introduce a Cognitive-Affective-Normative (CAN) model of technology acceptance to explain the intention to use this technology in the field of consumer behavior; and second, to analyze the differences in the intention to use it based on whether the intended implant recipient is oneself or one's child (i.e., the moderating effect of the end user). A multi-group analysis was performed to compare the results between the two groups: implant "for me" (Group 1) and implant "for my child" (Group 2). The model largely explains the intention to use the insideable technology for the specified groups [variance explained (R (2)) of over 0.70 in both cases]. The most important variables were found to be "positive emotions" and (positive) "subjective norm." This underscores the need to broaden the range of factors considered to be decisive in technology acceptance to include variables related to consumers' emotions. Moreover, statistically significant differences were found between the "for me" and "for my child" models for "perceived ease of use (PEU)" and "subjective norm." These findings confirm the moderating effect of the end user on new insideable technology acceptance.


Scaling up human mesenchymal stem cell manufacturing using bioreactors for clinical uses.
Human mesenchymal stem cells (hMSCs) are multipotent cells and an attractive therapeutic agent in regenerative medicine and intensive clinical research. Despite the great potential, the limitation that needs to be overcome is the necessity of ex vivo expansion because of insufficient number of hMSCs presented within adult organs and the high doses required for a transplantation. As a result, numerous research studies aim to provide novel expansion methods in order to achieve appropriate numbers of cells with preserved therapeutic quality. Bioreactor-based cell expansion provide high-level production of hMSCs in accordance with good manufacturing practice (GMP) and quality standards. This review summarizes current knowledge about the hMSCs manufacturing platforms with a main focus to the application of bioreactors for large-scale production of GMP-grade hMSCs.


The Influence of Occupation on Self-perceived Vocal Problems in Patients With Voice Complaints.
This study aimed to examine the relationships among patient occupation, laryngeal diagnosis, perceptual dysphonia severity, and patient-perceived voice impairment. Adult patients presenting with a chief complaint of dysphonia over a 20-month period at a tertiary care, interdisciplinary voice center were included in this retrospective cohort study. Patients were categorized by profession: vocal performers, high occupational voice demand, low or no occupational voice demand, and retired. Associations between professional voice demand and clinician rating of dysphonia severity using the "Grade" score from the Grade, Roughness, Breathiness, Asthenia, and Strain scale and patient ratings of voice impairment using the Voice Handicap Index-10 (VHI-10) were tested using standard descriptive statistical methods. One hundred and sixty-three patients with a presenting complaint of dysphonia were evaluated. Significant associations were found on univariate and multivariable analysis among a patient's occupational voice demand, Grade, Roughness, Breathiness, Asthenia, and Strain grade, and VHI-10 score (P = 0.007 and P < 0.001, respectively). Patients subject to greater vocal demands as a result of their occupation had a greater perception of impairment, regardless of acoustic-perceptual severity, when compared with those with low or no occupational voice demand. Although voice diagnosis was significantly associated with VHI-10 score on univariate analysis, it failed to reach significance on multivariable analysis. Demographic measures such as gender and age also did not correlate with perceived vocal impairment. Patient-perception of voice impairment is influenced by occupational demand, independent of acoustic-perceptual dysphonia. Performers and people with high occupational voice needs demonstrate a unique sensitivity to subtle voice changes.


Socioeconomic gradients in the Westernization of diet in China over 20 years.
In low-middle income countries, urbanization leads to changes from traditional to Western diet, which are often accompanied by reductions in cardiometabolic health. Whether socioeconomic status buffers these urbanization-related diet changes over time is unknown. To examine whether the association between urbanization and a key indicator of Western diet, percent of calories from animal-source foods (1) varies depending on income and (2) whether this association changes over time. We used data from nine waves of the longitudinal, population-based China Health and Nutrition Survey [n = 22,360 Chinese adults (1991-2015)], followed across 24 years, including diet data from 3 repeated 24-h dietary recalls. We used simultaneous year-stratified linear regression models to examine whether changes in the association between urbanization level and percent of calories from animal-source foods differed by income. Models allowed for variation in associations across the 24 years of urbanization, accounting for within-individual correlation over time and controlling for age, sex, region, physical activity, and caloric intake. In 1991, on average 15% of calories for Chinese adults came from animal source foods and by 2015, this percentage rose to approximately one quarter of total calories. Over the 24 years of follow-up, urbanization and income were each strongly related to percent of calories from animal-source foods with differential association across income levels (p < 0.0001). We also found evidence that this association changed over time (p < 0.0001). Income gradients in animal source food consumption were smallest in the most urban areas in early years with some temporal variation, but over time income gradients narrowed in some later years in low and moderately urbanized areas. However, by 2015 there were few income differences in animal source food consumption across urbanization levels. Throughout 24-years of urbanization, income seemed to buffer the transition from traditional to Western diet. However, the degree to which income buffered these urbanization-related changes depended on the level and history of community urbanization. At later stages of urbanization when Western diet behaviors were more widespread, urban-rural differences in Western diet behaviors varied little by income.


