FDG-PET-driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study.
Dose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- patients were assigned ASCT, and PET4+ patients were treated with the investigator's choice. The primary end-point was the 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (ΔSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n = 109) or R-CHOP14 (n = 102). PET4-/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P = .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P = .08), leading to more salvage therapy (37% vs 26%; P = .07) and lower event-free survival (EFS; 4-year EFS, 31% vs 43%; P < .01), but progression-free survival (PFS) and overall survival (OS) were similar in both groups. PET2-/PET4- and PET2+/PET4- patients had similar outcomes. Using ΔSUVmax, 79% of the patients were PET2-/PET4- ΔSUVmaxPET0-4 >70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing an alternative to SIC, including ASCT.


Prognostic Value of Preoperative Coping Strategies for Pain in Patients with Residual Neuropathic Pain after Laminoplasty for Compressive Cervical Myelopathy.
Single-center retrospective cohort study. To clarify the prognostic value of preoperative coping strategies for pain due to compressive cervical myelopathy. Preoperative physical function, imaging and electrophysiological findings are known predictors of surgical outcomes. However, coping strategies for pain have not been considered. Postoperative questionnaires, concerning health-related quality of life (HRQOL) and daily living activities, were sent to 78 patients with compressive cervical myelopathy who had suffered from neuropathic pain before laminoplasty, and been preoperatively assessed with respect to their physical and mental status and coping strategies for pain. Hierarchical multiple regression analysis was performed to clarify the extent to which the patient's preoperative coping strategies could explain the variance in postoperative HRQOL and activity levels. Forty-two patients with residual neuropathic pain after laminoplasty were analyzed by questionnaires (28 men, 14 women; mean age, 62.7±10.2 years; symptom duration, 48.0±66.0 months). The valid response rate was 53.8%. Hierarchical multiple regression analysis showed that preoperative coping strategies, which involved coping self-statements, diverting attention, and catastrophizing, were independently associated with postoperative HRQOL and activity level, and could explain 7% to 11% of their variance. Combinations of the coping strategies for pain and upper/lower motor functions could explain 26% to 36% of the variance in postoperative HRQOL and activity level. Preoperative coping strategies for pain are good predictors of postoperative HRQOL and activities of daily living in patients with postoperative residual neuropathic pain due to compressive cervical myelopathy.


Correction: Plasma extracellular vesicle phenotyping for the differentiation of early-stage lung cancer and benign lung diseases.
Correction for 'Plasma extracellular vesicle phenotyping for the differentiation of early-stage lung cancer and benign lung diseases' by Liwen Yuan et al., Nanoscale Horiz., 2023, 8, 746-758, https://doi.org/10.1039/d2nh00570k.


Clinicopathologic correlations in a family with a TBK1 mutation presenting as primary progressive aphasia and primary lateral sclerosis.
Mutations in the TANK binding kinase 1 gene (TBK1) are associated with amyotrophic lateral sclerosis and/or frontotemporal dementia; however, the range of clinical phenotypes and neuropathological changes associated with these mutations have not yet been completely elucidated. We present the detailed clinical, neuroimaging, and neuropathological features of two brothers carrying the TBK1 p.Gly272_Thr331del mutation. Both presented with very similar and unusual clinical features including primary progressive aphasia and asymmetric-onset primary lateral sclerosis (PLS). Repeated electrophysiological studies failed to reveal any lower motor neuron involvement. Neuropathological evaluation of both cases revealed frontotemporal lobar degeneration with TDP-43 proteinopathy type B and selective involvement of upper motor neurons with TDP-43 inclusions. The stereotypical clinical presentation and neuropathological findings in these cases widen the phenotypic spectrum of TBK1 mutations and provide insights into the pathogenesis of PLS.


Cross-sectional analysis of pulsatile hemodynamics across the adult life span: reference values, healthy and early vascular aging: the Heinz Nixdorf Recall and the MultiGeneration Study.
Pulsatile hemodynamics predict major cardiovascular events. We aimed to provide comprehensive population-based reference values and to compare different measures of pulsatile hemodynamics to define early vascular aging (EVA) as well as healthy vascular aging (HVA). In 2721 participants from the population-based Heinz Nixdorf Recall Study and the associated MultiGeneration Study, free from diabetes, cardiovascular disease, and antihypertensive drugs, we performed high-fidelity radial tonometry, calibrated waveforms with brachial blood pressures and processed them with a validated transfer function, pulse wave analysis, and wave separation analysis. Aortic pulse wave velocity (aoPWV) was estimated with a validated regression formula. HVA was defined as the lowest, EVA as the highest age-specific decile of central pulse pressure (cPP), backward wave amplitude, and aoPWV. Overall, 56.4% of participants were female, age range 18-90 years. Brachial PP increased from middle age, whereas cPP increased across the entire adult life span. Wave reflections increased across all age groups, apart from a plateau in older male participants. Indices of wave reflection were higher in women than in men. AoPWV showed the most prominent rise with age in both sexes. EVA and HVA, defined by cPP and backward wave amplitude, differed mainly by hemodynamic variables. In contrast, EVA participants were characterized by a worse hemodynamic, anthropometric, metabolic, and inflammatory profile, if aoPWV was used to discriminate EVA and HVA. Age-specific and sex-specific reference values for central pulsatile hemodynamics in a general white population cohort are provided and may be utilized to define HVA and EVA.


Moyamoya disease in adults: the role of cerebral revascularization.
Moyamoya disease is a disorder characterized by bilateral progressive steno-occlusion of the terminal internal carotid arteries with associated development of a fragile network of basal collateral vessels. It most commonly presents in children, but is also frequently seen in adults, especially in the third or fourth decade of life. Adults afflicted with this disease have very different clinical characteristics as compared with children. For example, adults more commonly present with hemorrhage than cerebral ischemia, while children present with cerebral ischemia nearly 75% of the time and very rarely present with hemorrhage. This significantly impacts treatment considerations for the adult-onset moyamoya patient, as cerebral revascularization, though well accepted in the context of cerebral ischemia, is relatively controversial for the prevention of rehemorrhage. The purpose of this article is to review the pertinent general features of moyamoya disease, examine the clinical characteristics associated with the adult-onset form of this disease, and provide a detailed discussion regarding the indications, operative techniques, and outcomes of direct and indirect revascularization surgical procedures.


N-methyl-N'-nitro-N-nitrosoguanidine and benzo[a]pyrene-7,8-diol-9,10-epoxide inhibit glucocorticoid-inducible polyoma virus middle-T gene expression in rat mT-1 cells by a post-transcriptional mechanism.
Treatment of rat mT-1 cells with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) inhibited the steroid-induced expression of the polyoma virus middle-T (mT) gene. Rat mT-1 cells were derived from normal F111 fibroblasts transfected with a plasmid (pSVM-mT) containing a mT cDNA sequence linked to the mouse mammary tumor virus long terminal repeat, thus rendering the mT gene responsive to glucocorticoid hormones. Following a 1-h treatment period with either 100 ng/ml of MNNG or 100 ng/ml of BPDE, administration of 1 microM dexamethasone (DEX) for 24 h resulted in, respectively, 51 and 33% less induction of phosphorylated mT protein in carcinogen-treated than in solvent-treated cells. MNNG appeared to increase the basal level of phosphorylated mT antigen expression by 44%, whereas BPDE had little or no effect on the level of phosphorylated mT protein in uninduced cells. MNNG and BPDE had little or no effect on the level of total steroid-induced mT RNA following addition of DEX for 4 or 20 h. The concentrations of MNNG and BPDE used in these experiments caused, respectively, an 18 and 30% decline in cell number 24 h following carcinogen treatment and had no effect on cell viability as determined by trypan blue exclusion. Previous studies demonstrating the inhibitory effects of chemical carcinogens on the steroid-mediated induction of endogenous genes suggested that carcinogens mediate their effects via a pretranslational mechanism. The present study, using a recombinant DNA construct inserted into the cell genome, provides evidence that carcinogens can inhibit hormone-induced gene expression by a post-transcriptional mechanism as well.


Cultured muscle cells from insulin-resistant type 2 diabetes patients have impaired insulin, but normal 5-amino-4-imidazolecarboxamide riboside-stimulated, glucose uptake.
Impaired insulin action is a characteristic feature of type 2 diabetes. The study aims were to investigate whether after prolonged culture skeletal muscle cultures from insulin-resistant, type 2 diabetic patients (taking >100 U insulin/d) displayed impaired insulin signaling effects compared with cultures from nondiabetic controls and to determine whether retained abnormalities were limited to insulin action by studying an alternative pathway of stimulated glucose uptake. Studies were performed on myotubes differentiated for 7 d between passages 4 and 6. Insulin-stimulated glucose uptake (100 nm; P < 0.05) and insulin-stimulated glycogen synthesis (1 nm; P < 0.01) were significantly impaired in the diabetic vs. control cultures. Protein kinase B (PKB) expression and phosphorylated PKB levels in response to insulin stimulation (20 nm) were comparable in the diabetic and control cultures. 5-Amino-4-imidazolecarboxamide riboside (AICAR) mimics the effect of exercise on glucose uptake by activating AMP-activated protein kinase. There was no difference in AICAR (2 mm)-stimulated glucose uptake between diabetic vs. control myotube cultures (P = not significant). In conclusion, diabetic muscle cultures retain signaling defects after prolonged culture that appear specific to the insulin signaling pathway, but not involving PKB. This supports an intrinsic abnormality of the diabetic muscle cells that is most likely to have a genetic basis.


Are overweight and obese adolescents different from their peers?
To identify psychosocial and lifestyle indicators including alcohol consumption, that may distinguish overweight and obese adolescents from their peers, and align them with other adolescents with chronic conditions. The sample included 6 131 6th, 8th, and 10th grade public school Portuguese students, aged 11-16 years, who participated in the Health Behavior in School-Aged Children (HBSC)/WHO survey of adolescent health. Body mass index (BMI) was based on self reported weight and height. Separate analyses of psychosocial and behavioral variables were conducted by gender, age group, and BMI, using Chi square, and ANOVA. Obese and overweight teens when compared with non-overweight teens, were more likely to report a negative attitude towards their appearance; to believe that others made negative comments about them; had a lower level of life satisfaction; had more difficulty in making new friends, and were more likely to describe themselves as unhappy. Moreover, obese teens were significantly more likely than their non-obese peers to describe themselves as having health problems, to report drinking alcohol daily, as well as having been drunk more than 10 times. The present study provides further evidence regarding the association between overweight and obesity in adolescence, and body image dissatisfaction, poorer self-assessed health status, potential social isolation, decreased life satisfaction, and problematic alcohol consumption patterns. Overweight and obese adolescents should, where possible, be reached with appropriate interventions addressing the broad spectrum of their psychological needs, enhancing their skill development for behavioral change, and providing support for dealing with potentially harmful behaviors.


