Development of a high-throughput in vitro assay using a novel Caco-2/rat hepatocyte system for the prediction of oral plasma area under the concentration versus time curve (AUC) in rats.
Previously, we have shown that a novel Caco-2/human hepatocyte system is a useful model for the prediction of oral bioavailability in humans. In this study, we attempted to use a similar system in a high-throughput screening mode for the selection of new compound entities (NCE) in drug discovery. A total of 72 compounds randomly selected from three different chemotypes were dosed orally in rats. In vivo plasma area under the concentration versus time curve (AUC) from 0-6 h of the parent compound was determined. The same compounds were also tested in the Caco-2/rat hepatocyte system. In vitro AUC from 0-3 h in the Caco-2 rat hepatocyte system was determined. The predictive usefulness of the Caco-2/rat hepatocyte system was evaluated by comparing the in vivo plasma AUC and the in vitro AUC. Linear regression analysis showed a reasonable correlation (R2 = 0.5) between the in vivo AUC and the in vitro AUC. Using 0.4 microM h in vivo AUC as a cut-off, compounds were categorized as either low or high AUC. The in vitro AUC successfully matched the corresponding in vivo category for sixty-three out of seventy-two compounds. The results presented in this study suggest that the Caco-2/rat hepatocyte system may be used as a high-throughput screen in drug discovery for pharmacokinetic behaviors of compounds in rats.


Temporal trends in transcatheter aortic valve replacement use and outcomes by race, ethnicity, and sex.
To identify trends in transcatheter aortic valve replacement (TAVR) use and outcomes by race (non-Hispanic White, Black), ethnicity (Hispanic), and sex over time. Despite rapid growth in TAVR use over time, our understanding of its use and outcomes among males and females of underrepresented racial/ethnic groups remains limited. A retrospective analysis of hospitalizations from 2013 to 2017 from the Healthcare Cost and Utilization Project database was performed. White patients comprised 65% (n = 2.16 × 107 ) of all hospitalizations, yet they comprised 83% (n = 176,887) of the admissions for aortic stenosis (p < 0.0001). Among 91,693 hospitalizations for aortic valve replacement, 64,069 were surgical (34.0% female, 7.0% Hispanic, and 5.9% Black) and 27,624 were transcatheter (46.6% female, 4.5% Hispanic, and 4.4% Black). Growth in TAVR volumes was the slowest among minorities and females. Hispanic males, Hispanic females, and White females had the highest in-hospital mortality (2.7%-3.3%; compared to White males, adjusted odds ratio: Hispanic males 1.9 [1.2-3.0], Hispanic females 1.9 [1.2-3.1], and White females 1.4 [1.2-1.7]). Despite less baseline vascular disease, females of all races/ethnicities had more vascular complications than men (female 5% vs. male 3.5%, p ≤ 0.001). Further adjustment for vascular complications only partially attenuated mortality differences. Black and Hispanic patients had a longer mean length of hospital stay than White patients, which was most pronounced among females. Pacemaker requirements were consistently low among all groups. Differences in TAVR growth and outcomes by race, ethnicity, and sex over time highlight areas for focused efforts to close gaps in minimally invasive structural heart disease care.


AKT2 deficiency induces retardation of myocyte development through EndoG-MEF2A signaling in mouse heart.
Protein kinase B2 (AKT2) is implicated in diverse process of cardiomyocyte signaling including survival and metabolism. However, the role of AKT2 in myocardium development and the signaling pathway is rarely understood. Therefore, we sought to determine the effect of AKT2 deletion on heart development and its downstream targets. By using experimental animal models and neonatal rat cardiomyocytes (NRCMs), we observed that AKT2 deficiency induces retardation of heart development and increased systemic blood pressure (BP) without affecting cardiac function. Further investigation suggested that deficiency of AKT2 in myocardium results in diminished MEF2A abundance, which induced decreased size of cardiomyocytes. We additionally confirmed that EndoG, which is also regulated by AKT2, is a suppressor of MEF2A in myocardium. Finally, our results proved that AKT2 deficiency impairs the response to β-adrenergic stimuli that normally causes hypertrophy in cardiomyocytes by downregulating MEF2A expression. Our data are the first to show the important role of AKT2 in determining the size of myocardium, its deficiency causes retardation of cardiomyocyte development. We also proved a novel pathway of heart development involving EndoG and MEF2A regulated by AKT2.


Heme oxygenase-1: unleashing the protective properties of heme.
Heme oxygenase (HO)-1 catabolizes heme into three products: carbon monoxide (CO), biliverdin (which is rapidly converted to bilirubin) and free iron (which leads to the induction of ferritin, an iron-binding protein). HO-1 serves as a "protective" gene by virtue of the anti-inflammatory, anti-apoptotic and anti-proliferative actions of one or more of these three products. Administration of CO, biliverdin, bilirubin or iron-binding compounds is protective in rodent disease models of ischemia-reperfusion injury, allograft and xenograft survival, intimal hyperplasia following balloon injury or as seen in chronic graft rejection and others. We suggest that the products of HO-1 action could be valuable therapeutic agents and speculate that HO-1 functions as a "therapeutic funnel", mediating the beneficial effects attributed to other molecules, such as interleukin-10 (IL-10), inducible nitric oxide synthase (NOS2; iNOS) and prostaglandins. This Review is the third in a series on the regulation of the immune system by metabolic pathways.


Proton transport facilitating water-oxidation: the role of second sphere ligands surrounding the catalytic metal cluster.
The ability of PSII to extract electrons from water, with molecular oxygen as a by-product, is a remarkable biochemical and evolutionary innovation. From an evolutionary perspective, the invention of PSII approximately 2.7 Ga led to the accelerated accumulation of biomass in the biosphere and the accumulation of oxygen in the atmosphere, a combination that allowed for the evolution of a much more complex and extensive biosphere than would otherwise have been possible. From the biochemical and enzymatic perspective, PSII is remarkable because of the thermodynamic and kinetic obstacles that needed to have been overcome to oxidize water as the ultimate photosynthetic electron donor. This article focuses on how proton release is an integral part of how these kinetic and thermodynamic obstacles have been overcome: the sequential removal of protons from the active site of H2O-oxidation facilitates the multistep oxidation of the substrate water at the Mn4CaOx, the catalytic heart of the H2O-oxidation reaction. As noted previously, the facilitated deprotonation of the Mn4CaOx cluster exerts a redox-leveling function preventing the accumulation of excess positive charge on the cluster, which might otherwise hinder the already energetically difficult oxidation of water. Using recent results, including the characteristics of site-directed mutants, the role of the second sphere of amino acid ligands and the associated network of water molecules surrounding the Mn4CaOx is discussed in relation to proton transport in other systems. In addition to the redox-leveling function, a trapping function is assigned to the proton release step occurring immediately prior to the dioxygen chemistry. This trapping appears to involve a yet-to-be clarified gating mechanism that facilitates to coordinated release of a proton from the neighborhood of the active site thereby insuring that the backward charge-recombination reaction does not out-compete the forward reaction of dioxygen chemistry during this final step of H2O-oxidation.


Arsenic Bioremediation by Indigenous Heavy Metal Resistant Bacteria of Fly Ash Pond.
Fly ash (FA), the major by-product of coal-fired thermal power plants, causes significant environmental degradation owing to its injurious heavy metal contents. Leaching of arsenic (As) from ash ponds is especially significant as As released from FA can increase As concentration of drinking water above maximum contaminant level of 10 ppb. The aim of this paper was demonstration of As bioremediation potential of indigenous As resistant bacteria present in the weathered pond ash sample. Ten isolates belonging to Bacillus, Micrococcus, Kytococcus and Staphylococcus genera were characterized. Biochemical tests showed reduction of relatively non toxic arsenate to more toxic arsenite by two strains while four strains showed oxidation of arsenite to arsenate. Two exoplolysaccharide producing strains were shown to absorb As within their biomass. Total heterotrophs versus As resistant heterotrophs counting performed showed that FA was enriched with As resistant heterotrophs. Column leaching based microcosm study revealed overall As detoxification potential of the isolated microbes.


Single-nucleotide polymorphism analysis using fluorescence resonance energy transfer between DNA-labeling fluorophore, fluorescein isothiocyanate, and DNA intercalator, POPO-3, on bacterial magnetic particles.
To develop an analytical system for single-nucleotide polymorphisms (SNPs), the fluorescence resonance energy transfer (FRET) technique was employed on a bacterial magnetic particle (BMP) surface. A combination of fluorescein isothiocyanate (FITC; excitation 490 nm/emission 520 nm) labeled at the 5' end of DNA and an intercalating compound (POPO-3, excitation 534 nm/emission 570 nm) was used to avoid the interference from light scattering caused by nanoparticles. After hybridization between target DNA immobilized onto BMPs and FITC-labeled probes, fluorescence from POPO-3, which was excited by the energy from the FITC, was detected. The major homozygous (ALDH2*1), heterozygous (ALDH2*1/*2), and minor homozygous (ALDH2*2) genotypes in the blood samples were discriminated by this method. The assay described herein allows for a simple and rapid SNP analysis using a fully automated system.


Outcomes of locally advanced prostate cancer: a single institution study of 209 patients in Japan.
To investigate the outcomes for Asian populations with locally advanced/clinical stage III prostate cancer (PCa) treated with currently prevailing modalities. We reviewed the record of 209 patients with clinical stage III PCa, who were treated at Niigata Cancer Center Hospital between 1992 and 2003. Treatment options included hormone therapy-combined radical prostatectomy (RP+HT), hormone therapy-combined external beam irradiation (EBRT+HT) and primary hormone therapy (PHT). The 5- and 10-year overall survival rates were 80.3% and 46.1% in all cohorts, respectively. The survival rates were 87.3% and 66.5% in the RP+HT group, 94.9% and 70.0% in the EBRT+HT group and 66.1% and 17.2% in the PHT group, respectively. A significant survival advantage was found in the EBRT+HT group compared with that in the PHT group (P < 0.0001). Also, the RP+HT group had better survival than the PHT group (P = 0.0107). The 5- and 10-year disease-specific survival rates for all cases were 92.5% and 80.0%, respectively. They were 93.8% and 71.4% in the RP+HT group, 96.6% and 93.6% in the EBRT+HT group and 88.6% and 62.3% in the PHT group, respectively. A survival advantage was found in the EBRT+HT group compared with the PHT group (P = 0.029). No significant difference was found in disease-specific survival between the EBRT+HT and RP+HT groups or between the RP+HT and PHT groups. Although our findings indicate that radiotherapy plus HT has a survival advantage in this stage of PCa, we recommend therapies that take into account the patients'social and medical conditions for Asian men with clinical stage III PCa.


