Analysis of a novel protocol of pulsed intravenous cyclophosphamide for recalcitrant or severe ocular inflammatory disease.
To analyze the success rate of pulsed intravenous (IV) cyclophosphamide (CyP) for noninfectious ocular inflammatory disease and to identify risk factors for failure of therapy. Retrospective, interventional, noncomparative cohort study. One hundred ten eyes of 65 patients. Through a computer search of the Massachusetts Eye Research and Surgery Institution's database, we identified patients who were treated with IV CyP between May 2005 and April 2012. We obtained demographic and clinical information through review of the electronic health record of each patient. Clinical response, corticosteroid-sparing effect, recurrence rate, calculated "risk factors" for failure, visual acuity, and adverse reactions. Pulsed IV CyP achieved complete remission of inflammation (for ≥ 2 visits) in 54 patients (84.4%). Sustained remission of inflammation occurred in 70% of patients within 3 months, 86.6% of patients within 6 months, and 91.7% within 9 months. The mean time to achieving quiescence was 3.5 months. The success rate in reducing corticosteroid to prednisone ≤ 10 mg/d within 6 months, while maintaining control of ocular inflammation, was 89.7% (95% confidence interval [CI], 81.1-93.5%). The mean duration of clinical remission for those patients who had a positive response to CyP was 32.67 months (95% CI, 25.91-39.43). Relapse of vasculitis was observed in 1 patient (1.5%) after completing the course of therapy. Early initiation of therapy during the course of the disease was correlated with a lesser rate of recurrence (P = 0.028). The most common adverse effects were nausea (29%) and transient lymphopenia (26%). The mean best-corrected visual acuity (BCVA) improved from 0.59 ± 0.66 at baseline to 0.30 ± 0.54 at 6 months of follow-up (P<0.001). The mean follow-up period was 31.61 ± 20.47 months. Pulsed IV CyP employing our protocol results in an extremely high rate of sustained complete remission in patients with recalcitrant and fulminant, vision-threatening ocular inflammatory disorders, with an excellent safety profile in the hands of physicians trained and skilled in the art of this therapy. It also allows tapering and discontinuing corticosteroids in most patients. Early initiation of therapy may decrease the risk of relapses. The authors have no proprietary or commercial interest in any materials discussed in this article.


Long-term memory interference is resolved via repulsion and precision along diagnostic memory dimensions.
When memories share similar features, this can lead to interference, and ultimately forgetting. With experience, however, interference can be resolved. This raises the important question of how memories change, with experience, to minimize interference. Intuitively, interference might be minimized by increasing the precision and accuracy of memories. However, recent evidence suggests a potentially adaptive role for memory distortions. Namely, similarity can trigger exaggerations of subtle differences between memories (repulsion). Here, we tested whether repulsion specifically occurs on feature dimensions along which memories compete and whether repulsion is predictive of reduced memory interference. To test these ideas, we developed synthetic faces in a two-dimensional face space (affect and gender). This allowed us to precisely manipulate similarity between faces and the feature dimension along which faces differed. In three experiments, participants learned to associate faces with unique cue words. Associative memory tests confirmed that when faces were similar (face pairmates), this produced interference. Using a continuous face reconstruction task, we found two changes in face memory that preferentially occurred along the feature dimension that was "diagnostic" of the difference between face pairmates: (1) there was a bias to remember pairmates with exaggerated differences (repulsion) and (2) there was an increase in the precision of feature memory. Critically, repulsion and precision were each associated with reduced associative memory interference, but these were statistically dissociable contributions. Collectively, our findings reveal that similarity between memories triggers dissociable, experience-dependent changes that serve an adaptive role in reducing interference.


Identification of the cockroach neuropeptide Pea-CAH-II as a second adipokinetic hormone in the firebug Pyrrhocoris apterus.
A new member of the AKH/RPCH family was isolated from the corpora cardiaca of the firebug Pyrrhocoris apterus. It is the second adipokinetic peptide identified in this species. The peptide was characterized and its structure was deduced from the multiple MS(N) electrospray mass spectra as that of an octapeptide with the sequence pGlu-Leu-Thr-Phe-Thr-Pro-Asn-Trp-NH(2.) The peptide differs from the original P. apterus AKH (Pya-AKH) by one amino acid in position 3. Topical application and/or injection of the peptide induced lipid mobilization, but was inactive in mobilization of carbohydrates.


Metabolomics reveals the mechanism of Antarctic yeast Rhodotorula mucliaginosa AN5 to cope with cadmium stress.
Heavy metal pollution in Antarctica has far exceeded expectations. Antarctic yeast is widely present in polar marine environment. The mechanisms of metabolomics effect of heavy metal on polar yeast have not been reported previously. In this study, gas chromatography-mass spectrometry (GC-MS) wascarried out to performed the metabolite profiling analysis of Antarctic sea-ice yeast Rhodotorula mucilaginosa AN5 exposed to different cadmium (Cd) stresses of 5 mM (HM5), 10 mM (HM10) and 20 mM (HM20), respectively. Metabolic profile analysis showed that the composition and contents of cellular metabolites have been altered by cadmium. 93 different metabolites were identified altogether, among which 23, 58 and 81 different metabolites were found in HM5, HM10 and HM20 group respectively. MetaboAnalyst analysis showed that in HM5, HM10 and HM20 groups, 12, 24 and 31 metabolic pathways were involved in the stress of cadmium to R. mucilaginosa, respectively. By contrasting with Kyoto Encyclopedia of Genes and Genomes database, we discovered that exposure of yeast AN5 to Cd stress resulted in profound biochemical changes including amino acids, organic acids and saccharides. These results will supply a nonnegligible basis of studying the adaptive resistance mechanism of Antarctic yeast Rhodotorula mucilaginosa to heavy metal.


Mutations in cytochrome b that affect kinetics of the electron transfer reactions at center N in the yeast cytochrome bc1 complex.
We have examined the pre-steady-state kinetics and thermodynamic properties of the b hemes in variants of the yeast cytochrome bc1 complex that have mutations in the quinone reductase site (center N). Trp-30 is a highly conserved residue, forming a hydrogen bond with the propionate on the high potential b heme (bH heme). The substitution by a cysteine (W30C) lowers the redox potential of the heme and an apparent consequence is a lower rate of electron transfer between quinol and heme at center N. Leu-198 is also in close proximity to the b(H) heme and a L198F mutation alters the spectral properties of the heme but has only minor effects on its redox properties or the electron transfer kinetics at center N. Substitution of Met-221 by glutamine or glutamate results in the loss of a hydrophobic interaction that stabilizes the quinone ligands. Ser-20 and Gln-22 form a hydrogen-bonding network that includes His-202, one of the carbonyl groups of the ubiquinone ring, and an active-site water. A S20T mutation has long-range structural effects on center P and thermodynamic effects on both b hemes. The other mutations (M221E, M221Q, Q22E and Q22T) do not affect the ubiquinol oxidation kinetics at center P, but do modify the electron transfer reactions at center N to various extents. The pre-steady reduction kinetics suggest that these mutations alter the binding of quinone ligands at center N, possibly by widening the binding pocket and thus increasing the distance between the substrate and the bH heme. These results show that one can distinguish between the contribution of structural and thermodynamic factors to center N function.


Cutaneous sympathetic motor rhythms during a fever-like response induced by prostaglandin E(1).
Neuronal population discharges within the CNS and in somatic and sympathetic motor nerves often display oscillations. Peripheral oscillations may provide a window into central mechanisms, as they often show coherence with population activity of subsets of central neurones. The reduction in heat loss through the cutaneous circulation during fever may be mediated via sympathetic premotor neurones not utilised during normal temperature regulation. Consequently, here we assessed, in anaesthetised rats, whether the frequency signature of population sympathetic discharge observed in neurones innervating the tail (thermoregulatory) circulation changed during a fever-like response induced by intracerebroventricular injection of prostaglandin E(1). We found that when core temperature was raised to 38.8-40.5 degrees C sympathetic activity was abolished. Following administration of prostaglandin (400 ng or 1 microg per rat), activity was restored to levels seen prior to heating (154+/-53.5%; n=10). Injection of vehicle had no effect (n=7). Prior to heating when most animals were in central apnoea (14/18) two peaks were observed in autospectra of sympathetic activity: one at 0.68-0.93 Hz (T-peak) and another at the frequency of ventilation (2 Hz). Central respiratory drive was recruited during hyperthermia where it was 1:2 locked to the frequency of ventilation and following prostaglandin administration, an additional peak in sympathetic autospectra was seen at this frequency. Time-evolving spectra indicated that this peak resulted from the dynamic locking of the 'T-peak' to central respiratory drive. Our data show that during a fever-like response the dominant oscillations in sympathetic activity controlling a thermoregulatory circulation and their dynamic coupling to respiratory-related inputs are similar to those seen under normal conditions. Therefore, during this fever-like response, the neural substrate(s) underlying the oscillations is not reconfigured and remains capable of sculpturing the pattern of sympathetic neuronal discharge that may be regulated by several descending pathways.


Mediating role of emotional labour strategy in the association between patient/visitor incivility and nurses' fatigue: a cross-sectional study.
Fatigue is a common problem among nurses, and patient/visitor incivility is thought to lead to nurses' fatigue. However, the mechanism by which patient/visitor incivility leads to nurses' fatigue has not been well studied. The aim of this study is to examine whether the association between patient/visitor incivility and fatigue among Chinese nurses is mediated by emotional labour strategy. A cross-sectional study. In November 2019, a stratified cluster sample of 1207 nurses from two hospitals in China was used to collect data on fatigue, patient/visitor incivility and emotional labour strategy through online questionnaires. Emotional labour strategy has three dimensions: surface acting (SA), deep acting and natural acting. Complete responses were provided by 1036 (85.8%) participants. Student's t-test, one-way analysis of variance, Pearson correlation analysis and the PROCESS procedure (A modeling macro installed in SPSS to analyse mediation.) were adopted to analyse the data. Patient/visitor incivility and SA were positively related to fatigue (p<0.01), while natural acting was negatively related to fatigue (p<0.01). SA played as a mediator in the association between patient/visitor incivility and nurses' fatigue (95% CI 0.047 to 0.113, p<0.05). Patient/visitor incivility could contribute to Chinese nurses' fatigue. When nurses were exposed to patient/visitor incivility, they were more likely to use the SA emotional labour strategy, which would lead to fatigue. Nursing administrators should be aware of the seriousness of nurses' fatigue.