The variation of risk estimates through pregnancy in second trimester maternal serum screening for Down syndrome.
The variation of risk estimates in second trimester maternal serum screening for Down's syndrome has been shown to be considerable in quality control schemes, i.e. UKNEQAS. We studied the biological variation of risk estimates in 16 women through pregnancy. The maternal serum markers alpha-fetoprotein (AFP), human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and beta-hCG were determined six times during late first to late second trimester, and the associated likelihood ratios for Down syndrome were calculated. The interpersonal variation of markers, as well as that of the likelihood ratio, was much greater than the intrapersonal variation. The average intrapersonal standard deviation (SD) of the triple test log likelihood ratio was 0.2291, corresponding to a central 95-percentile interval 0.36-2.81 of the likelihood ratio. The interpersonal SD of the log likelihood ratio was 0.5482, corresponding to a central 95-percentile interval 0.08-11.87 of the likelihood ratio. The large difference between the intra- and interpersonal variation makes it unlikely that biological variation through pregnancy is a major contributor to the variation of risk estimates obtained several times in the same pregnancy. Rather, improvements in analytical quality and laboratory management must be expected to result in reduced variation and, in consequence, better performance of screening.


Childhood lymphomatoid granulomatosis: a report of 2 cases and review of the literature.
Lymphomatoid granulomatosis (LG) is a B-cell type lymphoproliferative disease. It mainly affects the lungs but may have extrapulmonary manifestations, especially in the central nervous system. The purpose of this study was to review the pediatric cases in the literature and add 2 new cases to the existing literature. A review of the literature was performed on children (0 to 18 years of age at diagnosis) with pathologically proven LG. We found 47 case reports, which, together with 2 new cases, were systematically analyzed. The median age was 12 years. The main symptoms were general, pulmonary, and neurological. Approximately one third of the patients were immunocompromised. High mortality rate was observed. Pediatric LG is a rare disease, which appears to be more frequently seen in immunocompromised patients, especially patients with leukemia. The disease has a high mortality rate; therefore, aggressive therapy according to a high-grade B-cell lymphoma protocol is justified.


Ferroptosis in pulmonary fibrosis: an emerging therapeutic target.
In recent years, the role of ferroptosis in pulmonary fibrosis has garnered increasing interest as a potential therapeutic target. Pulmonary fibrosis is a pathological process characterized by the accumulation of extracellular matrix in affected lung tissues, and currently, there are no effective therapies for preventing or reversing the fibrotic lesions. Ferroptosis is a form of programmed cell death that is regulated by a network of enzymes and signaling pathways. Dysregulation of ferroptosis has been implicated in several diseases, including pulmonary fibrosis. The accumulation of lipid peroxides in the course of ferroptosis causes damage to cell membranes and other cellular components, leading ultimately to cell death. Relevant targets for therapeutic intervention in ferroptosis include key enzymes, such as glutathione peroxidase 4, transcription factors like nuclear factor erythroid 2-related factor 2, and iron chelation. This review provides an overview of the emerging role of ferroptosis in pulmonary fibrosis and highlights potential therapeutic targets in this pathway. Further research is needed to develop safe and effective approaches targeting ferroptosis in treatment of pulmonary fibrosis.


Detectability of colorectal neoplastic lesions using a narrow-band imaging system: a pilot study.
Flat and depressed colorectal neoplastic lesions can be difficult to identify using conventional colonoscopy techniques. Narrow-band imaging (NBI) provides unique views especially of mucosal vascular network and helps in visualization of neoplasia by improving contrast. The aim of this study was to assess the feasibility of using NBI for colorectal neoplasia screening. Forty-seven consecutive patients, who underwent high definition colonoscopy (HDC) screening examinations revealing neoplastic lesions, were enrolled in our prospective study. No biopsies or resections were performed during the initial HDC, but patients in whom lesions were detected underwent further colonoscopies using NBI, with the results of the first examination blinded from the colonoscopist. They then received appropriate treatment. We compared diagnostic detection rates of neoplastic lesions for HDC and NBI procedures using total number of all identified neoplastic lesions as reference standard. Altogether, 153 lesions were detected and analyzed in 43 patients. Mean diagnostic extubation times were not significantly different (P = 0.18), but the total number of lesions detected by NBI was higher (134 vs 116; P = 0.02). Based on macroscopic type, flat lesions were identified more often by NBI (P = 0.04). As for lesion size, only flat lesions < 5 mm were detected more frequently (P = 0.046). Lesions in the right colon were identified more often by NBI (P = 0.02), but NBI missed two flat lesions >or= 10 mm located there. Narrow band imaging colonoscopy may represent a significant improvement in the detection of flat and diminutive lesions, but a future multi-center controlled trial should be conducted to fully evaluate efficacy for screening colonoscopies.


Nuclear status of human sperm cells by transmission electron microscopy and image cytometry: changes in nuclear shape and chromatin texture during spermiogenesis and epididymal transit.
Computer-assisted transmission electron microscopy (TEM) image cytometry was used to investigate changes in nuclear shape and chromatin texture of human sperm during normal spermiogenesis and epididymal transit. Analysis was performed on a large series of micrographs of longitudinal sections of nuclei from spermatids and epididymal caput and cauda sperm. Thirteen parameters characterizing nuclear shape and chromatin texture were measured. Quantitative data showed that from early spermiogenesis to the end of epididymal transit, a decrease in nuclear area and width occurred concomitantly with not only an increase in chromatin condensation but also an increase in heterogeneity of the degree of condensation. The oriented spatial arrangement of chromatin along the major nuclear axis as measured by gradient parameters indicated that in humans, condensation of chromatin begins in the posterior pole and proceeds apically; this is an important difference between humans and other mammalian species. Most parameters did not differ substantially in sperm from testis and caput epididymis, but did change as the cells moved from the caput to the cauda epididymis, indicating completion of nuclear maturation. Discriminant functions of basic parameters, as followed by canonical transformation and cluster representation, automatically classified the nuclei in a sequence that was found to concur with the biological maturation sequence during normal spermiogenesis and epididymal transit.


The Steinberg Centre for Simulation and Interactive Learning at McGill University.
Simulation allows for learner-centered health professions training by providing a safe environment to practice and make mistakes without jeopardizing patient care. It was with this goal in mind that the McGill Medical Simulation Center was officially opened on September 14, 2006, as a partnership between McGill University, the Faculty of Medicine and its affiliated hospitals. Its mandate is to provide state-of-the-art facilities to support simulation-based medical and allied health education initiatives. Since its inception, the center, recently renamed the Steinberg Center for Simulation and Interactive Learning (SCSIL), has undergone a major expansion and logged more than 130,000 learner visits. Educational activities are offered at all levels of medical and allied health care training, and include standardized patient encounters, partial task trainers, multidisciplinary courses, and high-fidelity trainers, among many others. In addition to its educational mandate, the center also supports an active research program, programs to enhance collaboration with disciplines outside of health care to spur innovation, and community outreach initiatives.


Conformational dynamics in a dipeptide after single-mode vibrational excitation.
The dynamics of conformational isomerization are explored in a methyl-capped dipeptide, N-acetyl-tryptophan methyl amide (NATMA), using infrared-ultraviolet (IR-UV) hole-filling and IR-induced population transfer spectroscopies. IR radiation selectively excites individual NH stretch vibrational fundamentals of single conformations of the molecule in the early portions of a gas-phase expansion, and then this excited population is collisionally recooled into its conformational minima for subsequent conformation-specific detection. Efficient isomerization is induced by the IR excitation that redistributes population between the same conformations that have population in the absence of IR excitation. The quantum yields for transfer of the population into the various conformational minima depend uniquely on which conformation is excited and on which NH stretch vibration is excited within a given conformation.


Inclusion of unexposed clusters improves the precision of fixed effects analysis of stepped-wedge cluster randomized trials.
Stepped-wedge cluster randomized trials (SW-CRTs) are typically analyzed using mixed effects models. The fixed effects model is a useful alternative that controls for all time-invariant cluster-level confounders and has proper control of type I error when the number of clusters is small. In principle, all clusters in SW-CRTs are designed to eventually receive the intervention, but in real-world research, some trials can end with unexposed clusters (clusters that never received the intervention), such as when a trial is terminated early based on interim analysis results. Typically, unexposed clusters are expected to contribute no information to the fixed effects intervention effect estimator and are excluded from fixed effects analyses. In this article we mathematically prove that inclusion of unexposed clusters improves the precision of the fixed effects least squares dummy variable (LSDV) intervention effect estimator, re-analyze data from a recent SW-CRT of a novel palliative care intervention containing an unexposed cluster, and evaluate the methods by simulation. We found that including unexposed clusters improves the precision of the fixed effects LSDV intervention effect estimator in both real and simulated datasets. Our simulations also reveal an increase in power and decrease in root mean square error. These improvements are present even if the assumptions of constant residual variance and period effects are violated. In the case that a SW-CRT concludes with unexposed clusters, these unexposed clusters can be included in the fixed effects LSDV analysis to improve precision, power, and root mean square error.


Activation of a neural brain-testicular pathway rapidly lowers Leydig cell levels of the steroidogenic acute regulatory protein and the peripheral-type benzodiazepine receptor while increasing levels of neuronal nitric oxide synthase.
Activation of a neural brain-testicular pathway by the intracerebroventricular injection of the beta-adrenergic agonist isoproterenol (ISO), the hypothalamic peptide corticotropin-releasing factor (CRF), or alcohol (EtOH) rapidly decreases the testosterone (T) response to human chorionic gonadotropin. To elucidate the intratesticular mechanisms responsible for this phenomenon, we investigated the influence of intracerebroventricular-injected ISO, CRF, or EtOH on levels of the steroidogenic acute regulatory (StAR) protein, the peripheral-type benzodiazepine receptor (PBR), and the cytochrome P450 side-chain cleavage enzyme in semipurified Leydig cells. ISO (10 microg), CRF (5 microg), or EtOH (5 microl of 200 proof, a dose that does not induce neuronal damage nor leaks to the periphery) rapidly decreased StAR and PBR but not cytochrome P450 side-chain cleavage enzyme protein levels. Levels of the variant of the neuronal nitric oxide synthase (nNOS) that is restricted to Leydig cells, TnNOS, significantly increased in response to ISO, CRF, and EtOH over the time course of altered StAR/PBR concentrations. However, pretreatment of the rats with N(w)nitro-arginine methylester, which blocked ISO-induced increases in TnNOS, neither restored the T response to human chorionic gonadotropin nor prevented the decreases in StAR and PBR. These results provide evidence of concomitant changes in Leydig cell StAR and PBR levels in live rats. They also indicate that activation of a neural brain-testicular pathway rapidly decreases concentrations of these steroidogenic proteins while up-regulating testicular NO production. However, additional studies are necessary to elucidate the functional role played by this gas in our model.