Hormone therapy of prostate cancer: is there a role for antiandrogen monotherapy?
Androgen suppressive maneuvers still represent the gold standard for prostate cancer patients. However, they are associated with side effects (fatigue, sexual impotence, hot flushes, anemia, anxiety, depression and osteoporosis) all of which have a negative impact on quality of life. Nonsteroidal antiandrogens compete with dihydrotestosterone for the linkage of its own receptors. These compounds are commonly used in combination with suppressive maneuvers. However, there is a growing experience with them as monotherapy, based on the possibility to spare gonadal function and therefore prevent the effects related to its suppression. Many studies have demonstrated the feasibility and safety of this approach, which can represent a valuable alternative to suppressive maneuvers for patients wishing to retain sexual function, especially for those without distant metastases. Unfortunately, none of the comparative studies performed so far had the power to detect the equivalence between monotherapy and castration.


Genes of Different Catabolic Pathways Are Coordinately Regulated by Dal81 in Saccharomyces cerevisiae.
Yeast can use a wide variety of nitrogen compounds. However, the ability to synthesize enzymes and permeases for catabolism of poor nitrogen sources is limited in the presence of a rich one. This general mechanism of transcriptional control is called nitrogen catabolite repression. Poor nitrogen sources, such as leucine, γ-aminobutyric acid (GABA), and allantoin, enable growth after the synthesis of pathway-specific catabolic enzymes and permeases. This synthesis occurs only under conditions of nitrogen limitation and in the presence of a pathway-specific signal. In this work we studied the temporal order in the induction of AGP1, BAP2, UGA4, and DAL7, genes that are involved in the catabolism and use of leucine, GABA, and allantoin, three poor nitrogen sources. We found that when these amino acids are available, cells will express AGP1 and BAP2 in the first place, then DAL7, and at last UGA4. Dal81, a general positive regulator of genes involved in nitrogen utilization related to the metabolisms of GABA, leucine, and allantoin, plays a central role in this coordinated regulation.


[Victor Khrisanfovich Kandinsky (1849-1889) : Contributions of a Russian psychiatrist to the concepts of pseudohallucination and schizophrenias].
The article highlights the important work of the Russian psychiatrist Victor Khrisanfovich Kandinsky. His merits, in particular those in the fields of hallucinations and schizophrenias, have hitherto been neglected despite the fact that several of his articles have been published in German medical journals. He defined the term pseudohallucination in a way which is still common today. For him the criterion which separates it from real hallucinations was that the patient is aware of the fallacy of the phenomena perceived. Furthermore, his concept of ideophrenia can be regarded as a one of the precursors to today's concept of schizophrenias.


[Epidemiological study of diabetes in the occupational environment].
Fasting blood sugar was determined in 277 subjects with early forms of silicosis during statutory outpatient examinations. Values were related to the clinical and occupational history and objective and blood chemistry parameters. The results showed that epidemiological examination is useful in the prevention and early diagnosis of diabetes in occupational environments.