Bone regeneration strategy inspired by the study of calcification behavior in deer antler.
Bone regeneration has attracted much attention from various researchers and inspired numerous strategies for bone formation. In this study, rapid calcification of deer antlers was studied to unravel bone biology by investigating mineral composition, morphology and microstructure. Calcification model was hypothesized and preliminarily established by in vitro experiments. In our model, mineral deposition and phase conversions in the gel matrix were mimicked. Results revealed that mineral metabolism including deposition and phase conversion plays key roles in calcification in vivo, which inspired the bone regeneration strategy with three main components, i.e. enhanced mineral nucleation, mineral ions sources and crystals habits. Rapid mineral metabolism of implant apatite biomaterials was supposed as the critical aspect of bone regeneration. This study will provide a relatively ideal model for peer bone regeneration studies.


Correction: Myosin Light Chain Kinase (MLCK) Gene Influences Exercise Induced Muscle Damage during a Competitive Marathon.
[This corrects the article DOI: 10.1371/journal.pone.0160053.].


Phage display and crystallographic analysis reveals potential substrate/binding site interactions in the protein secretion chaperone CsaA from Agrobacterium tumefaciens.
The protein CsaA has been proposed to function as a protein secretion chaperone in bacteria that lack the Sec-dependent protein-targeting chaperone SecB. CsaA is a homodimer with two putative substrate-binding pockets, one in each monomer. To test the hypothesis that these cavities are indeed substrate-binding sites able to interact with other polypeptide chains, we selected a peptide that bound to CsaA from a random peptide library displayed on phage. Presented here is the structure of CsaA from Agrobacterium tumefaciens (AtCsaA) solved in the presence and absence of the selected peptide. To promote co-crystallization, the sequence for this peptide was genetically fused to the amino-terminus of AtCsaA. The resulting 1.65 A resolution crystal structure reveals that the tethered peptide from one AtCsaA molecule binds to the proposed substrate-binding pocket of a symmetry-related molecule possibly mimicking the interaction between a pre-protein substrate and CsaA. The structure shows that the peptide lies in an extended conformation with alanine, proline and glutamine side chains pointing into the binding pocket. The peptide interacts with the atoms of the AtCsaA-binding pocket via seven direct hydrogen bonds. The side chain of a conserved pocket residue, Arg76, has an "up" conformation when the CsaA-binding site is empty and a "down" conformation when the CsaA-binding site is occupied, suggesting that this residue may function to stabilize the peptide in the binding cavity. The presented aggregation assays, phage-display analysis and structural analysis are consistent with AtCsaA being a general chaperone. The properties of the proposed CsaA-binding pocket/peptide interactions are compared to those from other structurally characterized molecular chaperones.


The scintigraphic and radiographic appearance of the ischiopubic synchondroses in normal children and in osteomyelitis.
Five cases of hematogenous osteomyelitis of the ischiopubic synchondrosis (IPS) were encountered among 180 patients with osteomyelitis treated over a 5-year period. Symptoms were poorly localized in all these IPS osteomyelitis patients. The IPS can normally show expansion and irregular mineralization radiographically and focal hyperconcentration of radiophosphates on scintigrams. Findings are frequently asymmetrical negating comparison with the contralateral side. In the cases of osteomyelitis, radiographs were abnormal at the time of presentation in only one of these five cases. In two of the four patients who had radionuclide bone scans, activity at the IPS exceeded that seen in a normal control population, but all showed loss of definition of the IPS and regional increased uptake permitting an early diagnosis.


Comparison of Intra- and Postoperative 3-Dimensional Digital Subtraction Angiography in Evaluation of the Surgical Result After Intracranial Aneurysm Treatment.
Postoperative three-dimensional digital subtraction angiography (3D-DSA) is the gold standard in evaluating intracranial aneurysm (IA) remnants after clipping. Should intraoperative 3D-DSA image quality be equally good as postoperative 3D-DSA, it could supplant the latter as standard of care for follow-up of clipped IA. To directly compare the quality of assessment of clipped IA by intraoperative and postoperative 3D-DSA. From a prospective cohort of 221 consecutive patients who underwent craniotomy for IA treatment in a hybrid operating room, we retrospectively studied 26 patients who had both intraoperative and postoperative 3D-DSA imaging of their clipped aneurysm. Comparison of intraoperative and postoperative 3D-DSA images (blinded for review) included parameters that affected image quality and differences between the 2 periods. In the 26 patients with 32 clipped IAs, the mean interval was 11 ± 7 mo between intraoperative and postoperative imaging 3D-DSA examinations. Reconstruction with multiple clips was used in 14 (44%) cases. Of 15 remnants, 9 (60%) were small (<2 mm). In comparing intraoperative and postoperative 3D-DSA, no discordance or discrepancy in assessment of the surgical result was noted for any clipped IA, and overall imaging quality was excellent for both modalities. Factors affecting minor differences in image quality were not identified. Compared with postoperative 3D-DSA, intraoperative 3D-DSA images achieved equally high quality and effective, immediate interpretation of the surgical clipping result. With comparable imaging quality and no discordant findings, intraoperative 3D-DSA could replace postoperative 3D-DSA to become the standard of care in IA surgery.


Insulin-like growth factor I stimulates cardiac myosin heavy chain and actin synthesis in the awake rat.
To determine the effect of insulin-like growth factor I (IGF-I) on cardiac contractile protein synthesis in vivo, we measured L-[ring-2, 6-3H]phenylalanine incorporation into myosin heavy chain and actin during intravenous infusions (4 h) of either saline or IGF-I (1 microgram. kg-1. min-1) in awake rats. After an overnight fast, IGF-I increased myosin synthesis by 29% compared with saline (11.5 +/- 0.8 vs. 8.9 +/- 0.6%/day, P < 0.01) and actin synthesis by 26% (7.2 +/- 0.3 vs. 5.7 +/- 0.3%/day, P < 0.01), with similar effects in left and right ventricles and a comparable effect on mixed cardiac protein. When amino acids were infused with IGF-I, a further increase in myosin synthesis was observed (P < 0.01). In fed rats, despite higher baseline synthesis rates than in fasted rats (P < 0. 01), IGF-I also increased the synthesis of myosin (12.3 +/- 0.5 vs. 9.9 +/- 0.5%/day, P < 0.01) and actin (8.8 +/- 0.3 vs. 7.5 +/- 0. 2%/day, P < 0.01) compared with saline. IGF-I infusion had no hypoglycemic effect and did not change heart rate or blood pressure. Thus relatively low-dose IGF-I has a direct action in vivo to acutely increase heart contractile protein synthesis in both fasted and fed awake rats.


Evaluation of impacts of soil fractions on phenanthrene sorption.
Phenanthrene sorption to soils and soil fractions was investigated using two contrasting soils with different clay mineral and organic carbon (OC) contents in an attempt to evaluate the contribution of each soil fraction to phenanthrene sorption and the applicability of the carbon-normalized distribution constant (K(OC)) in soils. Sorbents were characterized using surface analysis, solid-state (13)C NMR analysis, and glass transition temperature (T(g)) analysis to gain a insight into the chemical nature of OC in soils. Dissolved organic carbon (DOC) in the soil solution impeded the phenanthrene sorption, while humins accounted for the predominant phenanthrene sorption in soils. The contribution of OC to phenanthrene sorption in soil would be overestimated if only a K(OC)-approach was adopted, since clay minerals could account for much of the sorption, especially when OC was low in soils. Nitrogen gas was shown to be inappropriate for probing non-polar sorption capacity. The results obtained highlight the importance of clay minerals in governing the sorption of phenanthrene in soil, and emphasize the inapplicability of the carbon-normalized distribution coefficient K(OC) in soils.


Risk factors of anesthesia and surgery in bleomycin-treated patients.
The use of bleomycin as part of preoperative chemotherapy regimens for nonseminomatous germ cell tumors of the testis has gained increased acceptance. However, recent experience has suggested that patients so treated are at an increased risk of developing postoperative respiratory distress syndrome. The most clearly associated factor seems to be the fractional concentration of inspired oxygen intraoperatively and in the immediate postoperative period. Based on our experience and a review of the limited published reports, we recommend careful monitoring of fractional inspired oxygen and maintenance of the lowest tolerated oxygen concentration during this period.


The Role of Fluoride in the Prevention of Tooth Decay.
Although there are recommendations to prevent tooth decay by other means, this nonsystematic review finds that fluoride is the key to prevention and control of tooth decay. There are multiple fluoride modalities with effectiveness and safety of fluoride depending on dose and concentration. Prevention of tooth decay occurs at the individual level by fluoride use at home and with professional application and at the community level through fluoridation of water or salt.


Local distribution of C3 and C4 grasses in sites of overlap on Mount Kenya.
A zone of C3-C4 grass overlap has been identified on the northern slopes of Mount Kenya at elevations of 2,800-3,200 m. At higher elevations, C3 grasses predominate; below, C4 grasses predominate. At each of three elevational sites of overlap, a series of transects was surveyed for C4 and C3 grass composition. All transects were located in structurally similar vegetation (high elevation grassland) within 150 m of each other. Transects were run in a variety of topographic situations. Within each transect, several environmental parameters were measured. Both unweighted (species presence/absence) and weighted (by frequency) measures of %C4 composition were significantly correlated with dry season soil moisture. Drier transects contain significantly more C4 species, in greater frequency, than wetter transects. Other correlations of C4 composition (e.g. factors which tend to parallel soil moisture) were also found. This local trend parallels the larger scale tendency of C3 grasses to replace C4 grasses with increasing elevation. Finer scale habitat partitioning may account for C3-C4 overlap within transects.


Gap junctional intercellular communication as a biological "Rosetta stone" in understanding, in a systems biological manner, stem cell behavior, mechanisms of epigenetic toxicology, chemoprevention and chemotherapy.
In spite of the early speculation by Loewenstein that one of the critical distinguishing phenotypes of cancers from normal cells was the dysfunction of gap junctional intercellular communication (GJIC), this hypothesis has not captured the attention of most birth defects and cancer researchers. Moreover, even with later demonstrations that factors that influence normal development and carcinogenesis by modulating GJIC, such as chemical teratogens and tumor-promoting chemicals, inflammatory factors, hormones and growth factors, antisense connexin genes, knockout mouse models, human inherited mutated connexin genes, si-connexin RNA, chemopreventive and chemotherapeutic chemicals, it is rare that one sees any reference to these studies by the mainstream investigators in these fields. Based on the assumption that the evolutionarily conserved connexin genes found in metazoans are needed for normal development and the maintenance of health and T. Dobzhansky's statement "Nothing in biology makes sense except in the light of evolution," a short review of the roles of endogenous and exogenous modulators of GJIC will be made in the context of the multistage, multimechanism process of carcinogenesis, the stem cell theory of carcinogenesis, the discovery and characterization of normal adult stem "cancer stem" cells and the observation that two distinct classes of GJIC-deficient cancer cells are known. The implications of these observations to a "systems biological" view of the role of gap junctions and the nutritional prevention and treatment of several chronic diseases and cancer will be discussed.