Pancreatogastrostomy vs pancreatojejunostomy after pancreaticoduodenectomy: An updated meta-analysis of RCTs and our experience.
Pancreatoduodenectomy (PD) is one of the most important operations in hepatobiliary and pancreatic surgery. To evaluate the advantages and disadvantages of pancreaticojejunostomy (PJ) and pancreaticogastrostomy (PG). This meta-analysis was performed using Review Manager 5.3. All clinical randomized controlled trials, in which patients underwent PD with pancreatico-digestive tract reconstruction via PJ or PG, were included. The search of PubMed, Wanfang Data, EMBASE, and the Cochrane Library provided 125 citations. After further analysis, 11 trials were included from nine counties. In all, 909 patients underwent PG and 856 underwent PJ. Meta-analysis showed that pancreatic fistula (PF) was a significantly lower morbidity in the PG group than in the PJ group (odds ratio [OR] = 0.67, 95% confidence interval [CI]: 0.53-0.86, P = 0.002); however, grades B and C PF was not significantly different between the two groups (OR = 0.61, 95%CI: 0.34-1.09, P = 0.09). Postoperative hemorrhage showed a significantly lower morbidity in the PJ group than in the PG group (OR = 1.47, 95%CI: 1.05-2.06, P = 0.03). Delayed gastric emptying was not significantly different between the two groups (OR = 1.09, 95%CI: 0.83-1.41, P = 0.54). There is no difference in the incidence of grades B and C PF between the two groups. However, postoperative bleeding is significantly higher in PG than in PJ. Binding PJ or binding PG is a safe and secure technique according to our decades of experience.


Intracellular glucose metabolism after long term metabolic control with glyburide: improved glucose oxidation with unchanged glycogen synthase activity.
To determine whether improved metabolic control with long term glyburide treatment alters intracellular glucose metabolism independent of effects on glucose uptake (GU), we studied eight obese patients with noninsulin-dependent diabetes mellitus before and 7 months after glyburide therapy. Indirect calorimetry and skeletal muscle biopsies were performed in the basal state and during 300 pmol/m2.min insulin infusions, with glucose turnover rates determined by [3-3H]glucose turnover. During the glucose clamps, rates of GU were matched before and after treatment using equivalent hyperinsulinemia and variable levels of hyperglycemia. After glyburide treatment, rates of GU were decreased in the basal state [4.16 +/- 0.57 vs. 3.29 +/- 0.37 mg/kg fat free mass (FFM)/min; P < 0.05], but similar during glucose clamps (11.53 +/- 1.42 vs. 11.93 +/- 1.32 mg/kg FFM.min; P = NS) according to study design. In both the basal state and during glucose clamps after glyburide therapy, rates of glucose oxidative metabolism (Gox) increased by 68-78% [1.21 +/- 0.16 vs. 2.03 +/- 0.31 mg/kg FFM.min (P < 0.05) and 3.13 +/- 0.51 vs. 5.58 +/- 0.55 mg/kg FFM.min (P < 0.05), respectively], and rates of nonoxidative glucose metabolism decreased [2.96 +/- 0.68 vs. 1.25 +/- 0.21 mg/kg FFM.min (P < 0.05) and 8.40 +/- 1.50 to 6.30 +/- 1.40 mg/kg FFM.min (P < 0.01), respectively]. Circulating plasma FFA levels and rates of fat oxidation (Fox) remained unchanged in both the basal state and during clamp studies. Skeletal muscle glycogen synthase (GS) activity, expressed as fractional velocity, was unchanged by glyburide therapy (2.2 +/- 0.8 vs. 2.7 +/- 0.3% in the basal state and 7.3 +/- 1.8 vs. 6.1 +/- 0.9% during clamps; both P = NS). In summary, at both matched (during clamp studies) and unmatched (during basal studies) rates of GU, improved metabolic control with glyburide therapy resulted in marked improvement of Gox independent of the effects on GU. The improvement in Gox was not associated with changes in Fox, circulating FFA, or muscle GS activity. These data indicate that long term metabolic control achieved by glyburide therapy markedly improves Gox, but not skeletal muscle GS activity, in noninsulin-dependent diabetes mellitus independent of GU and Fox.


Soluble angiogenic factors in patients with acute pancreatitis.
Angiogenic factors are involved in the physiopathology of several inflammatory diseases and they probably play a role in the pathogenesis of acute pancreatitis (AP). To investigate if angiogenic factors are elevated in patients with AP, their relationship with severity and clinical evolution of AP, and their use as prognosis markers of AP. A case (25)-control (30) study was carried out. Patients with AP were classified according to severity (using Ranson and Glasgow scores) and according to their clinical evolution (taking into account the development of complications during hospital stay). Platelet-derived growth factor (PDGFBB), angiopoietin-1, angiopoietin-2 (Ang-2), angiopoietin tyrosine-kinase receptor, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), VEGF tyrosine-kinase receptor 1, and VEGF tyrosine-kinase receptor 2 were determined at 12 hours and then at 5 days after hospitalization. PDGFBB, Ang-2, angiopoietin tyrosine-kinase receptor, and HGF were significantly higher in cases (P<0.001), and in patients with unfavorable clinical evolution (P<0.001). PDGFBB and HGF were significantly higher in patients with severe AP (P<0.05). To predict unfavorable clinical evolution, PDGFBB, Ang-2, and HGF showed an area under receiver operating characteristic curve of 0.97. PDGFBB and HGF are related to severity of AP. These factors along with Ang-2 are related to clinical evolution and are useful in predicting the development of several complications during hospital stay. Therefore, these angiogenic factors could be useful as prognosis markers of AP.


Separation of tamsulosin enantiomers by capillary electrophoresis with tandem mass spectrometry and online stacking preconcentration.
The aim of our work was to develop a new method for the analysis of tamsulosin enantiomers by capillary electrophoresis connected with tandem mass spectrometry. The pharmacologically active (R)-enantiomer of tamsulosin, is used to treat benign prostatic hyperplasia and chronic prostatitis. Under the optimal conditions, background electrolyte consisting of 200 mM acetic acid titrated with NH4OH to pH 4.0 containing 4.0 mg mL-1 sulfated β-cyclodextrin, an injection time of 40 s at 50 mbar, a voltage of 20 kV and an optimized MS set-up (as e.g., sheath liquid containing 75 : 24.9 : 0.1 MeOH, H2O, and formic acid, v/v), a limit of detection of 1.6 nmol L-1 was achieved. The method was validated in terms of linearity, detection and quantification limits, precision, recovery, and selectivity. The results showed that the method can be used for the analysis of tamsulosin enantiomers in environmental samples, but generally, it can be applied to many different analytical tasks.


Differences of Socio-psychology, Eating Behavior, Diet Quality and Quality of Life in South Korean Women according to Their Weight Status.
We aimed at assessing psychological variables and eating behaviors on quality of diet and life in South Korean women according to their weight status. Socio-psychology, eating behavior, quality of diet and quality of life data were assessed in 114 women (mean age: 34.5 ± 8.09 years). NEO Personality Inventory (NEO-PI-RS) and coping styles questionnaire were used to assess socio-psychology variables, and eating behavior was assessed using the Eating Attitudes Test-26 (EAT-26), Dutch Eating Behavior Questionnaire (DEBQ), and General Food Craving Questionnaire Test (G-FCQ-T). Quality of diet was analyzed by Diet Quality Index-international (DQI-I), and obesity-related quality of life was evaluated using the Korean Obesity-related Quality of life Scale (KOQOL). Significant differences were in the psychological variables and eating behaviors in the obese group than the normal and overweight groups (p < 0.05). The overall score of DQI-I was significantly lower in the obese group than that of their counterparts (p < 0.05). BMI was positively correlated with neuroticism, emotional eating, and obesity-related quality of life, and negatively correlated with diet quality. Neuroticism was positively correlated with emotional eating and food craving. Emotional eating was positively correlated with obesity-related quality of life. In conclusion, women with a higher BMI had significantly more problematic eating behaviors, poor diet quality and quality of life.


Development of global cortical networks in early infancy.
Human cognition and behaviors are subserved by global networks of neural mechanisms. Although the organization of the brain is a subject of interest, the process of development of global cortical networks in early infancy has not yet been clarified. In the present study, we explored developmental changes in these networks from several days to 6 months after birth by examining spontaneous fluctuations in brain activity, using multichannel near-infrared spectroscopy. We set up 94 measurement channels over the frontal, temporal, parietal, and occipital regions of the infant brain. The obtained signals showed complex time-series properties, which were characterized as 1/f fluctuations. To reveal the functional connectivity of the cortical networks, we calculated the temporal correlations of continuous signals between all the pairs of measurement channels. We found that the cortical network organization showed regional dependency and dynamic changes in the course of development. In the temporal, parietal, and occipital regions, connectivity increased between homologous regions in the two hemispheres and within hemispheres; in the frontal regions, it decreased progressively. Frontoposterior connectivity changed to a "U-shaped" pattern within 6 months: it decreases from the neonatal period to the age of 3 months and increases from the age of 3 months to the age of 6 months. We applied cluster analyses to the correlation coefficients and showed that the bilateral organization of the networks begins to emerge during the first 3 months of life. Our findings suggest that these developing networks, which form multiple clusters, are precursors of the functional cerebral architecture.