Three-year quantitative magnetic resonance imaging and phosphorus magnetic resonance spectroscopy study in lower limb muscle in dysferlinopathy.
Natural history studies in neuromuscular disorders are vital to understand the disease evolution and to find sensitive outcome measures. We performed a longitudinal assessment of quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31 P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients. Quantitative MRI/31 P MRS data were obtained at 3 T in two different sites in 54 patients and 12 controls, at baseline, and three annual follow-up visits. Fat fraction (FF), contractile cross-sectional area (cCSA), and muscle water T2 in both global leg and thigh segments and individual muscles and 31 P MRS indices in the anterior leg compartment were assessed. Analysis included comparisons between patients and controls, assessments of annual changes using a linear mixed model, standardized response means (SRM), and correlations between MRI and 31 P MRS markers and functional markers. Posterior muscles in thigh and leg showed the highest FF values. FF at baseline was highly heterogeneous across patients. In ambulant patients, median annual increases in global thigh and leg segment FF values were 4.1% and 3.0%, respectively (P < 0.001). After 3 years, global thigh and leg FF increases were 9.6% and 8.4%, respectively (P < 0.001). SRM values for global thigh FF were over 0.8 for all years. Vastus lateralis muscle showed the highest SRM values across all time points. cCSA decreased significantly after 3 years with median values of 11.0% and 12.8% in global thigh and global leg, respectively (P < 0.001). Water T2 values in ambulant patients were significantly increased, as compared with control values (P < 0.001). The highest water T2 values were found in the anterior part of thigh and leg. Almost all 31 P MRS indices were significantly different in patients as compared with controls (P < 0.006), except for pHw , and remained, similar as to water T2 , abnormal for the whole study duration. Global thigh water T2 at baseline was significantly correlated to the change in FF after 3 years (ρ = 0.52, P < 0.001). There was also a significant relationship between the change in functional score and change in FF after 3 years in ambulant patients (ρ = -0.55, P = 0.010). This multi-centre study has shown that quantitative MRI/31 P MRS measurements in a heterogeneous group of dysferlinopathy patients can measure significant changes over the course of 3 years. These data can be used as reference values in view of future clinical trials in dysferlinopathy or comparisons with quantitative MRI/S data obtained in other limb-girdle muscular dystrophy subtypes.


The effect of seven vasopressors of halothane MAC in dogs.
We evaluated the effects of ephedrine, mephentermine, metaraminol, phenylephrine, methoxamine, noradrenaline and adrenaline on halothane anaesthetic requirement (MAC) in dogs. MAC increased significantly only during ephedrine infusion (50%) although significance was approached with mephentermine (21%). Phenylephrine, metaraminol, methoxamine, noradrenaline and adrenaline did not change MAC. Arterial pressure was increased 50-100% with all agents. Our results support the hypothesis that anaesthetic requirement may be related, in part, to release of brain noradrenaline.


Low-dose GH replacement improves the adverse lipid profile associated with the adult GH deficiency syndrome.
Adult growth hormone deficiency (AGHD) is associated with an adverse lipid profile. The majority of previous studies of GH replacement have used supraphysiological doses and reported favourable changes in the lipid profile. Whether this beneficial effect is the result of pharmacological GH therapy, or occurs in response to low-dose GH replacement aimed at normalization of the serum IGF-I, has not been fully elucidated. We studied 67 patients with GH deficiency using a low-dose individualized GH replacement regimen. GH was commenced at a dose of 0.27 mg/day and the GH dose titrated until the serum IGF-I was normalized. Serum lipids were assessed at baseline, 12 and 24 months. A reduction in total cholesterol (TC) was observed at 12 (6.01 vs. 5.77 mmol, P = 0.04) and 24 months (6.01 vs. 5.56, P = 0.09). The reduction in LDLC failed to reach significance at 12 months (3.97 vs. 3.8, P = 0.09), but was significant at 24 months (3.97 vs. 3.50, P = 0.02). Levels of HDLC did not change significantly at 12 or 24 months. Significant improvements in the TC/HDLC ratio were observed at both 12 (5.68 vs. 5.29, P = 0.01) and 24 months (5.68 vs. 4.86, P = 0.007). A significant fall in triglycerides (TG) was present at 12 months (2.07 vs. 1.83, P = 0.01), and was maintained at 24 months, but was no longer significant (2.07 vs. 1.89, P = 0.28). At 12 months there was no correlation between improvements in lipid parameters and either the change in IGF-I SD score or the GH dose. Using multivariate analysis the change in TC, LDLC and the TC/HDLC ratio with 12 months GH replacement were determined by the baseline TC, LDLC and TC/HDLC levels (R2 = 0.18, P = 0.004; R2 = 0.20, P = 0.006; and R2 = 0.33, P < 0.0001), respectively. Low-dose individualized GH replacement aimed at normalization of the serum IGF-I is associated with significant improvements in TC, LDLC, TGs and the TC/HDLC ratio. The greatest improvements are observed in patients with the most adverse lipid profiles at baseline. Improvements are independent of changes in the IGF-I SDS and GH dose.


Changes in glucose-6-phosphate dehydrogenase activity in Indian desert malaria vector Anopheles stephensi during aging.
Malaria parasite requires a specific time to replicate and disseminate in the mosquito's body before transmission to naïve hosts can occur. Vector control has a proven record in the prevention and control of malaria. The evaluation of vector control strategies requires accurate methods of predicting mosquito age. Anopheles stephensi is the principal malaria vector of the desert part of India. The objective of this study was to correlate the age of laboratory reared and field collected adults of An. stephensi with the glucose-6-phosphate dehydrogenase (g6pd) activity. The measurement of g6pd activity was carried out in a UV-vis spectrophotometer. The g6pd activity in the males and females An. stephensi was inversely proportional to their age. A significant correlation of the g6pd activity was recorded between the field collected and laboratory reared mosquitoes. The g6pd activity in the males An. stephensi was found to be significantly higher than the females. The finding of the present study is useful for the prediction of the age of males and females An. stephensi.


Population Pharmacokinetic Analysis of Dorzagliatin in Healthy Subjects and Patients with Type 2 Diabetes Mellitus.
Dorzagliatin is a first-in-class small molecule glucokinase activator (GKA) that improves pancreatic insulin secretion behavior and regulates hepatic glucose conversion in a glucose concentration-dependent manner. The primary objective of this study was to develop a population pharmacokinetic model of dorzagliatin to evaluate the influence of covariates, such as demographic characteristics and liver and kidney function, on the pharmacokinetics of dorzagliatin and provide a basis for medication guidance. The pharmacokinetic data of dorzagliatin in this study came from six clinical trials. Based on the combined data, a population pharmacokinetic model of dorzagliatin was established using NONMEM software (ICON, MD, USA, version 7.4.3). The algorithm used was first-order conditional estimation with interaction (FOCEI). The dorzagliatin population pharmacokinetic modeling analysis included 1062 subjects and 7686 observable concentrations. Covariates, including age (AGE), sex (GEND), body weight (TBW), body mass index (BMI), body surface area (BSA), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (CR), creatinine clearance (CRCL), and total bilirubin (TBIL), were screened using the forward-backward method. Model evaluation was performed using goodness-of-fit plots, prediction corrected visual prediction check (pcVPC), and bootstrap. Concentration data of dorzagliatin in the dose range were best characterized by a two-compartment model with sequential zero-order then first-order absorption and first-order elimination. The final model estimated dorzagliatin data for typical male subjects (69 kg body weight, 18 U/L AST and 55 years old); the apparent total clearance (CL/F) was 10.4 L/h, apparent volume of central compartment distribution (Vc/F) was 80.6 L, inter-compartmental clearance (Q/F) was 3.02 L/h, apparent volume of peripheral compartment distribution (Vp/F) was 26.5 L, absorption rate constant (Ka) was 3.29 h-1, and duration of zero-order absorption (D1) was 0.418 h. The inter-individual variation of CL/F, Vc/F, Vp/F, and D1 was 22.5%, 14.9%, 48.8%, and 82.8%, respectively. The two-compartment linear pharmacokinetic model with zero- and first-order sequential absorption adequately described the pharmacokinetic characteristics of dorzagliatin. Body weight, aspartate aminotransferase, and age had a statistically significant effect on the CL/F of dorzagliatin. Body weight and sex had a statistically significant effect on Vc/F. However, considering the clinically insignificant changes in the magnitude of steady-state exposure caused by these covariates, as well as the minimal changes in the steady-state exposure for individuals with mild and moderate impaired hepatic function and all stages of renal impairment, dose adjustments based on the tested covariates or for specific populations are deemed unnecessary.


Differential expression and cross-correlation between global regulator and pho regulon genes involved in decision-making under phosphate stress.
The differential gene expression under phosphate stress conditions leads to cross-talk between the global regulator, pho regulon, and metabolic genes. Promoter activity analysis of the selected 23 genes reveals the dynamic nature of real-time gene expression under different phosphate conditions. The expression profiles of the global regulator (rpoD, soxR, soxS, arcB, and fur), pho regulon (phoH, phoR, phoB, and ugpB), and metabolic genes (sdh, pfkA, ldh) varied significantly on phosphate level variation. Under stress conditions, soxR switches expression partners and co-expresses with rpoS instead of soxS. The partner-switching behavior of the genes under a challenging environment represents the intelligence of functional execution and ensures cell survival. The dynamic expression profile of the selected genes applies a time-lagged correlation to provide insight into the differential gene interaction between time-shifted expression profiles. Under different phosphate conditions, the minimum spanning tree graph revealed a different clustering pattern of selected genes depending on the computed distance and its proximity to other promoters.


Toxic effects of triclocarban on larval zebrafish: A focus on visual dysfunction.
Triclocarban (TCC) is considered an endocrine disruptor and shows antagonist activity on thyroid receptors. In view of the report that thyroid hormone signaling mediates retinal cone photoreceptor specification, we hypothesize that TCC could impair visual function, which is vital to wildlife. In order to verify our hypothesis, we assessed alteration in the retinal structure (retinal layer thickness and cell density), visually-mediated behavior, cone and rod opsin gene expression, and photoreceptor immunostaining in zebrafish larvae exposed to TCC at environmentally realistic concentrations (0.16 ± 0.005 µg/L, L-group) and one-fifth of the median lethal concentrations (25.4 ± 1.02 µg/L, H-group). Significant decrease in eye size, ganglion cell density, optokinetic response, and phototactic response can be observed in the L-group, while the thickness of outer nuclear layer, where the cell bodies of cone and rod cells are located, was significantly reduced with the down-regulation of critical opsin gene (opn1sw2, opn1mw1, opn1mw3, opn1lw1, opn1lw2, and rho) expression and rhodopsin immunofluorescence in the H-group. It should be noted that TCC could affect the sensitivity of zebrafish larvae to red and green light according to the results of behavioral and opsin gene expression analysis. These findings provide the first evidence to support our hypothesis that the visual system, a novel toxicological target, is affected by TCC. Consequently, we urgently call for a more in-depth exploration of TCC-induced ocular toxicity to aquatic organisms and even to humans.