The effects of topical capsaicin on rat urinary bladder motility in vivo.
The effects of topical capsaicin on urinary bladder motility were investigated following saline-induced distension of the bladder wall in urethane-anaesthetized rats and compared to the effects of topical substance P and acetylcholine. Capsaicin and substance P produced similar excitatory effects in both quiescent and rhythmically contracting bladders, i.e., a TTX resistant tonic contraction followed by a series of rhythmic, TTX sensitive, phasic contractions. Acetylcholine, in doses equieffective in producing TTX resistant contractions was less effective than capsaicin or substance P in triggering neurogenic rhythmic contractions of bladder muscle. Atropine pretreatment prevented the neurogenic component of the excitatory effect of both capsaicin and substance P. Repeated applications of capsaicin but not of substance P led to desensitization. Bladders of animals pretreated (4 days before) with a large dose of s.c. capsaicin developed insensitivity to topical capsaicin and a larger volume of saline was required to trigger neurogenic rhythmic contractions of the detrusor muscle. These results suggest that capsaicin acts by interfering with the mechanism(s) regulating the threshold for the micturition reflex to occur.


Preceramic and postceramic solder joints.
This investigation evaluated preceramic and postceramic soldering procedures. Three gap spaces and two soldering methods were evaluated. Wider gaps produced stronger joints. The strongest joints were achieved by using wider gaps and the oven soldering technique. Very wide gaps (0.76 mm.) are not recommended because of possible distortion through excessive solder shrinkage. However, in practice, many solder joints exceed the 0.31 mm. recommended minimum; these joints will not show decreased strength.


Short-acting novel MAO inhibitors: in vitro evidence for the reversibility of MAO inhibition by moclobemide and Ro 16-6491.
The inhibition of monoamine oxidase (MAO) in rat liver and brain by the short-acting MAO-A inhibitors moclobemide (Ro 11-1163 = p-chloro-N-[2-morpholinoethyl]benzamide) and brofaremine and by the short-acting MAO-B inhibitors Ro 16-6491 (N-[2-aminoethyl]-p-chloro-benzamide) and almoxatone, administered p.o. at roughly equieffective doses 2 h before decapitation, was investigated for its reversibility under various in vitro conditions. MAO A activity in liver homogenates, inhibited by moclobemide (300 mumol/kg) to approx. 15% of control, time dependently recovered during 0.5 to 2 h of incubation at 37 degrees C, irrespective of whether the homogenates were prepared and incubated in distilled water or Krebs-Ringer buffer (KRB). Dialysis of such homogenates for 4 h in distilled water at 37 degrees C (but not at 13 degrees C) led to a complete return of the MAO activity. In liver homogenates from rats pretreated with brofaremine (30 mumol/kg), dialysis for 4 h at 37 degrees C against distilled water caused only little recovery of the MAO activity. Likewise, MAO-B inhibited by Ro 16-6491 (30 mumol/kg) to approx. 4% of control returned to almost control activity after 4 h of dialysis at 37 degrees C, while inhibition induced by almoxatone (30 mumol/kg) was little or not reversed at all. In brain homogenates prepared in, and dialysed against, distilled water or KRB at 37 degrees C (but not at 13 degrees C), MAO-A inhibited by moclobemide (100-300 mumol/kg) to approx. 15% of control, partially (KRB) or almost completely (dist. water) returned to control activity after 4 h of dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)


Third ventricular meningiomas.
We report 13 patients with third ventricular meningiomas (TVM) and discuss the clinical, radiological, pathological and surgical features, as well as follow-up of these tumors. TVM are rare intracranial tumors, and because of this, there are few reports in the literature. Of 11,600 intracranial meningiomas that were surgically treated and pathologically confirmed at Beijing Tian Tan Hospital over a period of 10 years (2003-2013), 13 TVM were selected for a retrospective review. We recorded the clinical, radiological, pathological, and surgical data and statistically analyzed the preoperative, postoperative and 6 month postoperative Karnofsky performance scale (KPS) scores. TVM represented 0.11% of intracranial meningiomas. Radiologically, TVM were divided into three groups: anterior (n=3), posterior (n=3), and entire third ventricle (n=7). Three patients (23.1%) were misdiagnosed preoperatively. Total removal was achieved in 61.5% (8/13) of patients, and subtotal resection was achieved in 38.5% (5/13). Pathologically, the tumors were World Health Organization (WHO) Grade I in 11 patients (84.6%) and WHO Grade II in two (15.6%). There were no statistically significant differences in the preoperative, postoperative, or 6 month postoperative KPS scores (F=0.814; p=0.401). TVM without dural attachments are rare neoplasms that should be differentiated from choroid plexus papilloma, craniopharyngioma, and pineocytoma. Surgery is the optimal treatment and may result in a favorable prognosis, and understanding of the radiological subtype can help with the choice of surgical approach.


Norepinephrine-stimulated MAP kinase activity enhances cytokine-induced NO production by rat cardiac myocytes.
The effect of norepinephrine (NE) on cytokine-stimulated nitric oxide (NO) production by cardiac myocytes has not been previously reported. NE alone caused no significant increase in NO-2 levels over vehicle. Addition of NE to interleukin-1beta (IL-1beta) significantly increased inducible NO synthase (iNOS) mRNA expression, iNOS protein, and NO-2 production vs. IL-1beta alone. Addition of the alpha-adrenergic blocker prazosin or the beta-adrenergic blocker propranolol partially reduced the NE-mediated increase in iNOS mRNA expression and NO-2 production. Addition of prazosin and propranolol together completely abolished the NE-induced increase in iNOS mRNA expression and NO-2 production. NE significantly enhanced mitogen-activated protein (MAP) kinase activity that was reduced by prazosin, propranolol, and PD-98059, a selective MAP kinase kinase inhibitor. Addition of PD-98059 reduced the NE-mediated increase in iNOS mRNA expression and NO-2 production. We report for the first time that NE enhances IL-1beta-stimulated NO production by activation of alpha- and beta-adrenergic receptors through a novel MAP kinase mechanism.


Cellular heterogeneity in an ethylnitrosourea-induced glioma: malignancy, karyology and other properties of tumour cell types.
Two types of tumour cell have been obtained from a glioma transplacentally induced by ethylnitrosourea in a BD-IX rat. These were distinguished in culture by their different morphologies, responses to dibutyryl cyclic adenosine monophosphate, inducibility of glycerol phosphate dehydrogenase and growth in soft agar. They had different karyotypes, with distinctive numbers and arrangements of chromosomes. One cell type had an apparently normal diploid set of 42 whilst the other had 43 chromosomes. An additional chromosome No 4 was identified in the latter by Giemsa banding. Translocations and other abnormalities involving this chromosome were consistently observed. Both cell types produced malignant, astrocytic tumours when injected into newborn syngeneic rats, but with different latent periods and morphological features.


Compliance with donor age recommendations in oocyte donor recruitment advertisements in the USA.
IVF using donated oocytes offers benefits to many infertile patients, yet the technique also raises a number of ethical concerns, including worries about potential physical and psychological risks to oocyte donors. In the USA, oversight of oocyte donation consists of a combination of federal and state regulations and self-regulatory guidelines promulgated by the American Society for Reproductive Medicine. This study assesses compliance with one of these self-regulatory guidelines - specifically, ASRM's preferred minimum age for donors of 21. To assess compliance, 539 oocyte donor recruitment advertisements from two recruitment channels (Craigslist and college newspapers) were collected and evaluated. Of these, 61% in the Craigslist dataset and 43% in the college newspaper dataset listed minimum ages between 18 and 20, which is inconsistent with ASRM's preferred minimum age recommendation of 21. Advertisements placed by oocyte donor recruitment agencies were more likely than advertisements placed by clinics to specify minimum ages between 18 and 20. These results indicate that ASRM should evaluate and consider revising its donor age guidelines. IVF using donated human eggs can help many patients who have difficulty having children. However, the technique also raises ethical concerns, including concerns about potential physical and psychological harms to egg donors. In the USA, oversight of egg donation relies on a combination of federal and state regulation and professional self-regulation. Governmental regulations address only limited aspects of egg donation, such as the potential spread of infectious diseases and the reporting of success rates, leaving voluntary guidelines developed by an association of medical professionals to address most issues, including ethical concerns raised by the practice. One of these voluntary guidelines recommends that egg donors should be at least 21 years of age. In this article, we analysed 539 egg donor recruitment advertisements published on Craigslist and in college newspapers to see whether fertility clinics and egg donor recruitment agencies follow this recommendation. We found that 61% of advertisements in the Craigslist dataset and 43% of advertisements in the college newspaper dataset listed minimum ages between 18 and 20 and, thus, did not follow the recommendation that egg donors be at least 21 years of age. Advertisements placed by egg donor recruitment agencies were more likely than advertisements placed by fertility clinics to list minimum ages between 18 and 20. These results indicate that the American Society for Reproductive Medicine should evaluate and consider revising its donor age guidelines.


Efficacy of Transabdominal Ultrasound-guided Percutaneous Microwave Ablation in the Treatment of Symptomatic Adenomyosis: A Retrospective Cohort Study.
To evaluate and compare the clinical efficacy of transabdominal ultrasound-guided percutaneous microwave ablation (PMWA) in the treatment of symptomatic focal and nonfocal adenomyosis. Retrospective cohort study. Longyan First Affiliated Hospital of Fujian Medical University. From May 2019 to October 2021, 107 patients with symptomatic adenomyosis who refused hysterectomy received PMWA. Patients were divided into a focal group (n = 47, including 40 focal adenomyosis and 7 adenomyoma cases) and a nonfocal group (n = 60, including 36 diffuse and 24 mixed adenomyosis cases) according to the extent of lesion involvement. We collected and analyzed preoperative baseline data on patient characteristics; postoperative efficacy measures at 3, 6, and 12 months; and intraoperative and postoperative complications. There was a significant post-treatment reduction in the uterine corpus volume and cancer antigen 125 levels, an increase in hemoglobin levels, and an improvement in the Uterine Fibroid Symptom and Health-related Quality of Life scores (consisting of the Symptom Severity Scale and the Health-related Quality of Life scale), dysmenorrhea visual analog scale, and menstrual volume score (MVS) (all p <.05). One patient had recurrence. Most adverse events (72.0%) were mild. Although the nonfocal group had significantly greater anemia severity, higher Symptom Severity Scale and MVS, lower Health-related Quality of Life scale, greater extent and severity of myometrial involvement, and larger uterine corpus volume, after treatment, the uterine corpus volume, uterine corpus reduction rate, cancer antigen 125 levels, hemoglobin levels, Uterine Fibroid Symptom and Health-related Quality of Life score, dysmenorrhea visual analog scale, MVS score, and clinical response rate were similar between the groups (p >.05). PMWA had good, similar, short-term efficacy for symptomatic focal and nonfocal adenomyosis.