Comparative bioavailability of two cefadroxil products using serum and urine data in healthy human volunteers.
1. The aim of the present study was to assess the bioequivalence of two cefadroxil products, namely Ultracef (a reference product) in the form of a 500 mg capsule (produced by Bristol-Myers Squibb Laboratories, Princeton, NJ, USA) and Roxil (a test product) in the form of a 500 mg capsule (produced by Tabuk Pharmaceutical Manufacturing, Tabuk, Saudi Arabia). 2. The study was performed under US Food and Drug Administration (FDA) guidelines (http://www.fda.gov/cder) on 24 healthy male subjects. Both products were administered orally as a single dose (1 x 500 mg capsule) separated by a 1 week washout period. Following oral administration, blood and urine samples were obtained and analysed for cefadroxil concentrations using a sensitive and specific HPLC assay. 3. There were no statistically significant differences between the two products in either the mean concentration-time profiles or the cumulative urinary excretion of cefadroxil at various times. Similarly, no statistical significance was observed in the pharmacokinetic parameters reflecting rate and extent of drug absorption. The relative extent of drug absorption, assessed by calculating the area under the curve (AUC) ratio for Roxil/Ultracef for 10 h and for infinity was 0.94 with 90% confidence limits (CL) of 0.91-0.98. In agreement with serum data, the average ratio (Roxil/Ultracef) of the cumulative amount of cefadroxil excreted in urine 10 h after the dose was found to be 0.97, with 90% CL of 0.88-1.05. The CL of the AUC and cumulative urinary excretion ratios are within the FDA accepted limits for bioequivalent products (0.80-1.25). 4. These findings show that serum and urine data of cefadroxil are in agreement and indicate that Roxil (the test product) and Ultracef (the reference product) are bioequivalent in terms of the rate and extent of drug absorption.


Issues in defining mental retardation.
Responses were made to MacMillan, Gresham, and Siperstein's (1993) criticisms of the new AAMR definition. The new AAMR definition does not raise the IQ limit and is not intended to increase the number of people considered to have mental retardation. There is no intent to change who is and who is not considered to have mental retardation. Instead, the intent is to change how people think about mental retardation: The old deficiency model is replaced with a new support model. MacMillan et al.'s criticisms are based on unfortunate misstatements of both the 1983 and the 1992 AAMR definitions of mental retardation and on misunderstandings of psychometric science. On the one hand, they argued that intelligence tests are culturally biased. On the other hand, they criticized the AAMR for not making greater use of inflexible IQ cutoffs in defining mental retardation. They misunderstood that cultural bias is an argument for, not against, flexibility in the interpretation of intelligence tests.


Membranes, energetics, and evolution across the prokaryote-eukaryote divide.
The evolution of the eukaryotic cell marked a profound moment in Earth's history, with most of the visible biota coming to rely on intracellular membrane-bound organelles. It has been suggested that this evolutionary transition was critically dependent on the movement of ATP synthesis from the cell surface to mitochondrial membranes and the resultant boost to the energetic capacity of eukaryotic cells. However, contrary to this hypothesis, numerous lines of evidence suggest that eukaryotes are no more bioenergetically efficient than prokaryotes. Thus, although the origin of the mitochondrion was a key event in evolutionary history, there is no reason to think membrane bioenergetics played a direct, causal role in the transition from prokaryotes to eukaryotes and the subsequent explosive diversification of cellular and organismal complexity.


[The problem of study of unexplainable antenatal fetal death].
The paperpresents the data on the causes ofperinatal mortality. Particular emphasis is placed on unexplainable antenatal fetal death, the absence of uniform terminology or a consensus classification of the causes of antenatal fetal death, and the principles in placental studies and stillborn baby autopsy. Various aspects of sophisticated relations in the mother-placenta-fetus system are considered. It is pointed out that the number of unexplainable antenatal fetal deaths can be reduced when the placenta is meticulously studied. A conventional protocol for stillborn baby autopsy and placental studies is noted to be elaborated.


Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators.
Ribonucleotide reductase (RR) catalyzes the rate-limiting step of dNTP synthesis and is an established cancer target. Drugs targeting RR are mainly nucleoside in nature. In this study, we sought to identify non-nucleoside small-molecule inhibitors of RR. Using virtual screening, binding affinity, inhibition, and cell toxicity, we have discovered a class of small molecules that alter the equilibrium of inactive hexamers of RR, leading to its inhibition. Several unique chemical categories, including a phthalimide derivative, show micromolar IC50s and KDs while demonstrating cytotoxicity. A crystal structure of an active phthalimide binding at the targeted interface supports the noncompetitive mode of inhibition determined by kinetic studies. Furthermore, the phthalimide shifts the equilibrium from dimer to hexamer. Together, these data identify several novel non-nucleoside inhibitors of human RR which act by stabilizing the inactive form of the enzyme.


Statistical image reconstruction from correlated data with applications to PET.
Most statistical reconstruction methods for emission tomography are designed for data modeled as conditionally independent Poisson variates. In reality, due to scanner detectors, electronics and data processing, correlations are introduced into the data resulting in dependent variates. In general, these correlations are ignored because they are difficult to measure and lead to computationally challenging statistical reconstruction algorithms. This work addresses the second concern, seeking to simplify the reconstruction of correlated data and provide a more precise image estimate than the conventional independent methods. In general, correlated variates have a large non-diagonal covariance matrix that is computationally challenging to use as a weighting term in a reconstruction algorithm. This work proposes two methods to simplify the use of a non-diagonal covariance matrix as the weighting term by (a) limiting the number of dimensions in which the correlations are modeled and (b) adopting flexible, yet computationally tractable, models for correlation structure. We apply and test these methods with simple simulated PET data and data processed with the Fourier rebinning algorithm which include the one-dimensional correlations in the axial direction and the two-dimensional correlations in the transaxial directions. The methods are incorporated into a penalized weighted least-squares 2D reconstruction and compared with a conventional maximum a posteriori approach.


Human cognition involves the dynamic integration of neural activity and neuromodulatory systems.
The human brain integrates diverse cognitive processes into a coherent whole, shifting fluidly as a function of changing environmental demands. Despite recent progress, the neurobiological mechanisms responsible for this dynamic system-level integration remain poorly understood. Here we investigated the spatial, dynamic, and molecular signatures of system-wide neural activity across a range of cognitive tasks. We found that neuronal activity converged onto a low-dimensional manifold that facilitates the execution of diverse task states. Flow within this attractor space was associated with dissociable cognitive functions, unique patterns of network-level topology, and individual differences in fluid intelligence. The axes of the low-dimensional neurocognitive architecture aligned with regional differences in the density of neuromodulatory receptors, which in turn relate to distinct signatures of network controllability estimated from the structural connectome. These results advance our understanding of functional brain organization by emphasizing the interface between neural activity, neuromodulatory systems, and cognitive function.


Staining method for hepatitis B surface antigen (HBs Ag) and its mechanism.
HBs Ag in the hepatocytes has been stained by the orcein method. As degenerative and necrotic cytoplasms of hepatocytes are occasionally stained also by this method, it is difficult to identify HBs Ag. The orcein dye has different staining properties from lot to lot, causing difficulty in obtaining stable results. Therefore, the author tried to modify the orcein method and found that the procedure using a sensitizer (ferric ammonium sulfate or uranium nitrate) after oxidizing the solution gave stable and satisfactory results. By this method, in the hepatocytes, only HBs Ag is stained positively. The mechanism of function of the sensitizer is not clear, but it is considered that ferric or uranium ions occupy small gaps in the protein molecular structure in the cells before orcein molecules occupy these gaps and that the method does not give any false positive result. It is also suggested that various HBs Ag staining dyes can react with sulfonic acid residue groups which are formed by the oxidization of disulfide group of proteins. Another new staining method for HBs Ag using resorcin fuchsin has been developed. The results of this method were also discussed.


Percutaneous transcatheter myectomy of subvalvar pulmonary stenosis in tetralogy of Fallot: a new palliative technique with an atherectomy catheter.
A male infant with tetralogy of Fallot was given a modified left Blalock-Taussig shunt at 11 days of age because of duct dependence. Twenty months later, because of increasing cyanosis and polycythaemia, he was given palliative treatment with balloon dilatation of the right ventricular outflow tract. Seven months later a right ventricular angiogram showed further progression of the infundibular stenosis with poor anterograde opacification of the pulmonary arteries. He underwent percutaneous transcatheter myectomy of the infundibulum with an atherectomy catheter. One month later he was well and less cyanosed.


Polymerization contraction force of packable composites.
The maximum rate of shrinkage force development and maximum contraction force was evaluated for four packable composites and a hybrid composite control. One of the packable composites demonstrated a significantly higher maximum force rate and maximum force than the other materials; the three remaining packable composites had maximum force rates and maximum forces that were statistically similar to the conventional hybrid composite control.


[Safety aspects of bronchoalveolar lavage in risk patients in childhood--continuous end-expiratory pCO2 monitoring].
Although bronchoalveolar lavage (BAL) is a useful tool even in childhood pulmonary diseases, only little is known about the problems attendant to its use. Hence, we investigated from a total of 212 rigid bronchoscopy procedures 22 patients of 1-10 years of age. General inhalation anaesthesia was performed and BAL was carried out using a paediatric standardised protocol. BAL volume was adjusted to body weight. Before BAL and 2, 7 and 20 minutes after BAL capillary blood gas, blood pressure, heart rate and SaO2 were measured. Continuously end-tidal PCO2 (ET (PCO2) measurement was done by using a catheter placed in the main stream bronchus. Mean ET PCO2 increased from 39.6 +/- 9.5 mmHg to 45.7 +/- 6.87 mmHg. Concomitantly mean capillary PCO2 increased from 46.68 +/- 10.7 mmHg to 50.1 +/- 10.47 mmHg. Correlation of ET PCO2 compared to cap PCO2 was good (r = 0.89). One patient showed desaturation up to 72% another patient hypercapnia up to 77 mmHg. We conclude that generally speaking BAL is a safe procedure, even in high-risk patients. Complications are minor and of little consequence to the patient. However, severe unforeseen events may occur. Therefore, bronchoscopy and bronchoalveolar lavage should not be performed without availability of an intensive-care unit.