Open abdomen treatment after aortic aneurysm repair with vacuum-assisted wound closure and mesh-mediated fascial traction.
Open abdomen (OA) treatment is sometimes necessary after surgery for aortic aneurysm (AA), to prevent or treat abdominal compartment syndrome (ACS). A multicentre study evaluating vacuum-assisted wound closure (100-150 mmHg) and mesh-mediated fascial traction (VAWCM) was performed. All patients treated with OA after AA repair (2006-2009) were prospectively registered at four centres; those treated <5 days were excluded. All surviving patients underwent a 1-year follow-up, including computed tomography (CT) examination. Among 1041 patients treated with open or endovascular repair of AA, 28 (2.9%) had OA treatment with VAWCM; another two had VAWCM after hybrid operations for thoraco-abdominal AA. Eighteen (60%) were operated on for rupture and 12 (40%) electively. Eight had suprarenal or thoraco-abdominal aneurysms. Eight (27%) died within 30 days, none due to OA-related complications. Four died before abdominal closure; primary delayed fascial closure was achieved in all survivors. One-year mortality was 50%. Ten (33%) had bowel ischaemia requiring bowel resection. Late potential OA-related infectious complications occurred in five (17%), all of whom first developed intestinal ischaemia: entero-atmospheric fistulae (two), graft infections (two), aorto-enteric fistula (one). One year follow-up with clinical evaluation and CT showed no signs of graft infection. Incisional hernias occurred in 9 of 15 patients (60%); only three were symptomatic. VAWCM provided high fascial closure rate after AA repair and long-term OA treatment. Infectious complications occur after intestinal ischaemia and prolonged OA treatment, and are often fatal. The poor prognosis among patients needing OA after AA surgery may be improved by using VAWCM, permitting earlier closure.


TRAF7 enhances ubiquitin-degradation of KLF4 to promote hepatocellular carcinoma progression.
The tumor necrosis factor receptor-associated factor 7 (TRAF7) is a component of the tumor necrosis factor alpha (TNF-α)/nuclear factor kappa B (NF-κB) pathway and is a putative E3-ubiquitin ligase. Based on importance of chronic inflammation in hepatocellular carcinoma (HCC), we investigated the biological effects and the molecular mechanisms of deregulated TRAF7 signaling in HCC. Our results showed that high TRAF7 expression in HCC samples was inversely associated with Krüppel-like factor 4 (KLF4) expression and the prognosis of HCC patients. TRAF7 could degrade KLF4 protein through ubiquitin by interacting with its N-terminus. The up-regulation of TRAF7 promoted HCC cell migration and invasion in vivo and in vitro, and TRAF7 knockdown had the opposite effects. Restoration of KLF4 abrogated the motility promotion induced by TRAF7. TRAF7 promotes HCC cell motility through inducing KLF4 protein turnover.


Glucose metabolism and the channeling of glycolytic intermediates in permeabilized L-929 cells.
L-929 cells (mouse fibroblasts) permeabilized with dextran sulfate (DSP cells) carry out vigorous and linear rates of glycolysis when supplied with a suitable incubation medium. Glycolysis in DSP cells is pH dependent, being strongly inhibited at pH 6.5. Compared to their nonpermeabilized counterparts, DSP cells exhibit faster glycolytic rates, but tend to convert a smaller proportion of the glucose utilized to lactate. [14C]Glucose is converted to lactate by DSP cells without dilution from endogenous substrates. When exogenous 12C-labeled glycolytic intermediates (12C-I) are added to glycolyzing DSP cells the [14C]lactate produced from [14C]glucose is diluted to varying extents, depending on the intermediate. However, the extent of that dilution (reduced specific activity) is not that expected from the complete mixing of exogenous 12C-I with their corresponding 14C-labeled intermediates coming from [14C]-glucose. DSP cells also respire and convert glucose to CO2. The amount of 14CO2 produced from [14C]glucose is also reduced by addition of most 12C-I, an interesting exception being pyruvate, which had no measurable effect on 14CO2 production and caused only a modest stimulation of respiration in glycolyzing DSP cells. These results suggest that channeling, or some other form of coupling, takes place between the glycolytic production of pyruvate and its further oxidation. These observations confirm previously published data and add further support to the proposition that channeling of glycolytic intermediates occurs in DSP cells but is of the "leaky" type. Although abundant evidence in the literature indicates that various glycolytic enzymes associate with F-actin, as well as other elements of the cytomatrix, we observed no effect of cytochalasin D on lactate production even at very high concentrations of this compound. Our results are compared with those from other laboratories and discussed in the context of metabolic organization.