Sex differences in cell genesis, hippocampal volume and behavioral outcomes in a rat model of neonatal HI.
Hypoxia-ischemia (HI) of the brain in near-term and term infants is a leading cause of infant mortality and lifelong disability but current therapeutic approaches remain limited. Males consistently display greater vulnerability to the deleterious consequences of HI in both humans and animal models. Neurogenesis increases after neonatal HI and offers a potential therapeutic target for recovery. The steroid hormone estradiol has been extensively explored as a neuroprotectant in adult models of stroke but with mixed results. Less consideration has been afforded to this naturally occurring agent in the developing brain, which has unique challenges from the adult. Using a model of term HI in the rat we have explored the impact of this insult on cell genesis in the hippocampus of males and females and the ability of estradiol treatment immediately after insult to restore function. Both short-term (3 days) and long-term (7 days) post-injury were assessed and revealed that only females had markedly increased cell genesis on the short-term but both sexes were increased long-term. A battery of behavioral tests revealed motor impairment in males and compromised episodic memory while both sexes were modestly impaired in spatial memory. Juvenile social play was also depressed in both sexes after HI. Estradiol therapy improved behavioral performance in both sexes but did not reverse a deficit in hippocampal volume ipsilateral to the insult. Thus the effects of estradiol do not appear to be via cell death or proliferation but rather involve other components of neural functioning.


Multiaxial characterization of depressive patients.
A review of the literature on the comprehensive description of depressive patients revealed prominent concern with syndromic subtypes, course of illness, and personality factors, followed by severity, concomitant physical disorders, psychosocial stressors, and adaptive functioning. The descriptive value of multiaxial approaches for depression was illustrated through the application of an extended DSM-III formulation to all 3455 depressive (bipolar depression, major depression, dysthymic disorder, and atypical depression) and 7837 nondepressive patients of all ages and sexes presenting for evaluation and care at the Psychiatric Institute of the University of Pittsburgh during a period of 53 months. Twenty-six percent of the depressive patients received an additional diagnosis in axis I, the most frequent of which were substance use disorder, anxiety disorder, and condition not attributable to a mental disorder. In axis II, depressive patients presented a differentially higher frequency of dependent personality disorder and the "anxious/fearful" cluster of personality disorders. In axis III, 47% of the depressive vs. 40% of the nondepressive patients had a positive diagnosis of physical illness, with a significantly higher frequency among depressive patients attained by acquired hypothyroidism, migraine, essential hypertension, unspecified abdominal hernia, and unspecified arthropathies. Specific stressors differentially more frequent among depressive patients were those of conjugal, parenting, and occupational types and those reflecting the impact of physical illness. Overall stressor severity was at severe, extreme, or catastrophic levels for 42% of the depressive and 31% of the nondepressive patients. The highest level of adaptive functioning in the past year was good, very good, or superior for 44% of the depressive and 29% of the nondepressive patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Indications and Outcomes for Intermittent Catheterization following Bulbar AUS Cuff Placement.
To evaluate the functional and surgical impact of CIC protocols in men with a bulbar AUS in place. Stress urinary incontinence (SUI) and poor bladder emptying are both sequelae of prostate cancer treatment, though there is sparse data to guide concomitant management. The safety of intermittent catheterization (CIC) in men with an artificial urinary sphincter (AUS) at the bulbar urethra remains unclear. We performed a retrospective review of all bulbar urethral AUS procedures at our institution. Inclusion criteria were patients with a history of prostate cancer treatment, AUS placement for SUI, and a history of CIC before and/or after AUS placement. All eligible cases were retrospectively reviewed. Surgical and continence outcomes were analyzed. A total of 57 patients were identified with a history of CIC and AUS placement under the care of two surgeons. Eighteen continued to perform CIC or first initiated CIC after AUS placement and 39 discontinued CIC prior to AUS placement. The incidence of erosion was no different amongst patients who continued or discontinued CIC after AUS placement (17.9% vs 22.2%, P = .79). There was no difference in future AUS removal or replacement (56.4% vs 44.4%, P = .41). Both groups experienced improvement in urinary incontinence after placement of an AUS. Bulbar AUS placement in the setting of continuous intermittent catheterization can be considered in patients who are not surgical candidates for definitive treatment of their outlet obstruction.


Cytotoxic sesquiterpene lactones from Vernonia pachyclada from the Madagascar rainforest.
Bioassay-guided fractionation of the cytotoxic leaf extract of Vernonia pachyclada Baker led to the isolation of three new sesquiterpene lactones, designated glaucolides K-M (1-3). The structures of the new compounds were determined using 1D and 2D NMR spectroscopy, and the structure and stereochemistry of 1 were confirmed by single-crystal X-ray diffraction. Compound 3 showed moderate activity in the A2780 human ovarian cancer cell line, with an IC50 of 3.3 microM.


Pyrolysis of cannabidiol. Structure elucidation of a major pyrolytic conversion product.
Pyrolysis of cannabidiol, one of the major constituents of Cannabis sativa, yields a mixture of components. Next to previously identified products, a major conversion product has now been isolated and identified. The unusual and stereospecific route of formation of this compound with altered chromophore is discussed.


Health status, cognitive coping, and depressive symptoms: testing for a mediator effect.
Research has established a link between health status and symptoms of depression in persons with rheumatoid arthritis (RA), but the effects of "cognitive coping" variables have not been extensively studied. We examined the mediator effect of a cognitive coping variable (Pain Control and Rational Thinking factor score from the Coping Strategies Questionnaire) over the course of a pharmacological intervention. Data were analyzed from 54 persons with RA, all of whom met diagnostic criteria for major depression. Measures of depression, health status, and cognitive coping were collected at 4 different stages of a pharmacological (antidepressant) study as follows: (1) at baseline, (2) postintervention, (3) 6 month followup, and (4) 15 month followup. Results indicated that a direct relationship existed between health status and depression at all 4 time periods. However, this relationship was mediated by cognitive coping only at the postintervention and the 6 month followup. A cognitive coping variable was found to mediate the relationship between health status and depression, but only at moderate levels of depression.


The effect of maternal hyperglycemia on acid base balance and lung liquid production in the fetal sheep.
In 10 chronically catheterized fetal sheep, the effects of 100 g of glucose infused (intravenous) to the pregnant ewe on lung liquid production and acid-base status were investigated. Maternal and fetal hyperglycemia occurred within 15 min of the infusion of glucose. There was a significant increase in fetal PCO2 from 41.67 +/- 1.00 to 46.89 +/- 1.83 mm Hg and a decrease in fetal arterial pH from 7.42 +/- 0.016 to 7.33 +/- 0.026 (n = 7). This acidosis was probably the result of fetal lactacidemia. There was also a decrease in fetal PO2 (p less than 0.001) following the infusion of glucose to the ewe. This, along with the acidosis, might account for the increased risk of unexplained fetal death in the diabetic pregnancy especially near term. Following the infusion of glucose to the ewe there was an increase in maternal plasma osmolality by 16 +/- 3.35 mosmol/kg (n = 9) and in fetal plasma osmolality by 14 +/- 2.64 mosmol/kg (n = 9; p less than 0.001). Fetal lung liquid production fell from 0.195 +/- 0.04 to 0.093 +/- 0.02 ml/min (n = 6; p less than 0.001). There was no change in the excretion of osmol by the lungs. The decreased lung liquid production was probably due to a decrease in the net movement of fluid across the pulmonary epithelium.


Salmonella YqiC exerts its function through an oligomeric state.
Protein oligomerization occurs frequently both in vitro and in vivo, with specific functionalities associated with different oligomeric states. The YqiC protein from Salmonella Typhimurium forms a homotrimer through its C-terminal coiled-coil domain, and the protein is closely linked to the colonization and invasion of the bacteria to the host cells. To elucidate the importance of the oligomeric state of YqiC in vivo and its relation with bacterial infection, we mutated crucial residues in YqiC's coiled-coil region and confirmed the loss of trimer formation using chemical crosslinking and size exclusion chromatography coupled with multiple angle light scattering (SEC-MALS) techniques. The yqiC-knockout strain complemented with mutant YqiC showed significantly reduced colonization and invasion of Salmonella to host cells, demonstrating the critical role of YqiC oligomerization in bacterial pathogenesis. Furthermore, we conducted a protein-protein interaction study of YqiC using a pulled-down assay coupled with mass spectrometry analysis to investigate the protein's role in bacterial virulence. The results reveal that YqiC interacts with subunits of Complex II of the electron transport chain (SdhA and SdhB) and the β-subunit of F0 F1 -ATP synthase. These interactions suggest that YqiC may modulate the energy production of Salmonella and subsequently affect the assembly of crucial virulence factors, such as flagella. Overall, our findings provide new insights into the molecular mechanisms of YqiC's role in S. Typhimurium pathogenesis and suggest potential therapeutic targets for bacterial infections.


Dyskeratosis congenita: report of a case and review of the literature.
A case of dyskeratosis congenita in a 10-year-old white boy is reported. The triad of oral leukoplakia, nail dystrophy, and skin pigmentation was present. Other associated anomalies included dysphagia and varied immunoglobulin levels, although there was no evidence of anemia, pancytopenia, and ocular involvement. Since it may be associated with future malignant change, dyskeratosis congenita should be considered in all cases in which an obscure white lesion exists in the mouth.


The radiation-induced lesions which trigger the bystander effect.
The ionizing radiation induced bystander effect is initiated by damage to a cellular molecule which then gives rise to a signal exported to other cells. The nature of this damage is considered with the understanding that it may not be the same as that responsible for the traditional cellular effects of radiation. Consideration is give to amounts of endogenous damage and to radiation yields of the various candidate lesions.


Hemorphins: substrates and/or inhibitors of dipeptidyl peptidase IV. Hemorphins N-terminus sequence influence on the interaction between hemorphins and DPPIV.
Hemorphins are endogenous peptides belonging to the family of "atypical" opioid peptides released from sequentially hydrolyzed hemoglobin. In this paper, we report an inhibitory effect of these peptides on dipeptidyl peptidase IV (DPPIV) activity, known to be involved in regulatory functions such as the activation or inactivation of peptides. The structure activity research revealed that hemorphins N-terminus sequence influences nature of the interaction between hemorphins and DPPIV. Kinetic studies conducted with purified DPPIV demonstrated that hemorphin-7 (H7) constitutes a good substrate (K(cat)/K(m) of 137 mM(-1) s(-1)) for this enzyme but could also act as a selective competitive inhibitor by substrate binding site competition. These blood-derived peptides could represent endogenous regulators of this enzyme activity.