Anatomy-guided Dense Individualized and Common Connectivity-based Cortical Landmarks (A-DICCCOL).
Establishment of structural and functional correspondences of human brain that can be quantitatively encoded and reproduced across different subjects and populations is one of the key issues in brain mapping. As an attempt to address this challenge, our recently developed Dense Individualized and Common Connectivity-based Cortical Landmarks (DICCCOL) system reported 358 connectional landmarks, each of which possesses consistent DTI-derived white matter fiber connection pattern that is reproducible in over 240 healthy brains. However, the DICCCOL system can be substantially improved by integrating anatomical and morphological information during landmark initialization and optimization procedures. In this paper, we present a novel anatomy-guided landmark discovery framework that defines and optimizes landmarks via integrating rich anatomical, morphological, and fiber connectional information for landmark initialization, group-wise optimization and prediction, which are formulated and solved as an energy minimization problem. The framework finally determined 555 consistent connectional landmarks. Validation studies demonstrated that the 555 landmarks are reproducible, predictable, and exhibited reasonably accurate anatomical, connectional, and functional correspondences across individuals and populations and thus are named anatomy-guided DICCCOL or A-DICCCOL. This A-DICCCOL system represents common cortical architectures with anatomical, connectional, and functional correspondences across different subjects and would potentially provide opportunities for various applications in brain science.


HEART score performance in Asian and Caucasian patients presenting to the emergency department with suspected acute coronary syndrome.
The HEART score is a simple and effective tool to predict short-term major adverse cardiovascular events in patients suspected of acute coronary syndrome. Patients are assigned to three risk categories using History, ECG, Age, Risk factors and Troponin (HEART). The purpose is early rule out and discharge is considered safe for patients in the low risk category. Its performance in patients of Asian ethnicity is unknown. We evaluated the performance of the HEART score in patients of Caucasian, Chinese, Indian and Malay ethnicity. The HEART score was assessed retrospectively in 3456 patients presenting to the emergency department with suspected acute coronary syndrome (1791 Caucasians, 1059 Chinese, 344 Indians, 262 Malays), assigning them into three risk categories. The incidence of major adverse cardiovascular events within six weeks after presentation was similar between the ethnic groups. A smaller proportion of Caucasians was in the low risk category compared with Asians (Caucasians 35.8%, Chinese 43.5%, Indians 45.3%, Malays 44.7%, p<0.001). The negative predictive value of a low HEART score was comparable across the ethnic groups, but lower than previously reported (Caucasians 95.3%, Chinese 95.0%, Indians 96.2%, Malays 96.6%). Also the c-statistic for the HEART score was not significantly different between the groups. These results show that the overall performance of the HEART score is equal among Caucasian and Asian ethnic groups. The event rate in the low risk group, however, was higher than reported in previous studies, which queries the safety of early discharge of patients in the low risk category.


The impact of body mass index on oncoplastic breast surgery: A multicenter analysis.
Obesity has nearly tripled in the last 50 years. During the last decades, oncoplastic breast surgery has become an important choice in the surgical treatment of breast cancer. An association exists between higher body mass index (BMI) and wound complications for major operations, but there is scarce literature on oncoplastic surgery. Hence, our aim was to compare the complication rates among patients who underwent oncoplastic surgery, stratified by BMI. Patient data were analyzed from the National Surgical Quality Improvement Program database (NSQIP) for oncoplastic breast procedures (2005-2020). Patients were stratified according to World Health Organization obesity classifications. Multivariate logistic regression was performed to assess risk factors for complications (overall, operative, and wound-related). From a total of 6887 patients who underwent oncoplastic surgery, 4229 patients were nonobese, 1380 had Class 1 obesity (BMI: 30 to <35 kg/m2 ), 737 Class 2 obesity (BMI: 35 to <40 kg/m2 ), and 541 Class 3 obesity (BMI: ≥ 40 kg/m2 ). Greater operative time was found according to higher BMI (p < 0.001). Multivariate analysis adjusted for baseline characteristics showed that patients with obesity Class 2 (odds ratio [OR] = 1.51, 95% confidence interval [CI]: 1.03-2.23, p = 0.037) and 3 (OR = 1.87, 95% CI 1.24-2.83, p = 0.003) had increased risk of overall and wound complications compared with Nonobese patients. Comparing obese with nonobese patients, there were no differences in rates of deep SSI, organ/space SSI, pneumonia, reintubation, pulmonary embolism, deep vein thrombosis, urinary tract infection, stroke, bleeding, postoperative sepsis, length of stay, and readmission. Oncoplastic surgery is a safe procedure for most patients. However, caution should be exercised when performing oncoplastic surgery for patients with Class 2 or 3 obesity (BMI ≥ 35 kg/m2 ), given there was a higher rate of overall and wound-specific complications, compared with patients who were not obese or had Class 1 obesity.


Lipotoxicity in Obesity: Benefit of Olive Oil.
The clinical implication of Lipotoxicity in obesity derives primarily from its potential to progress to insulin resistance, endothelial dysfunction and atherosclerosis. Olive oil rich diet decrease accumulation of triglyceride in the liver, improved postprandial triglyceride levels, improve glucose and GLP-1 response in insulin resistant subjects, and up regulate GLUT-2 expression in the liver. The exact molecular mechanism is unknown but, decreasing NFkB activation, decreasing LDL oxidation and improving insulin resistance by less production of inflammatory cytokines (TNF-a, IL-6) and improvement of kinases JNK-mediated phosphorylation of IRS-1 are the principle mechanisms. The beneficial effect of the Mediterranean diet derived from monounsaturated fatty acids (MUFA), mainly from olive oil. In this review we document lipotoxicity in obesity and the benefit of olive oil.


Markers of human skeletal muscle mitochondrial biogenesis and quality control: effects of age and aerobic exercise training.
Perturbations in mitochondrial health may foster age-related losses of aerobic capacity (VO2peak) and skeletal muscle size. However, limited data exist regarding mitochondrial dynamics in aging human skeletal muscle and the influence of exercise. The purpose of this study was to examine proteins regulating mitochondrial biogenesis and dynamics, VO2peak, and skeletal muscle size before and after aerobic exercise training in young men (20 ± 1 y) and older men (74 ± 3 y). Exercise-induced skeletal muscle hypertrophy occurred independent of age, whereas the improvement in VO2peak was more pronounced in young men. Aerobic exercise training increased proteins involved with mitochondrial biogenesis, fusion, and fission, independent of age. This is the first study to examine pathways of mitochondrial quality control in aging human skeletal muscle with aerobic exercise training. These data indicate normal aging does not influence proteins associated with mitochondrial health or the ability to respond to aerobic exercise training at the mitochondrial and skeletal muscle levels.


Specificity of phonological representations in U.S. English-speaking late talkers and typical talkers.
Late talkers are a heterogeneous group of children who experience delayed language development in the absence of other known causes. Late talkers show delays in expressive phonological development, but less is known about their receptive phonological development. In the current study, U.S. monolingual English-speaking typical talkers (TTs) (n = 23, mean age = 26.27 months, 57% male; 78.3% White) and late talkers (n = 22, mean age = 24.57 months, 59% male, 72.7% White) completed a Looking-While-Listening task to assess their sensitivity to mispronunciations. Results revealed that late talkers and TTs looked to the referent of a word for a shorter duration when it was mispronounced than when it was correctly pronounced, suggesting they were sensitive to mispronunciations. However, there were no significant differences between the two groups in their sensitivity to mispronunciations.


[Construction and application of virtual patients in prosthodontics].
In recent years, with the rapid development of digital technology, the application of oral virtual patients in prosthodontics, orthodontics, oral and maxillofacial surgery, and other disciplines has gradually increased. Although the focus on oral virtual patients varies in different disciplines, the application of oral virtual patients in assisting the prediction of treatment effects and the formulation of treatment plans will have good prospects. The construction accuracy and presentation effects of oral virtual patients can be influenced by the source of three-dimensional (3D) image, and methods of registration. Based on the studies and clinical experiences of our team, researches of other teams, the source of 3D images, the construction methods, and the clinical applications of virtual patients in prosthodontics will be presented, so as to provide a reference for normalized application and development of oral virtual patients and to offer a future development direction of oral virtual patients.


Pseudo-complementary PNA actuators as reversible switches in dynamic DNA nanotechnology.
The structural reorganization of nanoscale DNA architectures is a fundamental aspect in dynamic DNA nanotechnology. Commonly, DNA nanoarchitectures are reorganized by means of toehold-expanded DNA sequences in a strand exchange process. Here we describe an unprecedented, toehold-free switching process that relies on pseudo-complementary peptide nucleic acid (pcPNA) by using a mechanism that involves double-strand invasion. The usefulness of this approach is demonstrated by application of these peptide nucleic acids (PNAs) as switches in a DNA rotaxane architecture. The monomers required for generating the pcPNA were obtained by an improved synthesis strategy and were incorporated into a PNA actuator sequence as well as into a short DNA strand that subsequently was integrated into the rotaxane architecture. Alternate addition of a DNA and PNA actuator sequence allowed the multiple reversible switching between a mobile rotaxane macrocycle and a stationary pseudorotaxane state. The switching occurs in an isothermal process at room temperature and is nearly quantitative in each switching step. pcPNAs can potentially be combined with light- and toehold-based switches, thus broadening the toolbox of orthogonal switching approaches for DNA architectures that open up new avenues in dynamic DNA nanotechnology.


Subjective vision assessment in companion dogs using dogVLQ demonstrates age-associated visual dysfunction.
Dim light vision as assessed by proxy and clinical tools is commonly impaired in older humans and impacts quality of life. Although proxy visual assessment tools have been developed for dogs, it is unclear if they are sensitive enough to detect subtle visual dysfunction in older dogs. We sought to determine if a newly designed proxy visual function questionnaire could detect age-associated differences in visual behaviors in varying lighting conditions in dogs. A 27-item questionnaire (the dog variable lighting questionnaire, dogVLQ) was designed to assess visual behavior in dogs in different lighting settings. We conducted the dogVLQ, a previously validated visual function questionnaire the dog vision impairment score and performed light- and dark-adapted electroretinography (ERG) on a subset of dogs. Questionnaire scores were analyzed for dog age associations using correlation analysis. Questionnaire responses from 235 dog owners were obtained (122 female, 112 male dogs), 79 of which underwent ERG (43 female, 36 male dogs). Bright light visual behavior was significantly associated with light-adapted bright flash ERG amplitudes, visual behavior in near darkness was associated with dark-adapted ERG amplitudes. The dogVLQ identified worse vision in older dogs in bright light, dim light, and darkness; predicted onset was younger for vision in near darkness. Older dogs had more difficulty navigating transitions between lighting conditions. Subjective dog owner assessment of visual function associates with objective measurement of retinal function in dogs and supports reduced vision-mediated behaviors in older dogs.