[The Malady of Emperor Frederick III. and Virchow's diagnostic role].
Crownprince Frederick Wilhelm of Prussia was once the hope of the liberal movement in Germany. He embodied and lived a humanistic ideal based on the spirit of the enlightenment. Starting in January 1887 the passionate pipe smoker suffered on an unusual long hoarseness. A polyp of the vocal cord was diagnosed. Although this diagnosis seemed harmless, an odyssee was launched that made history. Rudolf Virchow-the foremost pathologist of that time-was involved in the following histological diagnosis. His role and that of the sprouting histopathology will be presented in this essay.


Pranlukast, a cysteinyl leukotriene receptor-1 antagonist, protects against chronic ischemic brain injury and inhibits the glial scar formation in mice.
We have recently reported the neuroprotective effect of pranlukast (ONO-1078), a cysteinyl leukotriene receptor-1 (CysLT1) antagonist, on cerebral ischemia in rats and mice. In this study, we further determined whether the effect of pranlukast is long lasting and related to the formation of a glial scar in cerebral ischemic mice. Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). After ischemia, pranlukast (0.1 mg/kg) was injected intraperitoneally for 5 consecutive days. Neurological deficits and sensorimotor function were determined during 70 days after ischemia. Brain lesion and glial scar formation were detected at the end of the experiment. Pranlukast did not reduce mortality, but significantly improved neurological deficits and promoted sensorimotor recovery during 70 days. At the end of the experiment, pranlukast significantly reduced lesion volume, and increased neuron densities in the cortex and hippocampal CA1 region in the ischemic hemispheres. Importantly, pranlukast also remarkably reduced the thickness of a scar wall in the ischemic hemispheres. These findings indicate that pranlukast has a long-lasting protective effect on focal cerebral ischemia in mice, and inhibit the ischemia-induced glial scar formation, providing further evidence of the therapeutic potential of pranlukast in the treatment of ischemic stroke.


Can blood gas analysis indicate when mechanical ventilation should start in patients with acute myocardial infarction?
Arterial blood gas analysis of 69 patients with acute myocardial infarction were evaluated to provide a basis for respiratory care. Patients were divided into two groups: group A which received oxygen therapy only (n = 38) and group B which received oxygen therapy with mechanical ventilation (n = 31). The patients in group B were further divided into surviving cases (n = 14) and fatal cases (n = 17). On admission patients assigned to group B had lower PaO2 values than those placed in group A. In group B, there was no difference in the P/F value before mechanical ventilation of the surviving and the fatal cases, but the survivors demonstrated an improvement of the P/F value and an increase in cardiac index after mechanical ventilation. It may be reasonable to assume that a P/F value of less than 250 serves as an indicator for the initiation of mechanical ventilation. An increase in the P/F value after mechanical ventilation seems to be a valuable index to estimate prognosis in respiratory failure.


Gadolinium-Enhancing Lesions Lead to Decreases in White Matter Tract Fractional Anisotropy in Multiple Sclerosis.
Although MRI identification of new lesions forms the basis for monitoring disease progression in multiple sclerosis patients, how lesion activity relates to longitudinal white matter changes in the brain is unknown. We hypothesized that patients with gadolinium-enhancing lesions would show greater longitudinal decline in fractional anisotropy in major tracts compared to those with stable disease. Thirty patients with relapsing-remitting multiple sclerosis were included in this study-13 had enhancing lesions at baseline and 17 did not. Each patient underwent at least two 3 Tesla contrast-enhanced MRI scans with a DTI sequence with a median interval of 2.1 years between scans. The forceps major and minor of the corpus callosum and the bilateral corticospinal tracts were selected as the major white matter tracts of interest. These tracts were reconstructed using region-of-interest placement on standard anatomical landmarks and a fiber assignment by continuous tracking algorithm using TrackVis (version 0.5.2.2) software. Mixed-effects regression models were used to determine the association between enhancing lesions and subsequent longitudinal change in fractional anisotropy. In patients with enhancing lesions, there was greater decline in fractional anisotropy compared to those with stable disease in the forceps major (P = .026), right corticospinal tract (P = .032), and marginally in the left corticospinal tract (P = .050), but not the forceps minor (P = .11). Fractional anisotropy of major white matter tracts declined more rapidly in patients with enhancing lesions, suggesting greater diffuse white matter injury with active inflammatory disease. DTI may provide a means of monitoring white matter injury following relapses.


The closure property of [Formula: see text]-tensors under the Hadamard product.
In this paper, we investigate the closure property of [Formula: see text]-tensors under the Hadamard product. It is shown that the Hadamard products of Hadamard powers of strong [Formula: see text]-tensors are still strong [Formula: see text]-tensors. We then bound the minimal real eigenvalues of the comparison tensors of the Hadamard products involving strong [Formula: see text]-tensors. Finally, we show how to attain the bounds by characterizing these [Formula: see text]-tensors.


A new differentiated cell line (Dif 5) derived by retinoic acid treatment of F9 teratocarcinoma cells capable of extracellular matrix production and growth in the absence of serum.
Treatment of F9 teratocarcinoma cells with all trans retinoic acid (RA) causes them to differentiate into two or three morphologically distinct cell types. Whereas the majority of these retinoid-derived cells exhibit properties resembling parietal endoderm, a small percentage of this differentiated cell population manifests properties distinct from the parietal endoderm cell type. The isolation and partial characterization of such a non-parietal endoderm cell line (Dif 5) derived from F9 cells following prolonged (44 days) exposure to 1 microM retinoic acid are described. Unlike the retinoid-induced parietal endoderm-like cell population, which exhibits a dramatic, characteristic morphological change upon treatment with 8-bromo cAMP, Dif 5 cells do not show any morphological change with exposure to this cAMP analog. Dif 5 cells synthesize and deposit an extracellular matrix consisting of several components of Reichert's membrane (fibronectin, laminin, and type IV collagen). This new cell line does not synthesize alpha-fetoprotein but does secrete plasminogen activator. An interesting property of these cells is their ability to grow in the absence of serum or other hormonal supplements. Yet the Dif 5 cells do exhibit density-dependent inhibition of growth. Unlike the parent F9 cells or parietal yolk sac (PYS-2) cells, these cells do possess specific cell surface receptors for epidermal growth factor (EGF). The growth-arrested Dif 5 cells can be reinitiated to proliferate by the addition of fetal calf serum (FCS) or EGF. The properties of Dif 5 cells determined fail to fulfill all the characteristics described for either parietal or visceral endodermal cells. This raises the possibility that Dif 5 cells might represent an endodermal cell type which is intermediate in differentiation to either parietal or visceral endoderm but which lacks the biochemical signal to complete this stage of differentiation. This new Dif 5 cell line should be of considerable value in studying the modulation of growth requirements and extracellular matrix formation during early embryonic development.


MHC-BPS: MHC-binder prediction server for identifying peptides of flexible lengths from sequence-derived physicochemical properties.
Major histocompatibility complex (MHC)-binding peptides are essential for antigen recognition by T-cell receptors and are being explored for vaccine design. Computational methods have been developed for predicting MHC-binding peptides of fixed lengths, based on the training of relatively few non-binders. It is desirable to introduce methods applicable for peptides of flexible lengths and trained by using more diverse sets of non-binders. MHC-BPS is a web-based MHC-binder prediction server that uses support vector machines for predicting peptide binders of flexible lengths for 18 MHC class I and 12 class II alleles from sequence-derived physicochemical properties, which were trained by using 4,208 approximately 3,252 binders and 234,333 approximately 168,793 non-binders, and evaluated by an independent set of 545 approximately 476 binders and 110,564 approximately 84,430 non-binders. The binder prediction accuracies are 86 approximately 99% for 25 and 70 approximately 80% for five alleles, and the non-binder accuracies are 96 approximately 99% for 30 alleles. A screening of HIV-1 genome identifies 0.01 approximately 5% and 5 approximately 8% of the constituent peptides as binders for 24 and 6 alleles, respectively, including 75 approximately 100% of the known epitopes. This method correctly predicts 73.3% of the 15 newly published epitopes in the last 4 months of 2005. MHC-BPS is available at http://bidd.cz3.nus.edu.sg/mhc/ .


Bis(2,4-dioxo-pentan-3-ido-κ2 O,O')dioxidomolyb-denum(VI): a redetermination.
The title compound, [Mo(C5H7O2)2O2] or cis-[MoO2(acac)2] (acac is acetyl-acetonate), contains a molybdenum(VI) atom coordinated by two acetyl-acetonate ligands and two doubly bonded oxido ligands in a distorted octa-hedral shape. The mol-ecule is chiral and the asymmetric unit contains two independent mol-ecules (one Δ, one Λ). Extensive C-H⋯O contacts are present throughout the structure. Data were collected at 100 K, providing higher precision of unit-cell parameters and atomic positions than previous determinations [Kamenar et al. (1973 ▸). Cryst. Struct. Commun. 2, 41-44.; Krasochka et al. (1975). Zh. Strukt. Khim. 16, 696-698].


Medical complications during pregnancy and childbirth in women with SCI in Switzerland.
A retrospective interview study of mothers with spinal cord injuries (SCIs) who gave birth over the last 15 years. To identify the medical complications of women with SCIs during pregnancy and childbirth in Switzerland and to describe how they dealt with these complications. Swiss Paraplegic Research in Nottwil, the University of Lausanne and participants' homes. Data were collected by self-reported questionnaires and descriptive analysis was conducted. Seventeen women with SCIs who gave birth to 23 children were included. Thirteen of the women were paraplegics and four were tetraplegics. All of them practiced an independent bladder management. Three women changed their bladder management techniques during pregnancy. Five women reported an increased bladder evacuation frequency during pregnancy, and six women reported a new onset or increase in incontinence. We observed no significant increase in bowel dysfunction or skin breakdown due to their pregnancies. Ten women were hospitalised during the course of their pregnancies. Aside from urinary tract infections/pyelonephritis, women were hospitalised for falls, hypertension, pneumonia, preeclampsia, pre-term labour or tachycardia. The results of our study clearly demonstrated that, although medical complications are not infrequent during pregnancy in women with SCIs, pregnancy and delivery in this group of women are possible without posing intolerable risks to the mothers or the children. Urological problems seemed to be the most frequent complication during pregnancy.