CD40 Generation 2.5 Antisense Oligonucleotide Treatment Attenuates Doxorubicin-induced Nephropathy and Kidney Inflammation.
Preclinical and clinical data suggest CD40 activation contributes to renal inflammation and injury. We sought to test whether upregulation of CD40 in the kidney is a causative factor of renal pathology and if reduction of renal CD40 expression, using antisense oligonucleotides (ASOs) targeting CD40, would be beneficial in mouse models of glomerular injury and unilateral ureter obstruction. Administration of a Generation 2.5 CD40 ASO reduced CD40 mRNA and protein levels 75-90% in the kidney. CD40 ASO treatment mitigated functional, transcriptional, and pathological endpoints of doxorubicin-induced nephropathy. Experiments using an activating CD40 antibody revealed CD40 is primed in kidneys following doxorubicin injury or unilateral ureter obstruction and CD40 ASO treatment blunted CD40-dependent renal inflammation. Suborgan fractionation and imaging studies demonstrated CD40 in glomeruli before and after doxorubicin administration that becomes highly enriched within interstitial and glomerular foci following CD40 activation. Such foci were also sites of ASO distribution and activity and may be predominately comprised from myeloid cells as bone marrow CD40 deficiency sharply attenuated CD40 antibody responses. These studies suggest an important role of interstitial renal and/or glomerular CD40 to augment kidney injury and inflammation and demonstrate that ASO treatment could be an effective therapy in such disorders.


Multivariate and geostatistical analyses of the spatial distribution and sources of heavy metals in agricultural soil in Dehui, Northeast China.
The characterization of the content and source of heavy metals in soils are necessary to establish quality standards on a regional level and to assess the potential threat of metals to food safety and human health. The surface horizons of 114 agricultural soils in Dehui, a representative agricultural area in the black soil region, Northeast China, were collected and the concentrations of Cr, Ni, Cu, Zn, and Pb were analyzed. The mean values of the heavy metals were 49.7 ± 7.04, 20.8 ± 3.06, 18.9 ± 8.51, 58.9 ± 7.16, and 35.4 ± 9.18 mg kg(-1) for Cr, Ni, Cu, Zn, and Pb, respectively. Anthropic activities caused an enrichment of Cu and Pb in soils. However, metal concentrations in all samples did not exceed the guideline values of Chinese Environmental Quality Standard for Soils. Multivariate and geostatistical analyses suggested that soil Cr, Ni, and Zn had a lithogenic origin. Whereas, the elevated Cu concentrations in the study area were associated with industrial and agronomic practices, and the main sources of Pb were industrial fume, coal burning exhausts, and domestic waste. Source identification of heavy metals in agricultural soil is a basis for undertaking appropriate action to reduce metal inputs.


3,4-Di-amino-pyridinium hydrogen malonate.
In the title salt, C5H8N3 (+)·C3H3O4 (-), the 3,4-di-amino-pyridinium cation is almost planar, with an r.m.s. deviation of 0.02 Å. The conformation of the hydrogen malonate anion is stabilized by an intra-molecular O-H⋯O hydrogen bond, which generates an S(6) ring. In the crystal, N-H⋯O hydrogen bonds link cations and anions into layers parallel to the ab plane.


Assessment of bacterial and viral gut communities in healthy and tumoral colorectal tissue using RNA and DNA deep sequencing.
Colorectal cancer (CRC) is known to present a distinct microbiome profile compared to healthy mucosa. Non-targeted deep-sequencing strategies enable nowadays full microbiome characterization up to species level. We aimed to analyze both bacterial and viral communities in CRC using these strategies. We analyzed bacterial and viral communities using both DNA and RNA deep-sequencing (Novaseq) in colorectal tissue specimens from 10 CRC patients and 10 matched control patients. Following taxonomy classification using Kraken 2, different metrics for alpha and beta diversities as well as relative and differential abundance were calculated to compare tumoral and healthy samples. No viral differences were identified between tissue types, but bacterial species Polynucleobacter necessarius had a highly increased presence for DNA in tumors (p = 0.001). RNA analyses showed that bacterial species Arabia massiliensis had a highly decreased transcription in tumors (p = 0.002) while Fusobacterium nucleatum transcription was highly increased in tumors (p = 0.002). Sequencing of both DNA and RNA enables a wider perspective of micriobiome profiles. Lack of RNA transcription (Polynucleobacter necessarius) casts doubt on possible role of a microorganism in CRC. The association of F. nucleatum mainly with transcription, may provide further insights on its role in CRC. Joint assessment of the metagenome (DNA) and the metatranscriptome (RNA) at the species level provided a huge coverage for both bacteria and virus and identifies differential specific bacterial species as tumor associated.


Polychlorinated naphthalenes (PCNs) in Chinese forest soil: Will combustion become a major source?
We collected O- and A-horizon soil samples in 26 Chinese mountainous forests to investigate the content, spatial pattern, and potential sources of polychlorinated naphthalenes (PCNs). Spatial patterns were influenced mainly by the approximation to sources and soil organic contents. High concentrations often occurred close to populated or industrialized areas. Combustion-related activities contributed to PCN pollution. Relatively high proportions of CN-73 in northern China may be attributed to coke consumption, while CN-51 could be an indicator of biomass burning in Southwest China. There are evidences that PCNs may largely derived from unintentional production. If uncontrolled, UP-PCN (unintentionally produced PCNs) emissions could increase with industrial development. The abnormally high concentrations at Gongga and Changbai Mountains appear to be associated with the high efficient of forest filter of atmospheric contaminants at these densely forested sites. We question whether this is caused by ecotones between forests, and raise additional questions for future analyses.


Statistical and Bioinformatics Analysis of Data from Bulk and Single-Cell RNA Sequencing Experiments.
High-throughput sequencing (HTS) has revolutionized researchers' ability to study the human transcriptome, particularly as it relates to cancer. Recently, HTS technology has advanced to the point where now one is able to sequence individual cells (i.e., "single-cell sequencing"). Prior to single-cell sequencing technology, HTS would be completed on RNA extracted from a tissue sample consisting of multiple cell types (i.e., "bulk sequencing"). In this chapter, we review the various bioinformatics and statistical methods used in the processing, quality control, and analysis of bulk and single-cell RNA sequencing methods. Additionally, we discuss how these methods are also being used to study tumor heterogeneity.


Human complement factor H Y402H polymorphism causes an age-related macular degeneration phenotype and lipoprotein dysregulation in mice.
One of the strongest susceptibility genes for age-related macular degeneration (AMD) is complement factor H (CFH); however, its impact on AMD pathobiology remains unresolved. Here, the effect of the principal AMD-risk-associated CFH variant (Y402H) on the development and progression of age-dependent AMD-like pathologies was determined in vivo. Transgenic mice expressing equal amounts of the full-length normal human CFH Y402 (CFH-Y/0) or the AMD-risk associated CFH H402 (CFH-H/H) variant on a Cfh-/- background were aged to 90 weeks and switched from normal diet (ND) to a high fat, cholesterol-enriched (HFC) diet for 8 weeks. The resulting phenotype was compared with age-matched controls maintained on ND. Remarkably, an AMD-like phenotype consisting of vision loss, increased retinal pigmented epithelium (RPE) stress, and increased basal laminar deposits was detected only in aged CFH-H/H mice following the HFC diet. These changes were not observed in aged CFH-Y/0 mice or in younger (36- to 40-week-old) CFH mice of both genotypes fed either diet. Biochemical analyses of aged CFH mice after HFC diet revealed genotype-dependent changes in plasma and eyecup lipoproteins, but not complement activation, which correlated with the AMD-like phenotype in old CFH-H/H mice. Specifically, apolipoproteins B48 and A1 are elevated in the RPE/choroid of the aged CFH-H/H mice compared with age-matched control CFH-Y/0 fed a HFC diet. Hence, we demonstrate a functional consequence of the Y402H polymorphism in vivo, which promotes AMD-like pathology development and affects lipoprotein levels in aged mice. These findings support targeting lipoproteins as a viable therapeutic strategy for treating AMD.


Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy.
The predictive role of the degree of endocrine responsiveness to preoperative chemotherapy (PCT) is unclear. We reviewed pretreatment biopsies of 553 patients with locally advanced breast cancer who were treated with PCT. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to the degree of estrogen (ER) and progesterone receptor (PgR) expression (ER and PgR absent, vs. ER or PgR 0-49%, vs. ER and PgR >or=50% of the cells positive). A statistically significant higher pCR rate was observed at the multivariate analysis for patients with ER and PgR absent tumors (17.7%) versus patients with tumors expressing high ER and PgR (0%) (OR 14.4 P < 0.001). Despite the higher incidence of pCR, a statistically significant worse disease-free survival (DFS), and overall survival (OS) was observed for patients with ER and PgR absent tumors versus patients with tumors expressing high ER and PgR (HR 6.4, 95% CI 3.5-11.6, for DFS; HR 3.6 95% CI 2.4-5.6 for OS). Response and outcome after PCT are correlated with the degree of expression of steroid hormone receptors. Studies on tailored preoperative therapies are needed.


Synthesis of the nonconserved dihydroorotase domain of the multifunctional hamster CAD protein in Escherichia coli.
CAD is the multifunctional protein of higher eukaryotes which catalyzes the first three steps of pyrimidine biosynthesis. Its enzymatic activities exist as independent domains in the order: N terminus-carbamylphosphate synthetase II(CPSase)-dihydroorotase(DHOase)-aspartate transcarbamylase(ATCase)-C terminus. To functionally define the minimum hamster cDNA region required to encode an active DHOase, expression constructs were generated. Many such constructs complement Escherichia coli mutants defective not only in DHOase but also in ATCase. Constructs deleted for most of the sequence encoding the ATCase domain continue to complement E. coli mutants defective in DHOase. All of these smaller constructs also lack the region encoding CPSase. Therefore, a 'genetic cassette', containing information for neither the CPSase nor the ATCase domain, can direct the synthesis of a polypeptide with DHOase activity. Interestingly, inclusion of a portion of the DHOase-ATCase interdomain bridge appears to be required for optimum activity.