Intracavitary administration of OK-432 with subcutaneous priming for malignant ascites in a case of advanced renal cell carcinoma.
The intracavitary injection of OK-432 (a streptococcal preparation) with subcutaneous priming has been shown to be an effective immunotherapy for patients with malignant effusion. We applied this treatment in a case of advanced renal cell carcinoma with massive ascites. The patient received 0.2 Klinishe Einheit (KE) OK-432 in the subcutaneous injection twice (day 1 and day 7) followed by 10KE OK-432 intra-abdominal administration (day 9). The treatment was performed safely without major side-effects except for transient pyrexia. A significant reduction of ascites was noted 1 month after the treatment without subsequent re-accumulation. Intracavitary injection of OK-432 with subcutaneous priming seems to be a simple, safe and effective treatment for ascites in advanced renal cell carcinoma.


A method for determining B1 field inhomogeneity. Are the biases assumed in heteronuclear relaxation experiments usually underestimated?
We describe a method allowing the determination of the effective B1 field amplitude distribution in a high-resolution NMR spectrometer. This method which can be adapted to almost any sequence, essentially consists of a mutation followed by a purging B0 gradient pulse. Experimental results obtained with this approach are described in homonuclear and heteronuclear cases. The experimental distributions are used to estimate the biases induced by B1 inhomogeneity, as well as the loss of RF power on heteronuclear transverse self-relaxation rate determination. In this type of measurement, the experimental biases induced on the intensities can be as large as 5% for long mixing times.


Olfactory bulb removal decreases androgen receptor binding in amygdala and hypothalamus and disrupts masculine sexual behavior.
In these experiments we examined the relationship between olfactory bulb removal, limbic system androgen receptor binding and male copulatory behavior. Sexually experienced male rats were castrated, and implanted with two 10 mm testosterone-filled silastic capsules. Animals then underwent either bilateral olfactory bulb removal (BOB) or sham surgery (Sham). Beginning 1-2 days postoperatively both BOB and Sham operates were given 4 tests for male copulation on alternate days. Less than 40% of BOB males ejaculated. In contrast, 80-100% of sham operates continued to ejaculate throughout the 4 postoperative tests. Cell nuclear androgen receptor binding was assessed in amygdala, hypothalamus, preoptic area and septum 1-2 and 8-9 days after either bulbectomy or sham surgery. We found that olfactory bulbectomy significantly reduces androgen receptor binding in amygdala and hypothalamus. The reduction in androgen receptor binding in amygdala occurs within 1-2 days following olfactory bulb removal and is correlated with the disruption of ejaculatory activity. These data suggest that the neuromodulation by olfactory bulb input to androgen-concentrating neurons in the amygdala and hypothalamus is necessary for effective copulation in male rats.


Medial Patellofemoral Ligament Reconstruction and Lateral Retinacular Lengthening in the Skeletally Immature Patient.
Patellar instability remains a ubiquitous and troublesome problem in orthopaedics and represents a challenge in the pediatric population. Reconstruction of the medial patellofemoral ligament (MPFL) has become a mainstay of patellar instability management in recent years. As with any procedure at or around the physes, there is concern among surgeons regarding safe placement of hardware and drilled tunnels. The authors describe a technique for anatomic MPFL reconstruction with the aid of fluoroscopic guidance to maintain a "safe zone" without violating the distal femoral physis. This technique allows for reliable MPFL reconstruction in the skeletally immature population with concomitant lateral lengthening, while requiring only minor deviations from the procedure in a skeletally mature patient.


Calixarene building block bis(2-hydroxyphenyl)methane (2HDPM) and hydrogen-bonded 2HDPM-H₂O complex in electronic excited state.
Intramolecular and intermolecular hydrogen bonding in electronic excited states of calixarene building blocks bis(2-hydroxyphenyl)methane (2HDPM) monomer and hydrogen-bonded 2HDPM-H₂O complex were studied theoretically using the time-dependent density functional theory (TDDFT). Twenty-four stable conformations (12 pairs of enantiomers) of 2HDPM monomer have been found in the ground state. From the calculation results, the conformations 1a and 1b which both have an intramolecular hydrogen bond are the most stable ones. The infrared spectra of 2HDPM monomer and 2HDPM-H₂O complex in ground state and S₁ state were calculated. The stretching vibrational absorption band of O₂-H₃ group in the monomer and complex disappeared in the S1 state. At the same time, a new strong absorption band appeared at the C=O stretching region. From the calculation of bond lengths, it indicates that the O₂-H₃ bond is significantly lengthened in the S₁ state. However, the C₁-O₂ bond is drastically shortened upon electronic excitation to the S₁ state and has the characteristics of C=O band. Furthermore, the intramolecular hydrogen bond O₂-H₃ · · · O₄ of the 2HDPM monomer and the intermolecular hydrogen bonds O₂-H₃ · · · O₇ and O₇- H₉...O₄ of 2HDPM-H₂O complex are all shortened and strengthened in the S₁ state.