Intracutaneous cornifying epithelioma (keratoacanthoma) in the dog: a retrospective study of 25 cases.
The clinical, histopathologic, and behavioral features of 25 cases of intracutaneous cornifying epithelioma (ICE) in the dog were reviewed. A typical ICE consisted of a keratin-filled crypt in the dermis and subcutis that opened to the skin surface. Most of these tumors occurred on the back, neck, sides of the thorax, and the shoulders. Two distinct patterns existed-a solitary form (single growth) and a generalized form (up to 40 growths). The Norwegian Elkhound appeared to be a breed predisposed to the development of the generalized type. Breed predilection for the solitary form was not observed. The ICE was a benign neoplasm, and simple surgical excision was curative except in the generalized cases in which additional growths developed. Keratoacanthoma of man and ICE of the dog were compared, and it was concluded that although they are similar in many respects they are not identical entities.


Knowledge, attitude, and practices on COVID-19 prevention and diagnosis among medical workers in the radiology department: A multicenter cross-sectional study in China.
The aim of this study was to investigate the knowledge, attitude, and practice (KAP) of medical workers in the radiology department toward the prevention and diagnosis of COVID-19. This multicenter cross-sectional study was conducted among medical workers in the radiology department of 17 hospitals between March and June 2022. A total of 324 medical workers were enrolled. The mean knowledge scores were 15.3 ± 3.4 (out of 23), attitude scores were 31.1 ± 5.6 (range 8-40), and practice scores were 35.1 ± 4.4 (range 8-40). Positive attitudes (OR = 1.235, 95% CI: 1.162-1.311, P < 0.001) and aged 41-50 years were independently associated with higher practice scores. Those with the better practice were more likely to be older (OR = 2.603, 95% CI: 1.242-5.452, P = 0.011), nurses (OR = 2.274, 95% CI: 1.210-4.272, P = 0.011) and with junior/intermediary/vice-senior title (OR = 2.326, 95% CI: 1.030-5.255, P = 0.042; OR = 2.847, 95% CI: 1.226-6.606, P = 0.015; OR = 4.547, 95% CI: 1.806-11.452, P = 0.001, respectively). Subgroup analysis revealed significant differences in knowledge between technicians and physicians and nurses and between staff working in tertiary hospitals and non-tertiary hospitals. Knowledge is positively correlated with attitude (β = 0.54, P < 0.001), and attitude is positively correlated with practice (β = 0.37, P < 0.001). Attitudes significantly mediated the association between knowledge and practice (β = 0.119, P < 0.001). The radiology medical workers showed moderate knowledge but good attitudes and practices of prevention and diagnosis of COVID-19. Attitudes were found to be positively associated with better practices of prevention and diagnosis of COVID-19. Attitudes significantly mediated the association between knowledge and practice.


Separation mechanisms for palonosetron stereoisomers at different chiral selector concentrations in MEKC.
The separation mechanisms for palonosetron (PALO) stereoisomers in MEKC using sodium cholate (SC) as surfactant and chiral selector have been studied, in a wide range of concentrations below and above the CMC. It was found that SC micelles only provide chirally selective recognition for 3a carbon chiral center in PALO molecules. The resolution of the configurations of 2 carbon chiral center is achieved by the difference of mobility in continuous phase. A schematic diagram depicting the separation mechanisms and the corresponding migration orders among all of four stereoisomers was proposed based on the measured separation parameters. A MEKC method to achieve the complete separation of four stereoisomers in very short time using a very low chiral selector concentration, instead of high concentrations generally considered, was developed based on the understanding of the mechanisms.


Knock-Down of HOXB8 Prohibits Proliferation and Migration of Colorectal Cancer Cells via Wnt/β-Catenin Signaling Pathway.
BACKGROUND There has been no research on the mechanism of HOXB8 action on colorectal cancer so far. This study was designed to investigate the mechanism of HOXB8 regulating colorectal cancer cell proliferation and invasion in vivo and in vitro. MATERIAL AND METHODS HOXB8 shRNA, HOXB8 overexpression, and negative control vector were designed and stably transfected into HCT116 cells. MTT assays were performed to detect cell proliferation. Western blot was utilized to detect HOXB8 expression level in HCT116 stable cells. The invasive and migration abilities were detected by Transwell assay and wound-healing assay. RESULTS HOXB8 knockdown inhibited cell proliferation. The invasiveness of HCT116 cells was significantly reduced following HOXB8 depletion compared with that in the shRNA control group, whereby the rates were reduced by 67% in HOXB8 knockdown group. The wound-healing rate of HOXB8 over-expression cells was significantly increased comparing with that of cells in the blank control group (P<0.05). HOXB8 knockdown promotes apoptosis of HCT116 cells. The expression of E-cadherin was restrained in the HOXB8 over-expression group and increased in the HOXB8 knockdown group. CONCLUSIONS Knock-down of HOXB8 prohibits the proliferation and migration of colorectal cancer cells via the Wnt/β-catenin signaling pathway and the downregulation of various factors, such as MMP2, c-Myc, CyclinD1,and vimentin. Our data suggested that HOXB8 has great potential to be developed as a novel therapeutic agent for the treatment of human colorectal cancer.


Immunohistochemical demonstration of IgG in Reed-Sternberg and other cells in Hodgkin's disease.
Spleens and lymph nodes fixed lightly for optimal immunocytochemistry or processed routinely for surgical diagnosis disclosed strong selective immunostaining for IgG in numerous immunocytes in tumor-free areas. Areas involved by Hodgkin's disease revealed, in addition, strong immunostaining for IgG but not IgM in Reed-Sternberg cells and faint to strong staining in Hodgkin cells as well. Ultrastructurally the Reed-Sternberg and Hodgkin cells displayed abundant polyribosomes and sparse granular reticulum and appeared to form unexportable IgG on unbound ribosomes.


Longitudinal MR imaging after unilateral MR-guided focused ultrasound thalamotomy: clinical and radiological correlation.
Magnetic-resonance-guided focused ultrasound (MRgFUS) thalamotomy uses multiple converging high-energy ultrasonic beams to produce thermal lesions in the thalamus. Early postoperative MR imaging demonstrates the location and extent of the lesion, but there is no consensus on the utility or frequency of postoperative imaging. We aimed to evaluate the evolution of MRgFUS lesions and describe the incidence, predictors, and clinical effects of lesion persistence in a large patient cohort. A total of 215 unilateral MRgFUS thalamotomy procedures for essential tremor (ET) by a single surgeon were retrospectively analyzed. All patients had MR imaging 1 day postoperatively; 106 had imaging at 3 months and 32 had imaging at 1 year. Thin cut (2 mm) axial and coronal T2-weighted MRIs at these timepoints were analyzed visually on a binary scale for lesion presence and when visible, lesion volumes were measured. SWI and DWI sequences were also analyzed when available. Clinical outcomes including tremor scores and side effects were recorded at these same time points. We analyzed if patient characteristics (age, skull density ratio), preoperative tremor score, and sonication parameters influenced lesion evolution and if imaging characteristics correlated with clinical outcomes. Visible lesions were present in all patients 1 day post- MRgFUS and measured 307.4 ± 128.7 mm3. At 3 months, residual lesions (excluding patients where lesions were not visible) were 83.6% smaller and detectable in only 54.7% of patients (n = 58). At 1 year, residual lesions were detected in 50.0% of patients (n = 16) and were 90.7% smaller than 24 h and 46.5% smaller than 3 months. Lesions were more frequently visible on SWI (100%, n = 17), DWI (n = 38, 97.4%) and ADC (n = 36, 92.3%). At 3 months, fewer treatment sonications, higher maximum power, and greater distance between individual sonications led to larger lesion volumes. Volume at 24 h did not predict if a lesion was visible later. Lesion visibility at 3 months predicted sensory side effects but was not correlated with tremor outcomes. Overall, lesions are visible on T2-weighted MRI in about half of patients at both 3 months and 1 year post-MRgFUS thalamotomy. Certain sonication parameters significantly predicted persistent volume, but residual lesions did not correlate with tremor outcomes.


The Use of Random Forests to Identify Brain Regions on Amyloid and FDG PET Associated With MoCA Score.
The aim of this study was to evaluate random forests (RFs) to identify ROIs on F-florbetapir and F-FDG PET associated with Montreal Cognitive Assessment (MoCA) score. Fifty-seven subjects with significant white matter disease presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial, had MoCA and F-florbetapir PET; 55 had F-FDG PET. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter (F-florbetapir PET), or pons (F-FDG PET). SUV ratio data and MoCA score were used for supervised training of RFs programmed in MATLAB. F-Florbetapir PETs were randomly divided into 40 training and 17 testing scans; 100 RFs of 1000 trees, constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: right posterior cingulate gyrus, right anterior cingulate gyrus, left precuneus, left posterior cingulate gyrus, and right precuneus. Amyloid increased with decreasing MoCA score. F-FDG PETs were randomly divided into 40 training and 15 testing scans; 100 RFs of 1000 trees, each tree constructed from a random subset of 16 training scans and 20 ROIs, identified ROIs associated with MoCA score: left fusiform gyrus, left precuneus, left posterior cingulate gyrus, right precuneus, and left middle orbitofrontal gyrus. F-FDG decreased with decreasing MoCA score. Random forests help pinpoint clinically relevant ROIs associated with MoCA score; amyloid increased and F-FDG decreased with decreasing MoCA score, most significantly in the posterior cingulate gyrus.


Endothelial cell antigens recognized by xenoreactive human natural antibodies.
Hyperacute rejection of vascularized, discordant xenografts is generally though to be initiated when natural antibodies of the recipient bind to endothelial cells of the donor organ. While rejection of such xenografts always occurs, the molecular targets of natural antibodies have not been elucidated. The aim of the experiments reported herein was to identify the molecules on porcine endothelial cells that would be recognized by human natural antibodies if a porcine organ were to be transplanted into a human (or rhesus). Toward the end, it was shown that the major components recognized by human serum on porcine endothelial cells are glycoproteins of 115kDa, 125kDa, and 135kDa (gp115/135). Reactivity with these glycoproteins was abrogated by enzymatic cleavage of N-linked oligosaccharides or of subterminal beta-D-gal residues suggesting that the determinants are located on oligosaccharides rather than on the polypeptide cores. The biological relevance of gp115/135 was suggested by experiments in which a similar series of components was shown to be recognized by rhesus natural antibodies and by the absorption of such antibodies by perfusion of porcine kidneys. The gp115/135 antigens were present on porcine platelets but not porcine RBC or lymphocytes. Nevertheless, purified RBC and lymphocytes absorbed human anti-gp115/135, suggesting that human natural antibodies recognize the same or crossreactive carbohydrate determinants expressed on the surface of a variety of cells.