Spontaneously Low Protein Intake in Elderly CKD Patients: Myth or Reality? Analysis of Baseline Protein Intake in a Large Cohort of Patients with Advanced CKD.
The recent guidelines on nutritional management of chronic kidney disease (CKD) advise a reduction in protein intake as early as CKD stage 3, regardless of age, to slow kidney function impairment. However, since elderly patients are usually considered as having a spontaneously reduced protein intake, nutritional interventions to reduce protein intake are often considered futile. This study aimed to assess the baseline protein intake of elderly CKD patients referred for nephrology care, and explore the need for dietary evaluations, focusing on the current recommendations for protein restriction in CKD. This is an observational study of CKD patients followed in the unit dedicated to advanced CKD patients in Le Mans, France. Patients with stages 3 to 5 not on dialysis were included. All patients were evaluated by an expert dietician to assess their baseline protein intake, whenever possible on the basis of a 7-days diet journal; when this was not available, dietary recall or analysis of delivered meals was employed. Demographic characteristics, underlying kidney disease, Charlson Comorbidity Index (CCI), Malnutrition-Inflammation Score (MIS), Subjective Global Assessment (SGA) and clinical and laboratory data were recorded. Between 15 November 2017 and 31 December 2020, 436 patients were evaluated in the unit. Their age distribution was as follows: "young": <60 (n = 62), "young-old": 60-69 (n = 74), "old": 70-79 (n = 108), "old-old": 80-89 (n = 140) and "oldest-old": ≥90 (n = 54). The prevalence of vascular nephropathies was higher in patients older than 70 years compared to younger ones, as did CCI and MIS (p < 0.001). Moderate nutritional impairment (SGA: B) was higher in elderly patients, reaching 53.7% at ≥90, while less than 3% of patients in the overall cohort were classified as SGA C (p < 0.001). The median protein intake was higher than the recommended one of 0.8 g/kg/day in all age groups; it was 1.2 g/kg/day in younger patients and 1.0 thereafter (p < 0.001). Patient survival depended significantly on age (p < 0.001) but not on baseline protein intake (p = 0.63), and younger patients were more likely to start dialysis during follow-up (p < 0.001). Over half of the patients, including the old-old and oldest-old, were still on follow-up two years after referral and it was found that survival was only significantly associated with age and comorbidity and was not affected by baseline protein intake. Our study shows that most elderly patients, including old-old and extremely old CKD patients, are spontaneously on diets whose protein content is higher than recommended, and indicates there is a need for nutritional care for this population.


A new sequence variant in mitochondrial DNA associated with high penetrance of Russian Leber hereditary optic neuropathy.
We have analyzed mitochondrial DNA sequence in 15 Russian LHON patients and found the new mtDNA sequence variant in one family (2 patients) who showed 100% penetrance of the disease in men. This family has a T14484C primary mutation, and four secondary mutations (T4216C, G13708A, G15812A, G15257A), which belong to the European haplogroup J. The new sequence variant of A9016G in the ATPase 6 gene changed highly conserved amino acid of isoleucine to valine, has not been found in the rest of 13 LHON patients and controls. This novel sequence variant may contribute to the 100% penetration of LHON disorder in men of this family.


Effect of visual blur on contrast sensitivity. Clinical implications.
Contrast sensitivity of normal subjects was measured under conditions of refractive blur that produced specific levels of visual acuity. Measurements were made at distance (with Vistech charts), at near (with Arden gratings), and with a pinhole to control pupil size. Under all conditions, when visual acuity was reduced by spherical lenses, there was a loss of contrast sensitivity over a broad range of spatial frequencies (i.e., not just at the higher frequencies that correlate with target letter size). By inference, it may be clinically hazardous to interpret contrast sensitivity results in patients with reduced acuity (from any cause) relative only to standard contrast sensitivity values based on subjects with normal visual acuity. If the potential effects of acuity are taken into account, contrast sensitivity testing can distinguish between deficits that are roughly equivalent to the loss of acuity and those which indicate more distinctive pathology of the media, retina, or optic nerve.


Salvage Therapies for Radiorecurrent Prostate Cancer.
We report available salvage options in patients with biochemical recurrence after radiation therapy for prostate cancer. We performed MEDLINE® searches for various salvage options and reviewed the most recent publications on each modality. Salvage radical prostatectomy, brachytherapy, cryotherapy and high intensity focused ultrasound are the main therapeutic options available for men with biochemical recurrence after radiation therapy. These modalities have different side effect profiles. There is also wide variability in followup and reporting of oncologic outcomes. Androgen deprivation therapy remains the most common form of therapy after biochemical recurrence. No standard salvage therapy exists. Treatments are best administered at specialist centers where there is expertise with managing potential complications.


Treatment of cervical cancer with adjuvant chemotherapy versus adjuvant radiotherapy after radical hysterectomy and systematic lymphadenectomy.
To compare the clinical efficacy focused on post-treatment morbidity between adjuvant chemotherapy (CT) and pelvic radiotherapy (RT) after radical hysterectomy for patients with cervical cancer. A total of 125 patients with cervical squamous cell carcinoma who underwent radical hysterectomy and pelvic lymphadenectomy at Hokkaido University Hospital between 1991 and 2002 were enrolled in the study for retrospective analysis. Seventy patients with recurrent risk factors, including deep stromal invasion, lymph vascular space invasion, parametrial invasion, lymph node metastasis (LNM), and bulky tumor (>or=4 cm), received adjuvant therapy; 42 were treated with RT, and 28 were treated with CT. Almost all patients with multiple LNM received RT. Analyses were also performed on a subgroup of 50 patients without multiple LNM (23 RT, 27 CT). Clinical efficacy of post-treatment morbidity and survival was evaluated. Because there were more patients with multiple LNM in the RT group, we analyzed disease-free survival in 50 patients without multiple LNM. The 3-year disease-free survival rate was 82.6% with RT and 96.3% with CT (P = 0.16). Postoperative bowel obstruction was significantly more frequent in the RT group versus the CT (P = 0.007) and no-therapy (P = 0.0026) groups. Urinary disturbance was also more frequent in the RT group than in the CT (P = 0.0016) and no-therapy (P = 0.089) groups. CT has the equivalent therapeutic effect as RT with fewer postoperative complications for patients with intermediate risks. A prospective randomized trial is needed to compare CT combined with radical hysterectomy and pelvic lymphadenectomy to RT or chemoradiotherapy.


Do first and last letters carry more weight in the mechanism behind word familiarity?
Previous research has suggested a role of letter location information in familiarity-detection that occurs with word stimuli, but no studies have yet investigated whether certain letter positions are weighted more heavily in the feature-based mechanism behind word familiarity-detection. Based on psycholinguistic research suggesting that first and last letters are weighted more heavily than interior letters when it comes to reading words, we investigated whether first and last letters carry more weight in the mechanism behind word familiarity that results from feature familiarization in a list-learning paradigm. In two experiments, participants studied word fragments (e.g., RA_ _ _ _OP) and later rated the familiarity of complete words (e.g., RAINDROP). We varied whether the first and last or only interior letters were present at study. Participants consistently rated test words whose fragments went unidentified at study as more familiar when the first and last letters had been studied than when only interior letters had been studied. This suggests that first and last letters contribute more strongly to the word familiarity signal than interior letters.


22q11.2 deletions in patients with conotruncal defects: data from 1,610 consecutive cases.
The 22q11.2 deletion syndrome is characterized by multiple congenital anomalies including conotruncal cardiac defects. Identifying the patient with a 22q11.2 deletion (22q11del) can be challenging because many extracardiac features become apparent later in life. We sought to better define the cardiac phenotype associated with a 22q11del to help direct genetic testing. 1,610 patients with conotruncal defects were sequentially tested for a 22q11del. The counts and frequencies of primary lesions and cardiac features were tabulated for those with and those without a 22q11del. Logistic regression models investigated cardiac features that predicted deletion status in tetralogy of Fallot (TOF). Deletion frequency varied by primary anatomic phenotype. Regardless of the cardiac diagnosis, a concurrent aortic arch anomaly (AAA) was strongly associated with deletion status [odds ratio (OR), 5.07; 95 % confidence interval (CI), 3.66-7.04]. In the TOF subset, the strongest predictor of deletion status was an AAA (OR, 3.14; 95 % CI 1.87-5.27; p < 0.001), followed by pulmonary valve atresia (OR, 2.03; 95 % CI 1.02-4.02; p = 0.04). Among those with double-outlet right ventricle and transposition of the great arteries, only those with an AAA had a 22q11del. However, 5 % of the patients with an isolated conoventricular ventricular septal defect and normal aortic arch anatomy had a 22q11del, whereas no one with an interrupted aortic arch type A had a 22q11del. A subset of patients with conotruncal defects are at risk for a 22q11del. A concurrent AAA increases the risk regardless of the intracardiac anatomy. These findings help to direct genetic screening for the 22q11.2 deletion syndrome in the cardiac patient.


A phospholipid kinase regulates actin organization and intercellular bridge formation during germline cytokinesis.
The endgame of cytokinesis can follow one of two pathways depending on developmental context: resolution into separate cells or formation of a stable intercellular bridge. Here we show that the four wheel drive (fwd) gene of Drosophila melanogaster is required for intercellular bridge formation during cytokinesis in male meiosis. In fwd mutant males, contractile rings form and constrict in dividing spermatocytes, but cleavage furrows are unstable and daughter cells fuse together, producing multinucleate spermatids. fwd is shown to encode a phosphatidylinositol 4-kinase (PI 4-kinase), a member of a family of proteins that perform the first step in the synthesis of the key regulatory membrane phospholipid PIP2. Wild-type activity of the fwd PI 4-kinase is required for tyrosine phosphorylation in the cleavage furrow and for normal organization of actin filaments in the constricting contractile ring. Our results suggest a critical role for PI 4-kinases and phosphatidylinositol derivatives during the final stages of cytokinesis.


Subacute poisoning of mice with deltamethrin produces memory impairment, reduced locomotor activity, liver damage and changes in blood morphology in the mechanism of oxidative stress.
Deltamethrin (DEL) is a synthetic pyrethroid (PYR) insecticide, potent neurotoxicant. The current investigation was envisaged to explore behavioral, biochemical and morphologic effects of subacute poisoning with DEL in mice and to find one common mechanism of these changes. Mice were daily injected ip with different doses of DEL: 8.3, 20.75 or 41.5mg/kg bw for 28 days. Their memory retention in passive avoidance task (PA), fresh spatial memory in a Y-maze and locomotor activity were measured once weekly. On day 29, blood morphology, alanine transaminase (ALT) activity and creatinine concentration in the blood sera, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured in the livers and kidneys. Livers were examined with light microscopy. Significant impairment of memory retention was recorded on day 2, 7 and 28 after exposure to DEL. Fresh spatial memory was significantly impaired by the highest dose of DEL on day 1, 14 and 28. Locomotor activity was reduced at every stage of experiment in all the groups exposed to DEL. In the animals exposed to the highest dose of DEL activities of alanine transaminase (ALT) and SOD were elevated, GPx was reduced, lymphocyte infiltrates were detected in the livers and there were changes in blood morphology. The results obtained indicate that liver and bone marrow, apart from the central nervous system (CNS) are damaged in the course of subacute poisoning with DEL. The possible common mechanism of the damage is oxidative stress.