Use of Conventional and Alternative Tobacco and Nicotine Products Among a Sample of Canadian Youth.
The purpose of this study was to examine the use of conventional and alternative tobacco and nicotine products among secondary school students. Respondents were 44,163 grade 9-12 students who participated in Year 2 (2013-2014) of COMPASS, a cohort study of 89 purposefully sampled secondary schools in Ontario and Alberta, Canada. Past-month use of various tobacco and nicotine products was assessed, as well as correlates of use, using a generalized linear mixed effects model. Overall, 21.2% of the sample reported past-month use of any tobacco or nicotine product, with 7.2% reporting past-month use of e-cigarettes. E-cigarette users reported significantly greater prevalence of current use for all products. Students who were male, white, had more spending money, and had a history of tobacco use were more likely to report past-month use of e-cigarettes. Approximately one fifth of youth reported past-month use of a nicotine product, with e-cigarettes being the third most common product. Overall, the findings suggest a rapidly evolving nicotine market.


[A clinical study on head injuries in the aged].
We review 79 patients over 65 years old among 715 patients who underwent CT scans in the early period after head injuries, to study the characteristics of head injury in the aged. Among 79 aged patients, 24 developed posttraumatic subdural fluid collections, and in 13 of them chronic subdural hematomas developed subsequently. There were only three acute epidural hematomas. However, a high incidence of intracerebral lesions was noted, regardless of the presence of skull fracture. The pedestrian accident was the most frequent cause of head injury in the 36 aged patients admitted and the mortality rate of traffic accident in the aged was also highest. The relationship between Glasgow Coma Scale Score (GCS) on admission and the outcome was not parallel in the aged, because high GCS not rarely resulted in poor condition or death. Head injury is apt to occur and becomes severe in the aged pedestrian because of advancing carelessness and dull movements with age. The vulnerability of the brain to the injury and changes of intracranial environment in the aged tend to cause intracranial lesions much more than in the younger patients. Already-existing diseases and/or posttraumatic general complications also make clinical courses worse in the aged. It seems important for the improvement of the treatment that the characteristics described above are always taken into consideration throughout the period of the treatment in the aged, in order to eliminate worsening factors adequately. In addition, the social measures to cope with the suffering of the aged pedestrians from traffic accident should be considered and established in an aging society.


Effects of mandibular advancement device treatment on arterial stiffness and glucose metabolism in patients with mild to moderate obstructive sleep apnea: a prospective 1 year study.
An independent association between obstructive sleep apnea (OSA) and cardiovascular events has been reported, suggesting that OSA may lead to cardiometabolic dysregulation. We prospectively investigated the effect of mandibular advancement device (MAD) treatment on arterial stiffness, glucose metabolism, and certain inflammatory markers as predictors of cardiometabolic risk in mild to moderate OSA patients. A total of 18 patients with mild to moderate OSA were prospectively enrolled in the study to determine the effects of MAD treatment at 3 months and 1 year following initiation of the treatment. Sleep studies, arterial stiffness assessment, and laboratory analyses were obtained at the baseline and at the time of follow-up. The data collected at 1 year were compared to baseline values. There was a significant decrease in apnea-hypopnea index (AHI) after 1 year of treatment when compared to baseline (22.9 ± 5.9 to 9.7 ± 4.5, P < 0.001). Furthermore, MAD treatment was associated with reduced levels of fasting plasma glucose values after 1 year of treatment (5.3 ± 0.5 to 4.9 ± 0.5 mmol/L, P < 0.001), as well as fasting plasma insulin values (14.1 ± 7.8 to 10.9 ± 6.4 μU/mL, P < 0.05) and HOMA-IR (3.3 ± 1.8 to 2.4 ± 1.4, P < 0.001). There was significant improvement in pulse wave velocity (9.3 ± 1.9 m/s at baseline to 8.1 ± 1.7 m/s, P < 0.05) after 1 year of treatment. Plasma level of an inflammatory marker fibrinogen decreased significantly from 3.4 ± 0.7 at baseline to 3.0 ± 0.9, (P < 0.05) at 1-year follow-up. The MAD treatment improved arterial stiffness, glucose metabolism, and insulin resistance in mild to moderate OSA patients after 1 year of treatment.


Alternate regimens for ovulation induction in polycystic ovarian disease.
The patient with PCOD remains a challenge to the reproductive endocrinologist. Although successful induction of ovulation can often be achieved using standard therapeutic regimens of CC or hMG, too often this group of anovulatory patients fails to respond as expected. Over the past 10 to 15 years, alternate approaches to ovulation induction have been investigated with encouraging results. Whereas no one method is productive in all patients, these varied regimens offer us a number of options in dealing with this difficult clinical problem.


Supra-ependymal serotoninergic nerves in mammalian brain: morphological, pharmacological and functional studies.
Supra-ependymal nerves in mammals (mainly rats) have been shown to contain serotonin (5-hydroxytryptamine, 5-HT) by combined Falck-Hillarp fluorescence histochemistry, ultrastructural monoamine cytochemistry and pharmacology as well as by immunohistochemistry and autoradiography. Supra-ependymal 5-HT cells do not occur. At least in rats, virtually all supra-ependymal nerves contain 5-HT and in our opinion the occasionally described non-5-HT supra-ependymal nerve cells and their processes contribute little to the supra-ependymal nerve plexus (with the possible exception of those cells above the median eminence). The cells of origin of the supra-ependymal 5-HT nerves are situated in raphe nuclei. The axons and terminals (varicosities) contain small and large dense core vesicles in both of which 5-HT is stored. A co-transmitter has not been found among the candidates investigated so far (leu- and met-enkephalin, substance P and gamma-aminobutyric acid (GABA)). The nerves possess uptake mechanisms specific for 5-HT and possibly GABA. Occasionally desmosome-like junctions are observed between 5-HT nerve terminals and ependymal cells but no true synapses. The function of these nerves is not known. They do not appear to regulate ciliary movement, but might influence the shape of ependymal cells.


The neural cell adhesion molecule L1 is distinct from the N-CAM related group of surface antigens BSP-2 and D2.
The neural cell adhesion molecule L1 and the group of N-CAM related molecules, BSP-2 and D2 antigen, are immunochemically distinct molecular species. The two groups of surface molecules are also functionally distinct entities, since inhibition of Ca2+-independent adhesion among early post-natal mouse cerebellar cells by Fab fragments of both antibodies are at least additive, when compared with equal concentrations of the individual antibodies.


Liposomal temocene (m-THPPo) photodynamic treatment induces cell death by mitochondria-independent apoptosis.
The cell death pathway activated after photodynamic therapy (PDT) is controlled by a variety of parameters including the chemical structure of the photosensitizer, its subcellular localization, and the photodynamic damage induced. The present study aims to characterize a suitable m-THPPo liposomal formulation, to determine its subcellular localization in HeLa cells and to establish the cell death mechanisms that are activated after photodynamic treatments. Liposomes containing m-THPPo were prepared from a mixture of DPPC and DMPG at a 9:1 molar ratio. In order to procure the best encapsulation efficiency, the m-THPPo/lipid molar ratio was considered. HeLa cells were incubated with liposomal m-THPPo and the subcellular localization of m-THPPo was studied. Several assays such as TUNEL, annexin V/propidium iodide and Hoechst-33258 staining were performed after photodynamic treatments. The apoptotic initiation was assessed by cytochrome c and caspase-2 immunofluorescence. m-THPPo encapsulated in liposomes showed a decrease of the fluorescence and singlet oxygen quantum yields, compared to those of m-THPPo dissolved in tetrahydrofuran. Liposomal m-THPPo showed colocalization with LysoTracker® and it induced photoinactivation of HeLa cells by an apoptotic mechanism. In apoptotic cells no relocalization of cytochrome c could be detected, but caspase-2 was positive immediately after photosensitizing treatments. Photodynamic treatment with liposomal m-THPPo leads to a significant percentage of apoptotic morphology of HeLa cells. The activation of caspase-2, without the relocalization of cytochrome c, indicates a mitochondrial-independent apoptotic mechanism. These results provide a better understanding of the cell death mechanism induced after liposomal m-THPPo photodynamic treatment.


Highly sensitive and selective detection of nitrite ions using Fe3O4@SiO2/Au magnetic nanoparticles by surface-enhanced Raman spectroscopy.
A novel and pragmatic method was developed to detect the concentration of nitrite ions using Fe3O4@SiO2/Au magnetic nanoparticles (MNPs) by surface-enhanced Raman scattering (SERS). The as-prepared bifunctional nanocomposites can be used to simultaneously purify target molecules using external magnetic field and produce Raman fingerprint spectrum with trace level of target molecules. In acidic media, 4-aminothiophenol (4-ATP) molecules conjugated on Fe3O4@SiO2/Au MNPs were triggered by nitrite ions to form azo bonds, resulting in three new marker peaks on the SERS spectrum. Under optimized conditions, the detection limit based on the three marker peaks were 15.63, 13.69, and 17.77μM, which was much lower than the maximum NO2(-) concentration of 1.0mgL(-1) (71.4μM) allowed in drinking water as defined by U.S. Environmental Protection Agency (EPA). The specificity of this proposed method to detect nitrite ions was demonstrated using common ions as competitors. In addition, the SERS-based technique was successfully employed to detect nitrite ions in pond water, a synthetic urine solution, and pickle brine. Considering its good sensitivity and selectivity, the detection method is well suited for the detection of nitrite ions in real samples without pretreatment steps.


BehavioraL and biochemical changes caused by muscimol in mice withdrawN from haloperidol administration.
This study was designed to determine the behavioral and biochemical effects of the gamma-aminobutyric acid (GABA) agonist, muscimol, in mice withdrawn from chronic haloperidol administration. Mice received either haloperidol or vehicle In their drinking water for 35 days, after which the haloperidol was replaced with vehicle. Seven days after withdrawal from chronic treatment with haloperidol, the effect of apomorphine on the climbing behavior of haloperidol-withdrawn mice was markedly enhanced as compared to control mice that received only vehicle. Muscimol produced a dose-related reduction in the intensity of climbing behavior induced by apomorphine in both control and haloperidol-withdrawn mice. However, the inhibition of climbing behavior induced by muscimol was significantly greater in haloperidol-withdrawn animals. In addition, in haloperidol-withdrawn mice, muscimol produced a significant reduction in striatal homovanillic (HVA) levels with no change in striatal dopamine (DA) levels, suggesting a decrease in DA turnover. In support of this conclusion, muscimol decreased the disappearance of dopamine in haloperidol-withdrawn mice that were injected with alpha-methyl-p-tyrosine. Both the behavioral and biochemical effects of muscimol were blocked by the GABA antagonist, picrotoxin. These results indicate that after chronic haloperidol administration there is not only an enhanced response to dopaminergic agonists but also to GABAergic agonists.


Spermatic cord sarcoma in adults.
The clinical courses are presented for 6 patients with sarcoma of the spermatic cord seen between 1967 and 1976. There were 3 fibrosarcomas, 2 liposarcomas and 1 malignant fibrous histiocytoma, making the total reported cases of spermatic cord sarcoma 212. Management of spermatic cord sarcoma is discussed.