Perceptual accuracy as measured by the Rorschach: are American norms applicable for cross-cultural assessment?
Cross-cultural applications of Rorschach's test assume that American norms may be applied, but this assumption has little empirical basis. In fact, several such investigations have indicated that culture-specific norms must be employed on key variables employed to assess subjects' perceptual accuracy. The current study compared responses of 19 Spanish children who scored low on a reading measure and were considered by their teachers to experience significant reading problems with 19 peers who scored significantly higher on that reading measure and who experienced no apparent reading problems. Perceptual accuracy of both groups, as measured by the F+ and X+ percents, was virtually identical. Results are discussed in the context of other research which has questioned the cross-cultural applicability of American norms with respect to perceptual accuracy.


Dysembryoplastic neuroepithelial tumors located in the caudate nucleus area: report of four cases.
Dysembryoplastic neuroepithelial tumors (DNTs) histologically resemble gliomas but behave as stable lesions. These tumors initially were considered to be located exclusively within the supratentorial cortex. The four reported cases demonstrate that DNTs may also arise in the area of the caudate nuclei. Moreover, the peculiar topography of these lesions, which suggests a derivation from the subependymal plate, is in accordance with the putative origin of DNTs from secondary germinal layers. The patients experienced partial seizures (two patients), generalized seizures (one patient), or headaches (one patient). All patients were young (17-26 yr) at the onset of symptoms, and all had normal results from their neurological examinations. All lesions demonstrated a pseudocystic appearance on computed tomographic scans, were hypointense on T1-weighted magnetic resonance imaging scans, hyperintense on T2-weighted magnetic resonance imaging scans, and did not show contrast enhancement. The four tumors similarly lined the left or right caudate nuclei and expanded within the homolateral ventricle (three patients) or both lateral ventricles (one patient). In one patient, the tumor also involved the adjacent paraolfactory cortex. In all patients, stereotactic biopsies helped to identify a specific glioneuronal element of DNTs. None of the tumors was operated on. Radiotherapy was performed in only one patient. A long pre- and/or postbiopsy imaging follow-up, which was available in two nontreated patients (3 yr and 16 yr), demonstrated the perfect stability of the lesion. The occurrence of DNTs in this peculiar location needs to be considered to avoid misidentification as "ordinary" gliomas and prevent useless aggressive treatment.


[The matrix metalloproteinase gene family: structure, function, expression, and role in destructive joint disease].
The matrix metalloproteinases, i.e. collagenases, gelatinases and stromelysins, are members of a gene family. They are capable of degrading every component of the extracellular matrix. Tissue destruction observed in inflammatory joint disease is largely accounted for by the action of these enzymes. Among the most potent inducers of metalloproteinase expression are the inflammatory cytokines IL-1 and TNF-alpha. Studies of mechanisms of induction by these mediators at the transcriptional level have improved our understanding of the biological controls of metalloproteinase synthesis. Cytokine inhibitors might serve to inhibit or postpone the crippling consequences of metalloproteinase action.


Development and Validation of a New Clinical Diagnostic Screening Model for Osteoporosis in Postmenopausal Women.
Age and weight are not only strong predictive parameters for osteoporosis diagnosis but can also be easily acquired from patients. This study aimed to develop and validate a new diagnostic screening model for postmenopausal osteoporosis that uses only 2 parameters, viz., age and weight. The discriminative ability of the model was analyzed and compared with that of the osteoporosis self-assessment tool for Asians (OSTA) index. The age-weight diagnostic screening model was developed using a retrospective chart review of postmenopausal women aged ≥50 years who underwent dual energy X-ray absorptiometry at a tertiary hospital from November 2017 to April 2022. Logistic regression analysis was used to derive a diagnostic screening model for osteoporosis. A total of 533 postmenopausal women were included in the study. According to the highest Youden index value, a probability cut-off value of 0.298 was used in the diagnosis screening model at any site, which yielded a sensitivity of 84.3% and a specificity of 53.8%. For increased sensitivity as a screening tool, a cut-off value of 0.254 was proposed to obtain a sensitivity of 90.2% and a specificity of 42.2%. The area under receiver operating characteristic curves from all screening models were significantly higher than those from the OSTA index model (p<0.05). This study showed the feasibility of a postmenopausal osteoporosis diagnostic screening model that uses 2 strong predictors for osteoporosis diagnosis: age and weight. This age-weight diagnostic model is a simple, effective option in postmenopausal osteoporosis screening.


[Development strategy of Paris based on combination of domestic patent and current resource application and development].
Paris is a commonly used traditional Chinese medicine (TCM), and has antitumor, antibacterial, sedative, analgesic and hemostatic effects. It has been used as an ingredient of 81 Chinese patent medicines, with a wide application and large market demand. Based on the data retrieved from state Intellectual Property Office patent database, a comprehensive analysis was made on Paris patents, so as to explore the current features of Paris patents in the aspects of domestic patent output, development trend, technology field distribution, time dimension, technology growth rate and patent applicant, and reveal the development trend of China's Paris industry. In addition, based on the current Paris resource application and development, a sustainable, multi-channel and multi-level industrial development approach was built. According to the results, studies of Paris in China are at the rapid development period, with a good development trend. However, because wild Paris resources tend to be exhausted, the studies for artificial cultivation technology should be strengthened to promote the industrial development.


Comparison of the effectiveness and safety of cefpodoxime and ciprofloxacin in acute exacerbation of chronic suppurative otitis media: A randomized, open-labeled, phase IV clinical trial.
To compare the effectiveness and safety of cefpodoxime and ciprofloxacin for the treatment of mild to moderate cases of acute exacerbation of chronic suppurative otitis media (AECSOM). Adult patients diagnosed with AECSOM were screened and patients fulfilling the inclusion criteria were randomized to receive either cefpodoxime 200 mg twice daily or ciprofloxacin 500 mg twice daily orally for 7 days. The primary outcome of this randomized, open-labeled, phase IV clinical trial (Registration Number - CTRI/2011/10/002079) was clinical success rate at day 14 visit and the secondary outcome was incidence of adverse events (AEs). Forty-six patients were enrolled: 23 in the cefpodoxime group and 23 in the ciprofloxacin group. The clinical success rates were 95.6% in the cefpodoxime group versus 90.9% in the ciprofloxacin group. These rates are comparable, but no statistically significant difference was observed between the groups. Few mild and self-limiting AEs were observed and the tolerability of both the drugs was also good. The results of this randomized, open-labeled phase IV clinical trial showed that a 7-day course of cefpodoxime is therapeutically comparable to ciprofloxacin in terms of both clinical effectiveness and safety for the treatment of patients with AECSOM.


Whitening-dependent changes of fluorescence of extracted human teeth.
To evaluate in vitro the fluorescence properties of extracted human teeth whitened with 40% hydrogen peroxide. A total of 28 extracted human teeth were pumiced for 1 minute using a low-speed dental handpiece and a disposable rubber cup. Pre-whitening fluorescence measurements (T0), maximum excitation (Exmax ), maximum emission (Emmax ), and maximum intensity (Imax 108 ), were performed using a spectrofluorometer. After T0 measurements, the teeth were whitened using the in-office method with 40% hydrogen peroxide, three times for 20 minutes. The fluorescence parameters were measured under the same conditions 7 and 14 days after bleaching (T1 and T2, respectively). Exmax exhibited a broader range 7 days after whitening and decreased after 14 days. The Emmax and Imax 108 displayed a narrower range after whitening. The mean Exmax differed significantly between the time points (F = 20.09. P < .001). The corresponding analysis for the mean Emmax differed significantly between the time points (F = 16.69, P < .001). The same was true for the mean Imax 108 (F = 9.69, P < .001). Within the limitations of this study, whitening provoked statistically significant changes in fluorescence of the intact teeth in vitro. The appearance of human teeth and dental materials and their changes upon aging and exposure to different agents (staining, whitening) is a topic of great relevance to esthetic dentistry. While some appearance parameters, such as color, translucency, and gloss, have been thoroughly studied, fluorescence and its influence on overall tooth appearance is still not well understood, yet it has influenced the development of fluorescence emitting restorative materials.


Stepwise Treatment With Plant-Based Diet and Medication for Patient With Mild Ulcerative Colitis.
We regard inflammatory bowel disease as a lifestyle disease mainly mediated by a westernized diet. We developed a plant-based diet (PBD) to counter the westernized diet. PBD can induce remission without medication in a subset of mild cases of ulcerative colitis. Medication is provided when induction of remission is not achieved solely with PBD. We describe such a case in this report. A 34-year-old woman visited us in October 2016 with a complaint of loose stool for nearly 5 years. Laboratory examination revealed mild abnormalities including elevation of C-reactive protein (CRP). Ulcerative colitis was diagnosed due to diffuse colonic inflammation and pathological findings consistent with ulcerative colitis. She was admitted for educational hospitalization for 19 days in the middle of November, during which PBD was provided. A few days after admission, her stool became normal. CRP concentration decreased to within the normal range. However, colonoscopy on discharge showed minimum improvement. Thereafter, CRP was abnormal on three successive occasions, and her stool alternated between normal and loose. Sulfasalazine was initiated at the end of March 2017. Thereafter, her stool was normally formed, and CRP decreased to normal. Endoscopic remission was confirmed in August. Her PBD score, which evaluates adherence to PBD, was 8 before admission, and 37 and 16 at 7 and 21 months after discharge, respectively. Medication was administered when restoration of a healthy dietary lifestyle was insufficient to induce remission. Our stepwise treatment makes the shift from one-size-fits-all medication toward medication to the right patient. http://www.umin.ac.jp UMIN000019061.


Activated ERM protein plays a critical role in drug resistance of MOLT4 cells induced by CCL25.
We have previously demonstrated that the CCR9/CCL25 signaling pathway plays an important role in drug resistance in human acute T-lymphocytic leukemia (T-ALL) by inducing activation of ERM protein with polarized distribution in T-ALL cell line MOLT4. However, the mechanism of action of the activated ERM protein in the drug resistance of MOLT4 cells induced by CCL25 remains uncharacterized. Here we investigated the mechanism of CCR9/CCL25-initiated drug resistance in CCR9-high-expressing T-ALL cells. Our results showed that 1) the function of P-gp was increased after treatment with CCL25; 2) P-gp colocalized and co-immunoprecipitated with p-ERM and F-actin in CCL25 treated cells; and 3) ERM-shRNA conferred drug sensitivity coincident with release of ERM interactions with P-gp and F-actin after treatment with CCL25. These data suggest it is pivotal that P-gp associate with the F-actin cytoskeleton through p-ERM in CCR9/CCL25 induced multidrug resistance of T-ALL cells. Strategies aimed at inhibiting P-gp-F-actin cytoskeleton association may be helpful in increasing the efficiency of therapies in T-ALL.