Electron-transfer and charge-transfer clastic binding hypotheses for drug-receptor interactions.
The origins and development of clastic binding hypotheses for interaction of morphines with the opiate receptor and various hallucinogens with their putative receptors are reviewed. Possible alternative explanations of the facts which led to the clastic binding hypotheses are offered. Possible integration of the clastic binding processes into other, better-recognized processes at the receptors is considered.


'Vets must be strong advocates for animal rights'.
Steven McCulloch, European veterinary specialist in animal welfare science, ethics and law, argues that the veterinary profession must support animal rights, but not the abolition of animal use.


Survival Benefit of Adjuvant Chemotherapy After Pancreatoduodenectomy for Ampullary Adenocarcinoma: a Propensity-Matched National Cancer Database (NCDB) Analysis.
The benefit of adjuvant chemotherapy (AC) after pancreatoduodenectomy (PD) for ampullary adenocarcinoma is uncertain. We aimed to evaluate the association of AC with survival in patients with resected ampullary adenocarcinoma. Using the National Cancer Database (NCDB) data from 2004 to 2016, patients with non-metastatic ampullary adenocarcinoma who underwent PD were identified. Patients with neoadjuvant radiotherapy and chemotherapy and survival < 6 months were excluded. Propensity score matching was used to account for treatment selection bias. A multivariable Cox proportional hazards model was then used to analyze the association of AC with survival. Of 3186 (43%) AC and 4172 (57%) no AC (noAC) patients, 1720 AC and 1720 noAC patients remained in the cohort after matching. Clinicopathologic variables were well balanced after matching. After matching, AC was associated with improved survival (median 47.5 vs 39.6 months, p = 0.003), which remained after multivariable adjustment (HR: 0.83, CI95%: 0.76-0.91, p < 0.001). Multivariable interaction analyses showed that this benefit was seen irrespective of nodal status: N0 (HR: 0.81, CI95%: 0.68-0.97, p < 0.001), N1 (HR: 0.65, CI95%: 0.61-0.70, p < 0.001), N2 (HR: 0.73, CI95%: 0.59-0.90, p = 0.003), N3 (HR: 0.59, CI95%: 0.44-0.78, p < 0.001); and margin status: R0 (HR: 0.85, CI95%: 0.77-0.94, p < 0.001), R1 (HR: 0.69, CI95%: 0.48-1.00, p < 0.001). Stratified analyses by nodal and margin status demonstrated consistent results. In this large retrospective cohort study, AC after resected ampullary adenocarcinoma was associated with a survival benefit in patients, including patients with node-negative and margin-negative disease.


Evaluation of the antiproliferative, proapoptotic, and antiangiogenic effects of a double-stranded RNA mimic complexed with polycations in an experimental mouse model of leiomyoma.
To assess the antiproliferative, proapoptotic, and antiangiogenic effects of the double-stranded RNA mimic polyinosine-polycytidylic acid (pIC) complexed with polyethylenimine [pIC(PEI)] in xenografted human leiomyomas. Heterologous leiomyoma mouse model. University-affiliated infertility center. Ovariectomized and hormone-replaced nude mice (n = 16) who received human leiomyoma fragment transplantation. Leiomyoma fragments placed in the peritoneum of 5-week-old nude female mice and treated with the vehicle (n = 8) or 0.6 mg/kg [pIC(PEI)] (n = 8) for 4 weeks. The size of the leiomyoma implants, and cellular proliferation (Ki67), vascularization (PECAM), and apoptosis (OH-ends) assessed by quantitative immunohistochemical/immunofluorescent analysis of the recovered implants. No significant differences were observed in the size of the leiomyoma implants between groups. Vascularization and proliferation were significantly decreased, and apoptosis was increased in the [pIC(PEI)]-treated group versus control. We hypothesize that the antiangiogenic and apoptotic effects exerted by [pIC(PEI)] might lead to a decrease in lesion size in this animal model if the compound is administered for longer periods of time. This study provides promising data on [pIC(PEI)] as a potential novel therapeutic agent against human leiomyoma.


Microarray Analysis of Gene Expression Provides New Insights Into Denervation-Induced Skeletal Muscle Atrophy.
Denervation induces skeletal muscle atrophy, accompanied by complex biochemical and physiological changes, with potentially devastating outcomes even an increased mortality. Currently, however, there remains a paucity of effective strategies to treat skeletal muscle atrophy. Therefore, it is required to understand the molecular mechanisms of skeletal muscle atrophy and formulate new treatment strategies. In this study, we investigated the transcriptional profile of denervated skeletal muscle after peripheral nerve injury in rats. The cDNA microarray analysis showed that a huge number of genes in tibialis anterior (TA) muscles were differentially expressed at different times after sciatic nerve transection. Notably, the 24 h of denervation might be a critical time point for triggering TA muscle atrophy. According to the data from self-organizing map (SOM), Pearson correlation heatmap, principal component analysis (PCA), and hierarchical clustering analysis, three nodal transitions in gene expression profile of the denervated TA muscle might partition the period of 0.25 h-28 days post nerve injury into four distinct transcriptional phases. Moreover, the four transcriptional phases were designated as "oxidative stress stage", "inflammation stage", "atrophy stage" and "atrophic fibrosis stage", respectively, which was concluded from Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology (GO) analyses at each transcriptional phase. Importantly, the differentially expressed genes at 24 h post sciatic nerve transection seemed to be mainly involved in inflammation, which might be a critical process in denervation-induced muscle atrophy. Overall, our study would contribute to the understanding of molecular aspects of denervation-induced muscle atrophy, and may also provide a new insight into the time window for targeted therapy.


Urinary-tract infection and bacteraemia in hospitalized medical patients--a European multicentre prevalence survey on nosocomial infection.
A co-ordinated survey of 3899 medical patients in 169 wards, performed simultaneously in eight countries, showed a point-prevalence of urinary-tract infection (UTI) and bacteraemia of 12.6 and 1.6 per cent, respectively. One-half of the infections were acquired after the patients' admission. The bacteriological patterns of hospital- vs community-acquired infections were different, but showed no unexpected features. Antibiotic treatment was recorded in 22.3 per cent of the patients in this study, urinary-tract disinfectants, sulphonamides or penicillins being used in 95 per cent of those treated for UTI. The overall prevalence of urinary-tract drainage was 11.0 per cent with no significant difference between the two sexes. At ward level the rate of catheterized patients varied from below 5 per cent to more than 25 per cent, indicating--besides variations in the ward populations--differences in policies. The association between nosocomial UTI and the presence of an indwelling catheter and/or female sex was confirmed, while high age appeared to be a secondary risk factor among catheterized patients. The prevalence of nosocomial bacteraemia in patients with UTI was five times higher than in those without urinary-tract involvement, and a significant part of the nosocomial cases of both UTI and bacteraemia was clearly device-related. Guidelines for the use of indwelling catheters should be restrictive and provide for prompt removal. When introduced and followed they will effectively reduce nosocomial UTI and bacteraemia.


T helper cell differentiation: on again, off again.
Recent studies raise the possibility that T helper (Th) polarization may be attributable to generalized activation and regulated silencing rather than regulated activation of target cytokine genes. The binding of transcription factors GATA-3 or T-bet to specific enhancers does recruit transcription factors such as NFAT-1 to IL-4 or IFNgamma promoters, respectively; however, GATA-3 also intrinsically suppresses T-bet and vice versa. Silencing of GATA-3/T-bet, which is influenced by factors such as cytokines, is associated with irreversible Th polarization. For the first few divisions (perhaps reflecting the situation in lymph nodes), naive Th cells retain pluripotency; after further cell divisions (perhaps under the influence of an inflammatory cytokine milieu) they may become polarized appropriately to respond to the specific environment.


Persistent shoulder pain following a motor vehicle accident.
A 29-year-old woman had intermittent left shoulder pain during a 4-month period following a motor vehicle accident. Sudden development of a pleuritic component was noted. An elevated left hemidiaphragm of the chest radiograph prompted an ultrasound examination of the abdomen, which revealed a 15-cm complex mass in the left upper quadrant. At surgery, a tumor mass attached to the splenic artery, stomach, and diaphragm was removed. Pathologic studies revealed an encapsulated adrenal hematoma. This case represents an unusual cause of persistent shoulder pain due to diaphragmatic irritation by an adrenal hematoma.


Impact of total retrieved lymph nodes on staging and survival of patients with gastric cancer invading the subserosa.
To investigate the impact of total retrieved lymph nodes (tLNs) on staging and survival in patients with pT2b gastric cancer according to the nodal status. Clinicopathological characteristics and prognostic outcomes of 392 patients with pT2b gastric cancer between 1980 and 2005 were retrospectively investigated based on the nodal status. The number of metastatic lymph nodes (mLNs) was highly correlated with the number of tLNs (P<0.001). The overall 5-year and 10-year survival rates were 39.0% (153/392) and 17.9% (70/392), respectively. The survival rates in patients with pN0 cancers did not differ significantly from that in patients with pN1 cancer when the tLNs were 25 or less. However, the survival rate in patients with N0 cancers was significantly greater than that in patients with pN1 cancers when the tLNs were more than 25 (64.3% vs. 36.9%, chi(2)=4.339, P=0.037). Moreover, both 5- and 10-year survival rates differed significantly among patients with pN1, pN2 and pN3 gastric cancer regardless of tLNs. Multivariate analysis revealed that age, tumor focus number, tumor location, and mLN, but not tLNs, were independent prognostic predictors in patients with pT2b gastric cancer. To improve the accuracy of staging, no less than 15 tLNs should be pathologically examined in patients with pN1-3, and 25 tLNs for the patients with N0. More tLNs may not be associated with a better prognosis in pT2b disease because the extent of lymph node dissection is pre-defined for the operation.