Retinal Vascular Caliber Association with Nonperfusion and Diabetic Retinopathy Severity Depends on Vascular Caliber Measurement Location.
To evaluate the association of retinal nonperfusion and diabetic retinopathy (DR) severity with location of vascular caliber measurement using ultrawide field (UWF) imaging. Retrospective image review. Adults with diabetes mellitus. All images from subjects with same-day UWF fluorescein angiography (FA) and color imaging were evaluated. Predominantly peripheral lesions (PPL) and DR severity were graded from UWF color images. Nonperfusion was quantified using UWF-FA in defined retinal regions [posterior pole (PP), mid-periphery (MP), far-periphery (FP)]. Retinal vessel calibers were measured at an optic disc centered inner and outer zone. Nonperfusion index (NPI) in the PP, MP and FP. Mean arteriole and venule diameter in the inner and outer zones. Two hundred eighty-five eyes of 193 patients (24.9% mild nonproliferative DR [NPDR], 22.8% moderate NPDR, 37.5% severe NPDR and 14.7% proliferative DR [PDR]) were reviewed. No significant associations between inner zone arteriolar diameter and retinal NPI overall or in any retinal region. In the outer zone, eyes with thinnest arteriolar calibers (quartile 1) were associated with a 1.7- to 2.4-fold nonperfusion increase across all retinal regions compared to the remaining eyes (P = 0.002 [PP] to 0.048 [FP]). In the outer zone, the percentage of eyes in the thinnest quartile of retinal arteriolar diameter increased with worsening DR severity (mild NPDR: 10% vs PDR: 31%, P = 0.007). This association was not observed when measured within the inner zone (P = 0.129). All venular caliber associations were not statistically significant when corrected for potentially confounding factors. Thinner outer zone retinal arteriolar caliber (quartile 1) was more common in eyes with PPL compared to eyes without PPL (34.1% vs 20.8%, P = 0.017) as were thicker outer venular calibers (quartile 4) (33% vs 21.3%, P = 0.036). Presence of PPL was associated with thinner outer zone arteriolar caliber (109.7 ± 26.5μm vs 123.0 ± 29.5μm, P = 0.001). The association of vascular caliber with nonperfusion and DR severity differs based upon the retinal location at which vascular caliber is measured. Peripheral arterial narrowing is associated with increasing nonperfusion, worsening DR severity and presence of PPL. In contrast, inner zone retinal arteriolar caliber is not associated with these findings.


Spatial cone activity distribution in diseases of the posterior pole determined by multifocal electroretinography.
Thirty patients with a reduced central vision due to diseases of the posterior pole were examined with the VERIS system developed by Sutter and Tran (Vis Res 1992;32:433-446) to characterize the topography of electroretinographic (ERG) changes in comparison to the results in 30 normal volunteers. Diagnoses included Stargardt's macular dystrophy (SMD, n = 10), age-related macular degeneration (AMD, n = 5), cone dystrophy (CD, n = 5), central retinal vein occlusion (CRVO, n = 5), and autosomal dominant optic atrophy (ADOA, n = 5). The 61 local responses obtained from each subjects were grouped by eccentricity to form five concentric rings. The foveal ERG, originating from a central area of 2 degrees radius, was non-recordable or markedly diminished in all patients except those with optic atrophy, where amplitudes were found to be in the normal range. In patients with advanced stages of SMD, functional defects were larger and involved more peripheral areas than in patients with early stages of SMD or with AMD. A reduction of response amplitude even in the most peripheral ring (17-30.5 degrees eccentricity) was found in cone dystrophies and--moderately--in patients with advanced SMD and central retinal vein occlusion only. Prolonged implicit times were found in all but the patients in early stages of SMD and they were maximal in patients with CRVO. This study shows that the multifocal ERG (MFERG) can contribute to differential diagnosis of retinal diseases of the posterior pole especially in cases with a normal photopic Ganzfeld ERG.


Plasma proteomic profiling discovers molecular features associated with upper tract urothelial carcinoma.
Upper tract urothelial carcinoma (UTUC) is often diagnosed late and exhibits poor prognosis. Limited data are available on potential non-invasive biomarkers for disease monitoring. Here, we investigate the proteomic profile of plasma in 362 UTUC patients and 239 healthy controls. We present an integrated tissue-plasma proteomic approach to infer the signature proteins for identifying patients with muscle-invasive UTUC. We discover a protein panel that reflects lymph node metastasis, which is of interest in identifying UTUC patients with high risk and poor prognosis. We also identify a ten-protein classifier and establish a progression clock predicting progression-free survival of UTUC patients. Finally, we further validate the signature proteins by parallel reaction monitoring assay in an independent cohort. Collectively, this study portrays the plasma proteomic landscape of a UTUC cohort and provides a valuable resource for further biological and diagnostic research in UTUC.


Regulatory effect of isovitexin on MAPK/NF-κB signal in mice with acute ulcerative colitis.
The aim of this study was to investigate the anti-inflammatory effects and mechanism of isovitexin on ulcerative colitis mice and RAW264.7 cells. The results showed that isovitexin had strong antioxidant and anti-inflammatory effects, and could restore intestinal barrier integrity (p < 0.01). In addition, isovitexin inhibited the expression of MyD88, TLR4 and NF-κB p65 proteins. At the same time, isovitexin can inhibit the activation of MAPK/NF-κB signaling pathway in RAW264.7 cells. In conclusion, isovitexin has a protective effect on UC mice, and its improvement mechanism of UC might be related to MAPK/NF-κB signaling pathway.


Impact of Structured Patient-Centered Preoperative Pain Consult and Interventions From a Dedicated Perioperative Pain Service: A Case Series of 4 Patients.
Opioid-tolerant individuals have greater risk of perioperative complications and worse clinical outcomes. A preoperative screening process and structured approach to opioid-tolerant patients was developed to identify and optimize these patients before elective surgery.


The Tokyo subway sarin attack has long-term effects on survivors: A 10-year study started 5 years after the terrorist incident.
The Tokyo subway sarin attack in 1995 was an unprecedented act of terrorism that killed 13 people and sickened more than 6,000. The long-term somatic and psychological effects on its victims remain unknown. We conducted analyses on the self-rating questionnaire collected annually by the Recovery Support Center (RSC) during the period from 2000 to 2009. The RSC is the only organization that has large-scale follow-up data about sarin attack victims. The prevalence of self-reported symptoms was calculated over 10 years. We also evaluated the prevalence of posttraumatic stress response (PTSR), defined as a score ≥ 25 on the Japanese-language version of the Impact of Event Scale-Revised. The multivariate Poisson regression model was applied to estimate the risk ratios of age, gender, and year factor on the prevalence of PTSR. Subjects were 747 survivors (12% of the total) who responded to the annual questionnaire once or more during the study period. The prevalence of somatic symptoms, especially eye symptoms, was 60-80% and has not decreased. PTSR prevalence was 35.1%, and again there was no change with time. The multivariate Poisson regression model results revealed "old age" and "female" as independent risk factors, but the passage of time did not decrease the risk of PTSR. Although symptoms in most victims of the Tokyo subway sarin were transient, this large-scale follow-up data analysis revealed that survivors have been suffering from somatic and psychological long-term effects.


Mutation in the immunodominant epitope of the HPV16 E7 oncoprotein as a mechanism of tumor escape.
Infection with high-risk types of human papillomavirus (HPV) can cause the development of malignant tumors. To study mechanisms responsible for immune escape of tumor cells infected with HPV16, we previously used mouse oncogenic TC-1 cells producing HPV16 E6 and E7 oncoproteins to derive TC-1 clones resistant to immunization against E7. We have found immunoresistance of the clones to correlate with the point mutation in the E7 oncogene, which resulted in the N53S substitution in the immunodominant epitope RAHYNIVTF (aa 49-57). Here, we have shown that this mutation reduced stabilization of H-2D(b) molecules on RMA-S cells and eliminated immunogenicity of E7. The resistance of TC-1 clones was E7-specific as immunization against E6 inhibited tumor growth. Transduction of the TC-1/F9 clone carrying the mutated epitope with the wild-type E7 gene restored susceptibility to immunization against E7. Our results suggest that mutagenesis of tumor antigens can lead to the escape of malignant cells and should be considered in the development and evaluation of cancer immunotherapy.


Functional status analysis of RNH1 in bladder cancer for predicting immunotherapy response.
Bladder cancer (BLCA) typically has a poor prognosis due to high rates of relapse and metastasis. Although the emergence of immunotherapy brings hope for patients with BLCA, not all patients will benefit from it. Identifying some markers to predict treatment response is particularly important. Here, we aimed to determine the clinical value of the ribonuclease/angiogenin inhibitor 1 (RNH1) in BLCA therapy based on functional status analysis. First, we found that RNH1 is aberrantly expressed in multiple cancers but is associated with prognosis in only a few types of cancer. Next, we determined that low RNH1 expression was significantly associated with enhanced invasion and metastasis of BLCA by assessing the relationship between RNH1 and 17 functional states. Moreover, we identified 95 hub genes associated with invasion and metastasis among RNH1-related genes. Enrichment analysis revealed that these hub genes were also significantly linked with immune activation. Consistently, BLCA can be divided into two molecular subtypes based on these hub genes, and the differentially expressed genes between the two subtypes are also significantly enriched in immune-related pathways. This indicates that the expression of RNH1 is also related to the tumour immune response. Subsequently, we confirmed that RNH1 shapes an inflammatory tumour microenvironment (TME), promotes activation of the immune response cycle steps, and has the potential to predict the immune checkpoint blockade (ICB) treatment response. Finally, we demonstrated that high RNH1 expression was significantly associated with multiple therapeutic signalling pathways and drug targets in BLCA. In conclusion, our study revealed that RNH1 could provide new insights into the invasion of BLCA and predict the immunotherapy response in patients with BLCA.


Primary bone lymphoma of patella: A case report and review of literature.
Primary bone lymphoma (PBL) is rare bone disease that accounts for very small number of all primary bone tumors. Among the described sites of PBLs, the patella is an extremely rare example. To date, only a few cases of PBL affecting the patella have been reported. Clinically, these tumors have very similar presentation of pain, decreased range of motion and swelling and, sometimes, pathologic fractures. On radiographs, skeletal lymphoma commonly manifests as osteolytic lesions with ill-defined margins affecting the metaphysis of axial long bones. We present a rare case of patellar adult T-cell lymphoma/leukemia in a 58-year-old female who presented with left-knee pain and swelling. Computed tomography and magnetic resonance imaging revealed diffuse marrow replacement by a lesion with aggressive features. PET scan demonstrated neoplastic range hypermetabolic FDG uptake within this lesion. Ultrasound-guided biopsy was consistent with PBL.