Diagnosis of flour-induced occupational asthma in a cross-sectional study.
The diagnosis of occupational asthma is usually performed in epidemiology using a combination of symptoms and bronchial hyperresponsiveness, while in a clinical setting the 'gold standard' for the diagnosis of occupational asthma is the specific bronchial challenge test in the laboratory The aim of this study was to detect new cases of flour-induced occupational asthma (OA) in a group of workers exposed to grain and/or flour dust, by means of a step-by-step approach, as used in a clinical setting. In an epidemiological study, III millers and 186 bakers were examined by means of questionnaire, pulmonary function tests and skin-prick tests (SPT) to common allergens and to wheat flour dust extracts. From the whole sample, 82 subjects who showed asthma-like symptoms in the questionnaire and/or low forced expiratory volume in 1 sec (FEV1) were selected. Selected subjects underwent methacholine challenge test, and hyperreactive subjects underwent specific bronchial challenge with flour dust in the laboratory. Sixty-two of the selected subjects performed the methacholine challenge test, and 22 (33 8%) were hyperreactive (PD20 FEV1 <1 mg of methacholine). Fifteen of 22 hyperreactive subjects underwent specific bronchial challenge test (s BCT) with flour dust; a positive response was elicited in six subjects. These subjects can be diagnosed as having flour-induced occupational asthma. Atopy and skin sensitivity to flour was partially related to the response to flour bronchial challenge. Bronchial hyperreactivity can be observed in a small percentage of subjects with asthma-like symptoms and/or low FEV1, and a positive response to s BCTwas observed in a subgroup of hyperreactive subjects.Therefore, using these selection criteria, a diagnosis of flour-induced OA, as commonly performed in a clinical setting, can be performed in few previously undiagnosed subjects.This approach could be relevant for an early diagnosis ofoccupational asthma.


Control of postbiopsy renal hemorrhage with renal artery vasopressin infusion.
Persistent, severe renal hemorrhage resulted from a diagnostic renal biopsy in a 19-year-old woman with chronic renal insufficiency. Infusion of vasopressin into the renal artery through an angiographic catheter produced prompt resolution of bleeding. This method has distinct advantages over surgical intervention or transcatheter embolization in the control of traumatic renal hemorrhage.


tRNA-Related Sequences Trigger Systemic mRNA Transport in Plants.
In plants, protein-coding mRNAs can move via the phloem vasculature to distant tissues, where they may act as non-cell-autonomous signals. Emerging work has identified many phloem-mobile mRNAs, but little is known regarding RNA motifs triggering mobility, the extent of mRNA transport, and the potential of transported mRNAs to be translated into functional proteins after transport. To address these aspects, we produced reporter transcripts harboring tRNA-like structures (TLSs) that were found to be enriched in the phloem stream and in mRNAs moving over chimeric graft junctions. Phenotypic and enzymatic assays on grafted plants indicated that mRNAs harboring a distinctive TLS can move from transgenic roots into wild-type leaves and from transgenic leaves into wild-type flowers or roots; these mRNAs can also be translated into proteins after transport. In addition, we provide evidence that dicistronic mRNA:tRNA transcripts are frequently produced in Arabidopsis thaliana and are enriched in the population of graft-mobile mRNAs. Our results suggest that tRNA-derived sequences with predicted stem-bulge-stem-loop structures are sufficient to mediate mRNA transport and seem to be necessary for the mobility of a large number of endogenous transcripts that can move through graft junctions.


Optogenetic control of the Dab1 signaling pathway.
The Reelin-Dab1 signaling pathway regulates development of the mammalian brain, including neuron migrations in various brain regions, as well as learning and memory in adults. Extracellular Reelin binds to cell surface receptors and activates phosphorylation of the intracellular Dab1 protein. Dab1 is required for most effects of Reelin, but Dab1-independent pathways may contribute. Here we developed a single-component, photoactivatable Dab1 (opto-Dab1) by using the blue light-sensitive dimerization/oligomerization property of A. thaliana Cryptochrome 2 (Cry2). Opto-Dab1 can activate downstream signals rapidly, locally, and reversibly upon blue light illumination. The high spatiotemporal resolution of the opto-Dab1 probe also allows us to control membrane protrusion, retraction and ruffling by local illumination in both COS7 cells and in primary neurons. This shows that Dab1 activation is sufficient to orient cell movement in the absence of other signals. Opto-Dab1 may be useful to study the biological functions of the Reelin-Dab1 signaling pathway both in vitro and in vivo.


Diabetic retinopathy and dysregulated innate immunity.
Diabetic retinopathy (DR) is the progressive degeneration of retinal blood vessels and neurons. Inflammation is known to play an important role in the pathogenesis of DR. During diabetes, metabolic disorder leads to the release of damage-associated molecular patterns (DAMPs) both in the retina and elsewhere in the body. The innate immune system provides the first line of defense against the DAMPs. In the early stages of DR when the blood retinal barrier (BRB) is intact, retinal microglia and the complement system are activated at low levels. This low-level of inflammation (para-inflammation) is believed to be essential to maintain homeostasis and restore functionality. However, prolonged stimulation by DAMPs in the diabetic eye leads to maladaptation of the innate immune system and dysregulated para-inflammation may contribute to DR development. In the advanced stages of DR where immune privilege is comprised, circulating immune cells and serum proteins may infiltrate the retina and participate in retinal chronic inflammation and retinal vascular and neuronal damage. This review discusses how the innate immune system is activated in diabetes and DR. The view also discusses why the protective immune response becomes detrimental in DR.


Two allelic forms of mouse beta 2-microglobulin.
Two allelic forms of mouse beta 2-microglobulin (beta 2m), the small polypeptide chain of H-2 histocompatibility antigens, have been identified. The two forms can be distinguished by NaDodSO4/polyacrylamide gel electrophoresis. All inbred mouse strains express a single beta 2m isotype. Mice heterozygous for beta 2m synthesize both forms, showing codominant expression of beta 2m alleles. In mice heterozygous for both H-2 and beta 3m, individual H-2 histocompatibility antigens associate with both beta 2m forms. Preliminary structural studies indicate differences in peptide composition between the two forms.


Comparison of Biochemical Parameters in Patients with Hepatitis B, C, and Dual Hepatitis B and C in Northwest Pakistan.
The leading causes of hepatitis are viral infections, Hepatitis B virus (HBV) and Hepatitis C virus (HCV). Millions of people have been infected with these deadly viral infections worldwide, and in Pakistan, every tenth person is infected with these viruses. Different populations respond with different rates to infectious diseases due to host genomic differences. To evaluate and compare the biochemical parameters in different types of hepatitis (Hepatitis B, C, and Co-infection) and different ethnic groups, a total of 200 pre-screened patients were recruited from District Headquarters Teaching Hospital Dera Ismail Khan and Tank. Blood samples (5ml) were taken from patients and were assayed for biochemical parameters, including four liver function tests (LFTs) and two renal function tests (RFTs). In 200 patients, the mean scores of Alanine transaminase (ALT) were 376±335, 315±265, and 478±519 IU/L in HBV, HCV, and co-infected patients, respectively. Moreover, the mean score of ALT was 31±7.2 IU/l in the normal control group. All other biochemical parameters demonstrated elevated levels in co-infection, HBV, and HCV, respectively, except total proteins. The RFTs showed a threshold or upper normal limit (UNL); nonetheless, when compared to normal control subjects, RFTs parameters were high in infected patients, as compared to normal control. Ethnicity wise comparison of parameters indicated that Pushtoon ethnic group indicated a high degree of severity of HBV infection and co-infection, as compared to Saraiki and Rajpoot ethnic groups, while Saraiki ethnic group showed a higher severity of HCV than both of Pushtoon and Rajpoot. Rajpoot ethnic group was least affected than both Pushtoon and Saraiki ethnic groups. Co-infected patients were more severely affected, as compared to HBV and HCV patients. The ethnicity-wise study provided evidence that different ethnic groups showed different degrees of severity. There may be some genetic background involved in hepatitis B and C viral infection due to which all three ethnic groups showed different degrees of severity. In gender-wise comparisons, male patients were more affected than female patients.


Intracellular transport of microinjected 5S and small nuclear RNAs.
The mechanism by which some RNAs are segregated in the cell nucleus was analysed by microinjecting 32 P-labelled total RNA from HeLa cells into the cytoplasm of Xenopus oocytes. Small nuclear RNAs (u1, U2, U4, U5 and U6) migrated into the cell nucleus, where they became 30-60 fold more concentrated than in the cytoplasm. Other RNAs, such as tRNA and 7S RNA, remained in the cytoplasm, while 5S RNA became concentrated in the nucleolus. Studies with lupus erythematosus antibodies showed that the migrating RNAs become associated with oocyte RNA-binding proteins.


The importance of tissue handling of surgically removed breast cancer for an accurate assessment of the Ki-67 index.
Insufficient attention for the Ki-67 immunohistochemistry has been given to the importance of tissue handling for surgical breast cancer specimens. We sought to investigate the effect of fixation status on the Ki-67. We examined the effect of fixative, time to and duration of fixation using surgical specimens, and finally, compared the paired Ki-67 index in the tumour between core needle and surgical specimen. The Ki-67 was significantly higher when 10% neutral buffered formalin was used (p=0.0276). Insufficient fixation caused a drastic reduction in the Ki-67 index (p=0.0177), but not significant in oestrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Sixteen hours delayed time to fixation also caused a reduction of the Ki-67 (p=0.0284), but not significant in ER. Prolonged fixation significantly led to a gradual reduction in the Ki-67 in a time-dependent manner, but not in both ER and HER2. Finally, cutting the tumour before fixation improved fixation status and consequently caused an increased level of the Ki-67 index (p=0.0181), which resulted in a strong correlation of the Ki-67 between core needle and surgical specimen (r=0.8595). Tissue handling of surgical specimen is critical for assessing the Ki-67 compared with ER and HER2. We should pay more attention to tissue fixation status for the standard assessment of the Ki-67 index.