Mesoderm-specific B104 expression in the Drosophila embryo is mediated by internal cis-acting elements of the transposon.
The Drosophila melanogaster genome contains about 100 copies of the B104 transposable element, which is strongly expressed during embryogenesis. Here we show that B104 expression is restricted to the esophageal and amnioproctodeal regions of the embryo and to the developing mesoderm. Mesoderm-specific B104 expression requires the activity of the mesoderm-determining factors twist and snail. Virtually the same expression patterns were observed in Drosophila yakuba, a species that a separated from D. melanogaster by some 15 million years of evolution. We show that B104 expression is directed by internal sequences of the retrotransposon that are capable of acting as a cis-acting regulatory element in front of a heterologous Drosophila promoter. Our findings suggest that retrotransposon insertions can affect the expression patterns of endogenous genes by adding and distributing specific cis-acting control elements throughout the host genome. We therefore propose that transposable elements in addition to reducing the fitness of their hosts may also provide a rich pool of cis-acting sequences that contribute to the long-term evolutionary potential of the population in a beneficial manner.


Lateral suppression of rhythmic evoked responses in the dolphin's auditory system.
In the auditory system of bottlenose dolphins (Tursiops truncatus), a brain-evoked response to rhythmic sound amplitude modulations (the envelope-following response) was markedly suppressed by addition of another sound with a frequency 5-20 kHz higher and an intensity down to 40 dB lower than that of the amplitude-modulated signal. This effect was called paradoxical lateral suppression. This phenomenon was primarily observed when the amplitude-modulated stimulus had a carrier frequency above 30 kHz and modulation rates above 500 Hz. Only the sustained rhythmic response was suppressed, while the transient on-response was not. This indicates that the suppression influenced the ability of evoked potentials to follow rapid amplitude modulations. This prevents weak sounds from being masked by stronger ones.


The preparation and properties of immobilised dipeptidyl-aminopeptidase I (cathepsin C).
Dipeptidyl-aminopeptidase I (dipeptidyl-peptide hydrolase, EC 126.96.36.199) from bovine spleen has been immobilized by hydrophobic bonding to alkyl- or aryl-Sepharoses. Optimum binding occurred with octyl- and phenyl-Sepharoses. The activity of the immobilised dipeptidyl-aminopeptidase I has been determined using glycylarginyl-p-nitroanilide as substrate and the pH optimum of the immobilised enzyme determined as well as the stability of the enzyme to repeated use. Preliminary studies using immobilised dipeptidyl-aminopeptidase I for the digestion of methionine enkephalin have been carried out using reverse-phase HPLC to analyse the reaction.


A neural network theory of proportional analogy-making.
A neural network model that can simulate the learning of some simple proportional analogies is presented. These analogies include, for example, (a) red-square:red-circle :: yellow-square:?, (b) apple:red :: banana: ?, (c) a:b :: c:?. Underlying the development of this network is a theory for how the brain learns the nature of association between pairs of concepts. Traditional Hebbian learning of associations is necessary for this process but not sufficient. This is because it simply says, for example, that the concepts "apple" and "red" have been associated, but says nothing about the nature of this relationship. The types of context-dependent interlevel connections in the network suggest a semilocal type of learning that in some manner involves association among more than two nodes or neurons at once. Such connections have been called synaptic triads, and related to potential cell responses in the prefrontal cortex. Some additional types of connections are suggested by the problem of modeling analogies. These types of connections have not yet been verified by brain imaging, but the work herein suggests that they may occur and, possibly, be made and broken quickly in the course of working memory encoding. These working memory connections are referred to as differential, delayed and anti-Hebbian connections. In these connections, one can learn transitions such as "keep red the same"; "change red to yellow"; "turn off red"; "turn on yellow," and so forth. Also, included in the network is a kind of weight transport so that, for example, red to red can be transported to a different instance of color, such as yellow to yellow. The network instantiation developed here, based on common connectionist building blocks such as associative learning, competition, and adaptive resonance, along with additional principles suggested by analogy data, is a step toward a theory of interactions among several brain areas to develop and learn meaningful relationships between concepts.