Activation of Cyclic Adenosine Monophosphate Pathway Increases the Sensitivity of Cancer Cells to the Oncolytic Virus M1.
Oncolytic virotherapy is a novel and emerging treatment modality that uses replication-competent viruses to destroy cancer cells. Although diverse cancer cell types are sensitive to oncolytic viruses, one of the major challenges of oncolytic virotherapy is that the sensitivity to oncolysis ranges among different cancer cell types. Furthermore, the underlying mechanism of action is not fully understood. Here, we report that activation of cyclic adenosine monophosphate (cAMP) signaling significantly sensitizes refractory cancer cells to alphavirus M1 in vitro, in vivo, and ex vivo. We find that activation of the cAMP signaling pathway inhibits M1-induced expression of antiviral factors in refractory cancer cells, leading to prolonged and severe endoplasmic reticulum (ER) stress, and cell apoptosis. We also demonstrate that M1-mediated oncolysis, which is enhanced by cAMP signaling, involves the factor, exchange protein directly activated by cAMP 1 (Epac1), but not the classical cAMP-dependent protein kinase A (PKA). Taken together, cAMP/Epac1 signaling pathway activation inhibits antiviral factors and improves responsiveness of refractory cancer cells to M1-mediated virotherapy.


Glucocorticoid receptors in human fetal lung.
A specific dexamethasone binding protein of human fetal lung is described. Characterization of the receptor by sucrose density gradient centrifugation showed a sedimentation coefficient of approximately 7S (low ionic strength) and 4S (high ionic strength). Competition studies showed high specificity for glucocorticoids since binding of radioactive dexamethasone was inhibited by cortisol and corticosterone but not by testosterone and 17 beta-estradiol. Uptake of radioactive steroid by isolated lung nuclei required the presence of cytosol and was temperature dependent. The KCl-extractable nuclear complex sedimented at approximately 5S. Thus the dexamethasone binding components of the human fetal lung have properties similar to those described for steroid receptors present in target tissues. The concentration of receptor remained fairly constant between 15 and 28 weeks of gestation.


Reference genes expression stability in Avena sativa L. during compatible and incompatible interactions with Puccinia graminis.
A reliable qPCR experiment requires the selection of reference genes with a stable level of expression in a given experimental system. This study attempts to determine the reference genes (RGs) for the A. sativa-P. graminis experimental setup. We evaluated nine candidate reference genes in A. sativa (oat line Pg4 and the cultivar Kasztan) during compatible and incompatible interactions with different pathotypes of Puccinia graminis f. sp. avenae in six time points post-inoculation. The identification of genes with high expression stability was performed by four algorithms (geNorm, NormFinder, BestKeeper and ΔCt method). We found that the most appropriate combination of RGs for RT-qPCR data normalization were HNR (heterogeneous nuclear ribonucleoprotein 27C) + EF1A (elongation factor 1-alpha) + EIF4A (eukaryotic initiation factor 4A-3). The worst candidates for normalization in this dataset were CYP (cyclophilin) and TUA (alpha tubulin). Identified reference genes are suitable candidates for the standardization of gene expression studies in the A. sativa-P. graminis interaction system and potentially other related pathogens. To date, this is the first report of RGs selection in this pathosystem.


Improvement in scalp hair growth in androgen-deficient women treated with testosterone: a questionnaire study.
Androgens are thought to have an adverse effect on female scalp hair growth. However, our clinical experience of androgen replacement therapy in women with androgen deficiency, in which hair loss was seldom reported, led us to question this concept. To evaluate the effect of subcutaneous testosterone therapy on scalp hair growth in female patients. A total of 285 women, treated for a minimum of 1year with subcutaneous testosterone implants for symptoms of androgen deficiency, were asked to complete a survey that included questions on scalp and facial hair. Age, body mass index (BMI) and serum testosterone levels were examined. Out of the 285 patients, 76 (27%) reported hair thinning prior to treatment; 48 of these patients (63%) reported hair regrowth on testosterone therapy (responders). Nonresponders (i.e. no reported hair regrowth on therapy) had significantly higher BMIs than responders (P=0·05). Baseline serum testosterone levels were significantly lower in women reporting hair loss prior to therapy than in those who did not (P=0·0001). There was no significant difference in serum testosterone levels, measured 4weeks after testosterone implantation, between responders and nonresponders. No patient in this cohort reported scalp hair loss on testosterone therapy. A total of 262 women (92%) reported some increase in facial hair growth. Subcutaneous testosterone therapy was found to have a beneficial effect on scalp hair growth in female patients treated for symptoms of androgen deficiency. We propose this is due to an anabolic effect of testosterone on hair growth. The fact that no subject complained of hair loss as a result of treatment casts doubt on the presumed role of testosterone in driving female scalp hair loss. These results need to be confirmed by formal measurements of hair growth.


Clinical features and outcomes of patients in different age groups with non-valvular atrial fibrillation receiving oral anticoagulants.
Patients with non-valvular atrial fibrillation (NVAF) need prophylactically antithrombotic therapies to reduce the risk of stroke. We hypothesized that the prognostic benefits of prophylactic antithrombotic therapies outweighed the bleeding risk among very elderly (≥85 years old) patients. We analyzed clinical characteristics and outcomes of patients with NVAF in different age groups who had received different prophylactic antithrombotic therapies. We enrolled 3895 consecutive NVAF patients in the Macau Special Administrative Region (Macau SAR) of China from January 1, 2010, to December 31, 2018. Among 3524 patients [including 1252 (35.53%) very elderly patients] who completed the entire study, 2897 (82.21%) patients had a CHA2DS2-VASc score ≥ 2, 2274 (64.53%) had HAS-BLED score < 3, and 1659 (47.08%) had both of the above. The follow-up time was 3.80 (median, interquartile range 1.89-6.56) years. The primary outcome was the first occurrence of ischemic stroke, major bleeding, clinically relevant non-major gastrointestinal bleeding (CRNM-GIB), and all-cause mortality. A total of 2012 patients (57.09%) received no antithrombotic (NAT), 665 (18.87%) received antiplatelet (AP) agents, 371 (10.53%) received vitamin K antagonist (VKA), and 476 (13.51%) received non-vitamin K antagonist oral anticoagulants (NOACs). Eventually, 610 (17.31%) patients experienced thromboembolic events, with 167 (4.74%) strokes and 483 (13.71%) transient ischemia attack (TIA)/strokes. Bleeding events occurred in 614 (17.42%) patients, with 131 (3.72%) major bleeding, 381 (10.81%) CRNM-GIB and 102 (2.89%) minor bleeding events. All-cause deaths occurred in 483 (13.71%) patients. Compared with patients receiving NAT, patients receiving NOACs and VKA had fewer strokes (hazard ratio [HR]: 0.038; 95 %CI 0.004-0.401; p = 0.006 and HR: 0.544; 95 %CI 0.307-0.965; p = 0.037, respectively), and lower all-cause mortality (HR: 0.270; 95 %CI 0.170-0.429; p < 0.001 and HR: 0.531; 95 %CI 0.373-0.756; p < 0.001, respectively). Of note, very elderly patients with NVAF receiving NOACs had fewer strokes (adjust hazard ratio [adjHR]: 0.042; 95 %CI 0.002-1.003; p = 0.050) and lower all-cause mortality (adjHR: 0.308; 95 %CI 0.158-0.601; p = 0.001). Meanwhile, despite higher CRNM-GIB events (adjHR: 1.736; 95 %CI 1.042-2.892; p = 0.034), major bleeding events (adjHR: 1.045; 95 %CI 0.366-2.979; p = 0.935) did not significantly increase. VKA neither reduced strokes (adjHR: 1.015; 95 %CI 0.529-1.948; p = 0.963), nor improved all-cause mortality (adjHR: 0.995; 95 %CI 0.641-1.542; p = 0.981) in very elderly patients with NVAF. Antithrombotic treatment (VKA and NOACs) reduces stroke and improves prognosis in patients in different age groups with NVAF. The prognostic benefits of NOACs outweigh their bleeding risks in very elderly patients with NVAF.


The impact of MMX mesalazine on disease-specific health-related quality of life in ulcerative colitis patients.
Past studies with ulcerative colitis (UC) patients indicate that disease activity strongly predicts health-related quality of life (HRQL). To examine the degree to which daily treatment with MMX mesalazine predicts improved HRQL for patients with active UC and with stable HRQL for patients with quiescent UC. Data from two phases of a multicentre open-label trial were examined. In the acute phase, 132 patients with mild-to-moderate active UC received MMX mesalazine 2.4-4.8 g/day for 8 weeks, while 206 patients with quiescent UC received MMX mesalazine 2.4 g/day for a 12-month maintenance phase. Disease-specific HRQL was measured at baseline and endpoint of each phase using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Repeated-measures anova models examined baseline-endpoint changes in SIBDQ, stool frequency (SF), and rectal bleeding severity (RBS). Correlations assessed the associations between SIBDQ and SF/RBS scores, while ancova techniques tested the sensitivity of SIBDQ to disease recurrence. SIBDQ scores significantly increased for active mild-to-moderate UC patients following 8 weeks of treatment, while SIBDQ scores remained stable for quiescent UC patients following 12 months of treatment. Changes in SIBDQ scores correlated significantly with changes in SF and RBS scores. Patients with recurrent UC at maintenance phase endpoint had significantly lower SIBDQ scores than nonrecurrent patients. Daily MMX mesalazine therapy was associated with significant improvement in disease-specific HRQL for patients with mild-to-moderate active UC and with the maintenance of HRQL for patients with quiescent UC. In both patient groups, HRQL was significantly associated with disease activity.


A selective optical sensor for picric acid assay based on photopolymerization of 3-(N-methacryloyl) amino-9-ethylcarbazole.
A novel optical sensor based on covalent immobilization for picric acid assay has been described. To improve the stability of the sensor, a terminal double bond was attached to the fluorescent compound, 3-amino-9-ethylcarbazole (AEC), via methacryloyl chloride. The resultant compound, 3-(N-methacryloyl) amino-9-ethylcarbazole (MAEC) was copolymerized with 2-hydroxypropyl methacrylate on surface-modified quartz glass plates by UV irradiation. The resulting optical sensor (optode membrane) was used to determine picric acid based on fluorescence quenching. It shows a linear response toward picric acid in the concentration range of 9.33 x 10(-8) to 9.33 x 10(-5) mol l(-1), with rapid response, high stability and good selectivity to picric acid.


Cellular Therapy for Children with Central Nervous System Tumors: Mining and Mapping the Correlative Data.
Correlative studies should leverage clinical trial frameworks to conduct biospecimen analyses that provide insight into the bioactivity of the intervention and facilitate iteration toward future trials that further improve patient outcomes. In pediatric cellular immunotherapy trials, correlative studies enable deeper understanding of T cell mobilization, durability of immune activation, patterns of toxicity, and early detection of treatment response. Here, we review the correlative science in adoptive cell therapy (ACT) for childhood central nervous system (CNS) tumors, with a focus on existing chimeric antigen receptor (CAR) and T cell receptor (TCR)-expressing T cell therapies. We highlight long-standing and more recently understood challenges for effective alignment of correlative data and offer practical considerations for current and future approaches to multi-omic analysis of serial tumor, serum, and cerebrospinal fluid (CSF) biospecimens. We highlight the preliminary success in collecting serial cytokine and proteomics from patients with CNS tumors on ACT clinical trials.