Genetic polymorphism and variability in the Guangdong Hakka, Teochew, and Cantonese groups: A comprehensive analysis of 19 X-STRs.
X chromosomeshort tandem repeat (X-STR) loci are playing an increasingly important role inforensic work, identifying female traces in male contamination and explainingcomplex kinship analyses. In this study, we analyzed thegenetic polymorphism of 19 X-STR loci in the Guangdong Hakka, Teochew and Cantonese groups, respectively, aswell as in the Guangdong Hakka, Teochew andCantonese pooled Han. The genetic diversity and forensic characteristics of the19 X-STRs and 7 linkage groups were investigated, respectively. The experiments showed that the genetic diversity (GD) and polymorphism information content (PIC) in the pooledGuangdong Han ranged from 0.5320 to 0.9234 and 0.4369 to 0.9171, respectively, and the cumulative power of discrimination for males (PDM), power of discrimination for females (PDF) and mean paternity exclusion chance (MEC) were higher than 0.9999999, indicating that the 19 X-STRs had high geneticpolymorphism and discriminatory power. Genetic differences among Chinese Hansubgroups and among different Chinese populations were investigated byphylogenetic reconstruction and principal component analysis (PCA), respectively. Genetic analyses based on neighbor-joining (NJ) tree and principal component analysis plot showed that Cantonese, Teochew and Hakka were closely genetically related, and different populations with closer linguistic components had more genetic affinity. This study adds to the forensic X-STR database and demonstrates the forensic efficiency of 19 X-STRs for the Hakka, Teochewand Cantonese populations in Guangdong, and the pooled Han of Hakka, Teochewand Cantonese people in Guangdong.


Reduced tillering in Basmati rice T-DNA insertional mutant OsTEF1 associates with differential expression of stress related genes and transcription factors.
A T-DNA insertional mutant OsTEF1 of rice gives 60-80% reduced tillering, retarded growth of seminal roots, and sensitivity to salt stress compared to wild type Basmati 370. The insertion occurred in a gene encoding a transcription elongation factor homologous to yeast elf1, on chromosome 2 of rice. Detailed transcriptomic profiling of OsTEF1 revealed that mutation in the transcription elongation factor differentially regulates the expression of more than 100 genes with known function and finely regulates tillering process in rice by inducing the expression of cytochrome P450. Along with different transcription factors, several stress associated genes were also affected due to a single insertion. In silico analysis of the TEF1 protein showed high conservation among different organisms. This transcription elongation factor predicted to interact with other proteins that directly or indirectly positively regulate tillering in rice.


Hazard analysis of technologies for disposing explosive waste.
Hazards are identified for six different techniques for disposing decommissioned ammunition. Use has been made of functional modelling as a basis for hazard identification. Risk levels are estimated based on general accident rates in the chemical industry. The disposal techniques are "open burning" (OB), "open detonation" (OD), "closed detonation" (CD), "fluidised bed combustion" (FBC), "rotary kiln (RK) incineration", "mobile incineration". Closed detonation leads to most hazards and highest risk, followed by open burning and open detonation. The other three techniques are considerably safer. Risk due to transport is included in the analysis. Transport risk is not negligible for fluidised bed combustion and rotary kiln incineration at centrally located sites.


Comparison of the optical and visual quality of poly(methyl methacrylate) and silicone intraocular lenses.
We evaluated experimentally the optical quality of poly(methyl methacrylate) (PMMA) (Storz 68UV, AMO PC58) and silicone (AMO SI19, Adatomed 90D) intraocular lenses (IOLs) and compared the results with our clinical data. We measured surface and image quality using the Zygo laser interferometer and modulation transfer function (MTF) using the Ealing EROS MTF analyzer. Contrast acuity was tested clinically with glare and without glare (Regan charts); AMO PC58, n = 18; AMO SI19, n = 7; Adatomed 90D, n = 18). Modulation transfer function and image quality were slightly better with PMMA IOLs but the reduction of MTF with silicone lenses was within the 1/8 diopter defocus range. Surface quality of silicone IOLs was superior to that of PMMA IOLs. Contrast acuity measured clinically was also slightly better with PMMA IOLs at low contrast and with glare but differences were not significant. Our results suggest that optical and visual quality of silicone IOLs is slightly lower than with PMMA IOLs. Experimental and clinical results correlated closely. However, the small differences observed are unlikely to be significant clinically.


A three-stage eccDNA based molecular profiling significantly improves the identification, prognosis assessment and recurrence prediction accuracy in patients with glioma.
Glioblastoma (GBM) progression is influenced by intratumoral heterogeneity. Emerging evidence has emphasized the pivotal role of extrachromosomal circular DNA (eccDNA) in accelerating tumor heterogeneity, particularly in GBM. However, the eccDNA landscape of GBM has not yet been elucidated. In this study, we first identified the eccDNA profiles in GBM and adjacent tissues using circle- and RNA-sequencing data from the same samples. A three-stage model was established based on eccDNA-carried genes that exhibited consistent upregulation and downregulation trends at the mRNA level. Combinations of machine learning algorithms and stacked ensemble models were used to improve the performance and robustness of the three-stage model. In stage 1, a total of 113 combinations of machine learning algorithms were constructed and validated in multiple external cohorts to accurately distinguish between low-grade glioma (LGG) and GBM in patients with glioma. The model with the highest area under the curve (AUC) across all cohorts was selected for interpretability analysis. In stage 2, a total of 101 combinations of machine learning algorithms were established and validated for prognostic prediction in patients with glioma. This prognostic model performed well in multiple glioma cohorts. Recurrent GBM is invariably associated with aggressive and refractory disease. Therefore, accurate prediction of recurrence risk is crucial for developing individualized treatment strategies, monitoring patient status, and improving clinical management. In stage 3, a large-scale GBM cohort (including primary and recurrent GBM samples) was used to fit the GBM recurrence prediction model. Multiple machine learning and stacked ensemble models were fitted to select the model with the best performance. Finally, a web tool was developed to facilitate the clinical application of the three-stage model.


[Nodular amyloidosis of the lungs associated with Sjögren's syndrome].
Pulmonary amyloidosis can develop together with both primary or secondary amyloidosis, isolated or associated with amyloidosis of other organs. In the study a case of a 59 year old female with multiple nodules and diffuse amyloid infiltration in pulmonary parenchyma associated with Sjörgen's syndrome is presented. Amyloid deposits were also found in the surgically removed parotid salivary gland, mostly in its blood vessel walls.


Colistin-Induced Acute Kidney Injury and the Effect on Survival in Patients with Multidrug-Resistant Gram-Negative Infections: Significance of Drug Doses Adjusted to Ideal Body Weight.
Colistin is a lifesaving treatment for multidrug-resistant Gram-negative bacterial (MDR-GNB) infections along with its well-known nephrotoxicity. The controversy of colistin-induced acute kidney injury (AKI) on mortality is noted. This study aimed to determine the risk factors and impact of AKI on the survival and significance of colistin dosage. A retrospective cohort study was performed in adult patients who received intravenous colistin for MDR-GNB treatment between June 2015 and June 2017. Factors influencing colistin-induced AKI and survival were evaluated by Cox regression analysis. Cut-off levels of the colistin dose per ideal body weight (IBW) that significantly affected clinical outcomes were assessed with linearity trends and receiver operating characteristic analyses. AKI occurred in 68.5% of 412 enrolled patients with an incidence rate of 10.6 per 100 patients-days and a median time was 6 (3-13) days. Stages I-III of AKI were 38.3, 24.5, and 37.2%. Factors associated with colistin-induced AKI were advanced age, high serum bilirubin, AKI presented before colistin administration, increased daily colistin doses per IBW, and concomitant use of nephrotoxic drugs. Colistin-induced AKI was related to mortality (HR 1.74, 95% CI 1.06-2.86, p=0.028). In the non-AKI before colistin usage subgroup, the total dose and total dose/IBW were >1,500-2,000 mg and 30-35 mg/kg to benefit mortality reduction but were <2,500-3,000 mg and 45-50 mg/kg for risk reduction of AKI. A daily colistin dose/IBW >4.5 mg/kg/day also increased the risk of AKI. In the AKI developed before colistin subgroup, the cut-off values of total colistin dose >1250-1350 mg and total dose/IBW >23.5-24 mg/kg demonstrated significant risks of AKI. The incidence of AKI after colistin administration was high and impacted mortality. Prevention and early correction of these related factors are mandatory. Careful use of colistin was also both beneficial in mortality and AKI reductions.


Assessment of the FDA backgrounder on platinum in silicone breast implants: implications for public health policy.
A recent report by the U.S. Food and Drug Administration reviewed the literature on the subject of platinum in silicone gel-filled breast implants. In this study the author evaluates the FDA report for scientific accuracy and impartiality, and provides relevant discussions on financial conflicts of interest, an Institute of Medicine report, and public health policy. The study suggests that the FDA used discredited scientific practices in compiling its report. Reports by regulatory agencies should be scientifically accurate, with no partiality to industry. The current policy of one-way information flow from the FDA directly to those being informed needs to be revised. Greater importance should be placed on studies in which authors have no financial conflicts of interest.


[Advances in Surgical Approach and Resection of Non-small Cell Lung Cancer].
With the change of the spectrum of disease, the incidence and mortality of non-small cell lung cancer (NSCLC) has been high in global scale, since surgical intervention was applied to treat lung cancer, its status is increasing day by day, at present comprehensive treatment leaded by surgery has become the preferred scheme for NSCLC, there are many different kinds of surgical approaches and operation methods of disease, and the new technologies appear constantly, the paper aim to summarize the research progress of different operationmethods and surgical approach. With the development of software and hardware technology and the concept of minimally invasive thoracoscopic surgery was received by more people, minimally invasive thoracoscopic surgery has brought more benifit than traditional thoracotomy for lung cancer patients, minimally invasive thoracoscopic surgery reserve more lung tissue and improve the survival quality of patients due to better pulmonary function, we believe that minimally invasive thoracoscopic surgery can bring more benefits to people with surgical indications and surgical procedure further standardization. .


Update in fertility-sparing native-tissue procedures for pelvic organ prolapse.
Uterine-sparing prolapse surgery has been gaining back popularity with clinicians and patients. Although both prosthetic and native-tissue surgery procedures are described, the latter is progressively regaining a central role in pelvic reconstructive surgery, owing to a lack of mesh-related complications. Available native-tissue procedures have different advantages and pitfalls, as well as different evidence profiles. Most of them offer anatomical and subjective outcomes comparable with those of hysterectomy-based procedures. Moreover, native-tissue procedures in young women desiring childbearing allow to avoid synthetic material implantation, which may lead to potentially serious complications during pregnancy. As a consequence, we do think that offering a reconstructive native-tissue procedure for uterine preservation (with the exception of the Manchester procedure) is the safest option in women wishing for pregnancy. Sacrospinous ligament hysteropexy and high uterosacral ligament hysteropexy may be considered first-line options in consideration of the higher level of evidence and lack of adverse obstetrical outcomes.