Preoperative shuttle walking testing and outcome after oesophagogastrectomy.
Objective assessment of cardiorespiratory reserve has been recommended before major surgery to identify patients with impaired oxygen delivery who may be at increased operative risk. Access to formal cardiopulmonary exercise (CPX) testing is limited outside larger centres. Following a previous audit of morbidity and mortality after oesophagectomy, we decided to add a simpler form of exercise test to our preoperative screen and review the outcomes. Fifty-one patients who had surgical resection of an oesophageal cancer in our unit between April 2002 and April 2005 carried out an incremental shuttle walk exercise test before operation. Thirty-day outcome data were collected for each patient. Overall mortality in the group was 10%. No patient who walked 350 m or more died within 30 days. Five of the eight patients who could not achieve this distance died and two others remained in the critical care unit at 30 days. Preoperative shuttle walk testing using a standard protocol appears to be a sensitive indicator of operative risk in this group of patients. The apparent threshold value of 350 m is consistent with previously reported measures of functional capacity obtained using formal CPX testing.


2-Deoxyglucose as a substrate for glutathione regeneration in human and ruminant red blood cells.
2-Deoxyglucose was found to be a substrate for the regeneration of GSH from GSSG in the red blood cells of humans, sheep, goats and cattle. The regeneration rate with 2-deoxyglucose varied from 15 to 56% of the rate with glucose. It is likely that 2-deoxyglucose is phosphorylated to 2-deoxyglucose-6-phosphate by HK and is then oxidized to 2-deoxygluconate-6-phosphate by G6PD. The latter reaction would produce the NADPH required for GSH regeneration.


Hybridomas in a bioreactor cascade: modeling and determination of growth and death kinetics.
Hybridomas were cultured under steady-state conditions in a series of two continuous stirred-tank reactors (CSTRs), using a serum-free medium. The substrate not completely converted in the first CSTR, was transported with the cells to the second one and very low growth rates, high death rates, and lysis of viable cells were observed in this second CSTR. These conditions are hardly accessible in a single vessel, because such experiments would be extremely time-consuming and unstable due to a low viability. In contrast to what is often observed in literature, kinetic parameters could thus be derived without the neccessity for extrapolation to lower growth rates. Good agreement with literature averages for other hybridomas was found. Furthermore, showing that the reactor series is a valuable research tool for kinetic studies under extreme conditions, the possibility to observe cell death under stable and defined steady-state conditions offers interesting opportunities to investigate apoptosis and necrosis. Additionally, a model was developed that describes hybridoma growth and monoclonal antibody production in the bioreactor cascade on the basis of glutamine metabolism. Good agreement between the model and the experiments was found.


Multiphasic scaffold for scapholunate interosseous ligament reconstruction: A study in the rabbit knee.
Scapholunate interosseous ligament tears are a common wrist injury in young and active patients that can lead to suboptimal outcomes after repair. This research aims to assess a multiphasic scaffold using 3D-printing for reconstruction of the dorsal scapholunate interosseous ligament. The scaffold was surgically implanted in vivo in the position of the native rabbit medial collateral ligament. Two branches of treatment were implemented in the study. In the first group, the rabbits (n = 8) had the knee joint fixed in flexion for 4 weeks using 1.4 mm K-wires prior to sample harvesting. The second group (n = 8) had the rabbit knee joint immobilized for 4 weeks prior to K-wire removal and mobilization for an additional 4 weeks prior to sample harvesting. Overall, samples were harvested at 4 weeks post-surgery (immobilized group) and eight weeks post-surgery (mobilized group). Mechanical tensile testing (n = 5/group) and histology (n = 3/group) of the constructs were conducted. Tissue integration and maturation were observed resulting in increased mechanical strength of the operated joint at 8 weeks (P < .05). Bone and ligament tissues were regenerated in their respective compartments with structural and mechanical properties approaching those reported for the human dorsal SLIL ligament. Clinical Significance: This proof of concept study has demonstrated that the synthetic multiphasic scaffold was capable of regenerating both bone and ligament while also withstanding the physiological load once implanted in the rabbit knee. The artificial scaffold may provide an alternative to current techniques for reconstruction of scapholunate instability or other ligament injuries in the hand and wrist.


Interaction of thiourea with rat lung protein.
Administration of the pulmonary edemagenic agent [14C]Thiourea [( 14C]TU) to adult rats results in heterogeneous binding to lung protein. Indirect evidence suggests that TU may be binding to the amino acid cysteine, possibly via the SH moiety. The nature of the adduct is not known, but appears to involve one major and several minor species.


Caroli's syndrome in a post renal transplant patient: case report and review of the literature.
Caroli's syndrome is characterized by bile duct ectasia in association with hepatic fibrosis. It is usually transmitted in an autosomal recessive fashion and has been well documented to be associated with autosomal recessive polycystic kidney disease and occasionally with autosomal dominant polycystic kidney disease. However, there has been only few case reports published with Caroli's syndrome diagnosed postrenal transplantation.


Application of a new test for vitamin E deficiency to cystic fibrosis.
Cystic fibrosis patients with pancreatic insufficiency are at risk for the development of vitamin E deficiency. We report here the outcome of screening 13 cystic fibrosis patients with conventional descriptive measures of vitamin E status and a new functional test. The results were compared with those from age appropriate controls. Nine patients were found to be vitamin E sufficient based upon normal plasma vitamin E levels, the ratio of plasma vitamin E to total plasma lipids, and normal levels of in vitro erythrocyte malondialdehyde formation, the new functional measure of vitamin E status. Four patients considered vitamin E deficient, based upon low plasma vitamin E levels and plasma vitamin E to total plasma lipid ratios, demonstrated increased erythrocyte malondialdehyde formation in vitro when compared to age-matched controls. Since limited reference data in children are available to define normal plasma vitamin E levels and plasma vitamin E to total plasma lipid ratios, we suggest that for cystic fibrosis patients the functional in vitro malondialdehyde formation test may be a better measure of vitamin E status than static plasma levels.


The impact of an integrated PBL curriculum on clinical thinking in undergraduate medical students prior to clinical practice.
Problem-based learning (PBL) is a widely adopted educational approach in medical education that aims to promote critical thinking and problem-solving in authentic learning situations. However, the impact of PBL educational mode on undergraduate medical students' clinical thinking ability has been limitedly investigated. This study aimed to assess the influence of an integrated PBL curriculum on clinical thinking ability of medical students prior to clinical practice. Two hundred and sixty-seven third-year undergraduate medical students at Nantong University were recruited in this study and were independently assigned to either the PBL or control group. The Chinese version of the Clinical Thinking Ability Evaluation Scale was used to assess clinical thinking ability, and the students' performance in the PBL tutorials was assessed by tutors. All participants in both groups were required to complete the pre-test and post-test questionnaires to self-report their clinical thinking ability. A paired sample t-test, independent sample t-test and one-way analysis of variance test (ANOVA) were used to compare the difference in clinical thinking scores among different groups. Multiple linear regression was conducted to analyze the influencing factors correlated with clinical thinking ability. The clinical thinking ability of most third-year undergraduate medical students at Nantong University was at a high level. The PBL group had a higher proportion of students with high-level clinical thinking ability in the post-test compared to the control group. The pre-test scores of clinical thinking ability were similar between the PBL and control groups, but the post-test scores of clinical thinking ability in the PBL group were significantly higher than those in the control group. Additionally, there was a significant difference in clinical thinking ability between the pre-test and post-test in the PBL group. The post-test scores of sub-scales of critical thinking ability were significantly higher than the pre-test in the PBL group. Furthermore, the frequency of reading literature, time of PBL self-directed learning, and PBL performance score ranking were influencing factors on the clinical thinking ability of medical students in the PBL group. Moreover, there was a positive correlation between clinical thinking ability and the frequency of reading literature, as well as the scores of the PBL performance. The integrated PBL curriculum model has an active impact on improving undergraduate medical students' clinical thinking ability. This improvement in clinical thinking ability may be correlated with the frequency of reading literature, as well as the performance of the PBL curriculum.


[Evaluation of informative value of laboratory tests and test complexes for the occupational diseases].
The authors discuss the criteria for rational selection of laboratory parameters most informative for the diagnosis of occupational diseases. Such criteria as diagnostic significance, diagnostic specificity, diagnostic informative value according to Kulback (Igx), and diagnostic selectiveness ensure the optimal selection of laboratory parameters for the diagnosis of occupational diseases. Diagnostic sensitivity is not a stable value, as it depends on the disease severity and degree of exposure to harmful factors. Basic requirements, which should be taken account of when selecting the complex of laboratory methods for the diagnosis of occupational diseases, are defined.


20-Hydroxyecdysone acts in the male pupa to commit accessory glands toward trehalase production in the adult mealworm beetle (Tenebrio molitor).
During postecdysial adult maturation, the bean-shaped accessory reproductive glands (BAGs) of adult male mealworm beetles produce increasing amounts of trehalase. In order to determine when the BAGs become competent to produce trehalase, we transplanted pupal BAGs into 0-day female adults. After 8 days, trehalase activity had increased in BAGs from 4- and 5-day pupae (at the time of the pupal ecdysteroid peak) but not in those from 1- and 2-day pupae (before the ecdysteroid peak). BAGs from 0- and 2-day pupae were exposed to 20-hydroxyecdysone in vitro before implantation into 0-day female adults. Increase in trehalase activity was dose dependent. Both dose (ED50, 5 x 10(-6) M) and exposure time (greater than 6 hr) of hormone required are greater for commitment than for acceleration of pupal cell cycling (T. Yaginuma, H. Kai, and G.M. Happ, 1988, Dev. Biol. 126, 173-181). Since trehalase activity increased markedly in isolated adult male abdomens, factors from the cephalic and thoracic centers are not required to sustain trehalase production in the adult BAGs.


[Rhabdomyolysis induced by paliperidone palmitate].
Rhabdomyolysis is defined by disintegration of skeletal muscle fibres. Clinical presentation varies and is mostly associated with myalgias as well as elevation of creatine kinase in the serum. Mechanical damage, toxic medicinal factors, and predisposing factors such as myopathies may trigger the condition. This report describes a case of rhabdomyolysis uncovered by chance after administration of paliperidonepalmitate as depot medication in a 45 years old schizophrenic male patient after having tolerated oral risperidone without any problems. Routine screening for clinical manifestations and serum-creatin kinase maybe essential in unravelling antipsychotic-induced rhabdomyolysis.