Which is important in the evaluation of metastatic lymph nodes in head and neck cancer: palpation, ultrasonography, or computed tomography?
Evaluate palpation, ultrasonography (USG), and computed tomography (CT) with respect to their value for comparative determination of metastatic lymph nodes in head and neck cancer. A prospective study was conducted in a tertiary referral hospital. During September 1996 and April 1999, clinical investigation, USG, and CT were performed preoperatively on 48 patients who would undergo neck dissection for primary head and neck malignancy. The presence of metastatic lymph nodes in pathologic specimens were compared with the findings of palpation, CT, and USG. Twenty-two of the patients had positive lymph nodes on pathologic investigation. The sensitivity, specificity, negative predictive value, positive predictive value, and accuracy for palpation are 64%, 85%, 74%, 78%, and 75% respectively. Respective values for USG and CT for sensitivity, specificity, negative predictive value, positive predictive value, and accuracy are 72%, 96%, 80%, 94%, and 85% and 81%, 96%, 85%, 90%, and 87%. All of the pretreatment evaluation methods, palpation, CT, and USG yield results that are significantly different from the histopathologic results, suggesting that no pretreatment study can accurately assess the requirement to histopathologically stage the neck. USG findings are more correlated with the pathologic findings than palpation, but CT gives the most effective and reliable results when it is combined with USG in neck staging. Preoperative USG and CT scanning of the neck by an experienced radiologist is essential and useful for diagnosis, staging, and therapy choices. Statistical analysis was done with chi(2) test. The difference between histologic findings and palpation is significant (P = 0.0005). The difference between histologic findings and USG and CT is significant (P = 0.0001 and P = 0.0001).


EBV-associated lymphoepithelioma-like carcinoma of the pancreas: Case report with targeted sequencing analysis.
Lymphoepithelioma-like carcinomas are distinctive epithelial derived malignant neoplasms that have a syncytial growth pattern and lymphoid stroma. The majority of tumors with this appearance are Epstein Barr virus (EBV)-associated. We report a patient with a clinical presentation concerning for lymphoma who was diagnosed with an EBV-associated pancreatic carcinoma with a lymphoepithelioma-like pattern. Targeted sequencing analysis showed a molecular profile distinct from conventional ductal adenocarcinoma of the pancreas.


Quantitative investigation of the x-ray absorption coefficient in computed tomography. An approach to numerical diagnosis.
From printout data of 50 normal and 50 abnormal scans of a brain slice picking up the basal ganglia the numerical values of SD and DC were obtained and those values lying inside M + 2sigma were arbitrarily regarded as normal. By these criteria two cases (4%) were diagnosed as false negative and three cases (6%) as false positive, with a misdiagnosis rate of 5%.


Chemical architecture of the posterior striatum in the human brain.
The neurochemical organization of the posterior caudate nucleus (CN) (body, gyrus and tail) and putamen (Put) was analyzed in the human brain using adjacent sections stained for acetylcholinesterase (AChE), limbic system-associated membrane protein (LAMP), enkephalin (ENK), parvalbumin (PV), calbindin (CB) and tyrosine hydroxylase (TH). Striosomes were visualized in all striatal regions but the anterior two thirds of the CN tail. They were highly immunoreactive (-ir) for ENK and LAMP, devoid of PV and AChE staining, and surrounded by a ring of tissue with pale TH- and CB-ir neuropil. In the Put, other rings of tissue completely free of ENK labeling surrounded certain striosomes (clear septa). In the CN body, gyrus and tail some markers revealed gradients and heterogeneities along the dorsoventral and mediolateral axes. A rim of striatal tissue densely stained for ENK and LAMP and poorly labeled for PV was noticeable along the lateral edge of the Put and the dorsolateral sector of the CN body. Our results illustrate a chemical architecture in the posterior striatum that is heterogeneous and slightly different from that found in the more anterior striatum.


NAD(P)-dependent steroid dehydrogenase-like protein and neutral cholesterol ester hydrolase 1 serve as novel markers for early detection of gastric cancer identified using quantitative proteomics.
Gastric cancer (GC) is the third most common cause of cancer deaths worldwide. In the present study, we aimed to identify novel GC biomarkers by integrating isobaric tags of relative and absolute quantitation (iTRAQ) for aberrantly expressed proteins in GC patients. Using stable isotope tags, we labeled an initial discovery group comprising four paired gastric cancer and adjacent gastric tissue samples, and subjected them to LC-ESI-MS/MS. We used a validation set comprising 129 paired gastric cancer and adjacent gastric tissues from patients and benign healthy controls to validate the candidate targets. We identified two proteins, NAD(P)-dependent steroid dehydrogenase-like (NSDHL) and neutral cholesterol ester hydrolase 1 (NCEH1), that were significantly overexpressed in GC tissues. The sensitivity and specificity of NSDHL were 80.6% and 74.4%, respectively, in GC compared with a sensitivity of 25.6% in adjacent tissues and 24% in benign healthy controls. The area under the ROC curve (AUC) for NSDHL was 0.810 for GC detection. Overexpression of NSDHL in GC was significantly correlated with local tumor invasion. The sensitivity and specificity of NCEH1 were 77.5% and 73.6%, respectively, in GC compared with a sensitivity of 26.4% in adjacent tissues and 20% in benign controls. The AUC for NSDHL was 0.792. Overexpression of NCEH1 was significantly associated with tumor histological classification and local invasion. Moreover, a combined analysis of NSDHL and NCEH1 achieved a sensitivity and specificity of 85.7% and 83%, respectively, and the AUC was 0.872. The combined analysis of NSDHL and NCEH1 was significantly correlated with histological grade and TNM Ⅱ-Ⅳ staging. iTRAQ-labeled quantitative proteomics represents a powerful method to identify novel cancer biomarkers. The present study identified NSDHL and NCEH1 as useful biomarkers for screening, diagnosis, and prognosis of patients with gastric cancer.


The aortic root in subaortic stenosis.
This study investigated the size of the aortic root (AoR) and its effect on surgical outcome in patients with fixed subaortic stenosis. The diameter of the AoR was measured in two groups by means of two-dimensional echocardiography. Group A consisted of 138 normal subjects, aged 3 weeks to 20 years (mean 7.5 years). Group B consisted of 28 patients with fixed subaortic stenosis, aged 1.5 to 18 years (mean 9.5 years), 21 of whom had undergone surgical resection of the stenosis. Normal values and growth curves for AoR diameter were obtained from patients in group A. There was marked retardation of growth of the AoR among patients in group B, with seven patients having a small AoR diameter (less than 2 standard deviations). Postoperative gradients had a high correlation with the small size of diameter of the AoR (r = -0.84). In fixed subaortic stenosis the AoR may be small (25%). The presence of a small AoR has a marked effect on the optimal relief of fixed subaortic stenosis. The diameter of the AoR should be measured preoperatively, inasmuch as special surgical techniques may be required.


Bimolecular Fluorescence Complementation Assay to Evaluate HSP90-Client Protein Interactions in Cells.
Protein-protein interactions (PPI) in cells play a pivotal role in cellular function and dynamics. Cellular proteostasis is maintained by PPI networks between molecular chaperones, co-chaperones, and client proteins. Consequently, strategies to visualize and analyze PPI in cells are useful in understanding protein homeostasis regulation. The Bimolecular Fluorescence Complementation (BiFC) assay has emerged as a useful tool for studying PPI between proteins in live or fixed cells. BiFC is based on the detection of fluorescence generated when interacting protein pairs, produced as fusion proteins with either the N- or C-terminal fragment of a fluorescent protein, are in sufficient proximity to permit reconstitution of the split fluorophore. Here, we describe the application of the BiFC assay to a model of chaperone-client interactions using Hsp90 and the validated client protein CDK4. This assay allows for the distribution and spatiotemporal analysis of HSP90-CDK4 complexes in live or fixed cells and is amenable to studying the effects of inhibitors and mutations on chaperone-client protein networks.


[Neurotransmitter disturbances in some parts of the rat brain and their correction under chronic and intermittent alcohol intoxication].
The pool of key neuromediators and some neurotransmitter amino acids in cerebellum, hypothalamus and midbrain of rats exposed to chronic and different variants of interrupted alcohol intoxication was investigated. The most pronounced changes were recorded in midbrain. Chronic alcohol intoxication caused an increase in the concentrations of tyrosine, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), noradrenaline, tryptophan, serotonin, GABA and aspartate in this part of the rat brain. Interrupted alcohol intoxication with 4 days interval is accompanied by an increase in the content of tyrosine, and noradrenaline. Interrupted alcohol intoxication with 1 day interval leaded to an increase in the concentrations of tyrosine, DOPAC, noradrenalin, tryptophan, GABA, glycine and aspartate. The amino acids composition "Titacin" had a pronounced normalizing effect in the midbrain under interrupted alcohol intoxication with 1 day interval.


Correlation study of biological characteristics of non-small cell lung cancer A549 cells after transfecting plasmid by microbubble ultrasound contrast agent.
To explore the role of the abnormal expression of miRNAs in the development process of non-small cell lung cancer and the feasibility of ultrasound microbubble-mediated gene therapy after transfecting antisense miRNA-224 and miRNA-122a plasmids into non-small cell lung cancer A549 cells. Antisense miRNA-224 and miRNA-122a plasmids were transfected into non-small cell lung cancer A549 cells on the optimal ultrasound microbubble-mediated condition. We set up a control group. The cell proliferation activity, apoptosis, invasion ability were detected by MTT assay, Annexin V-PE, Transwell invasion experiment and colony formation assay, respectively. The expression of miRNA-224 decreased and the expression of miRNA-122a rose after the plasmids of target genes were transfected into non-small cell lung cancer A549 cells, and there were significant differences when compared with those of the control group (P < 0.05). After the plasmids of target genes were transfected into A549 cells, the growth of antisense miRNA-224 and miRNA-122a were inhibited, and the differences were significant as compared with the control group (P < 0.05). Besides, the inhibition of miRNA-122a group was the most significant and there was statistically significant difference as compared with miRNA-224 group (t = -4.694, P = 0.009). After the plasmids of target genes were transfected into A549 cells, the proportion of apoptotic cells increased, the invasive cells were decreased and the clone ability reduced, and also there was a significant difference as compared with those of the control group (P < 0.05). What's more, the apoptotic peak appeared in miRNA-122a group. Its invasion ability decreased most obviously (40.25 ± 3.97/visual field), the number of clone ability was 104.93 ± 4.87 and the inhibitory effect was the most obviously. There was statistically significant difference as compared with other groups (P < 0.05). A549 cells transfected by ultrasound microbubble-mediated antisense miRNA-224 and miRNA-122a plasmids possessed good transfection efficiency. The cell growth, invasion and colony-forming abilities of transfected A549 cells were suppressed, which laid a solid foundation for the gene therapy of non-small cell lung cancer.