Time Window for Induced Hypertension in Acute Small Vessel Occlusive Stroke With Early Neurological Deterioration.
Therapeutic-induced hypertension treatment (iHTN) is helpful for alleviating early neurological deterioration (END) in acute small vessel occlusive stroke. We examined the time parameters related to iHTN effectiveness in these patients. We retrospectively reviewed patients with acute small vessel occlusive stroke who underwent iHTN for END, defined as an increase of ≥2 points in total National Institutes of Health Stroke Scale (NIHSS) score or ≥1 point in motor items of NIHSS. The primary outcome was an early neurological improvement (ENI; a decrease of ≥2 points in total NIHSS score or ≥1 point in motor items of NIHSS), and the secondary outcome was any neurological improvement (a decrease of ≥1 point in the total NIHSS score). We conducted a multivariable logistic regression analysis, adjusting for demographics, risk factors, baseline clinical status, and intervention-related variables. We also generated a restricted cubic spline curve for the END-to-iHTN time cutoff. Among the 1062 patients with small vessel occlusive stroke screened between 2017 and 2021, 136 patients who received iHTN within 24 hours from END were included. The mean age was 65.1 (±12.0) years, and 61.0% were male. Sixty-five (47.8%) patients showed ENI and 77 (56.6%) patients showed any neurological improvement. END-to-iHTN time was significantly shorter in patients with ENI (150 [49-322] versus 290 [97-545] minutes; P=0.018) or any neurological improvement (150 [50-315] versus 300 [130-573] minutes; P=0.002). A 10-minute increase in the time between END and iHTN decreased the odds of achieving ENI (odds ratio, 0.984 [95% CI, 0.970-0.997]; P=0.019) or any neurological improvement (odds ratio, 0.978 [95% CI, 0.964-0.992]; P=0.002). The restricted cubic spline curve showed that the odds ratio of ENI reached its minimum at ≈3 hours. Among patients with small vessel occlusive stroke with END, a shorter interval between END and the initiation of iHTN was associated with increased odds of achieving neurological improvement. The efficacy of iHTN may be limited to induction within the first 3 hours of END.


Critical appraisal of prognostic factors for transobturator tape implantation.
The aim of the study was (1) to compare early results of transobturator tape (TOT) implantation in women with lower and higher Valsalva leak point pressure (VLPP) and (2) to find out significant and independent prognostic factors of TOT implantation. 97 female patients (pts) underwent TOT implantation between March 2004 and September 2007. We observed preoperative parameters including VLPP, urine leakage (PWT1), quality of life (IQOL1), age, BMI, parity, previous anti-incontinence surgery, hysterectomy status (HYE) and symptoms of OAB. According to VLPP value, pts were divided into two groups, namely those with lower VLPP values (< or =60 cmH2O) and those with higher VLPP values (> 60 cmH2O). Two different tapes were used for TOT implantation (resorbable and non-resorbable). Six months after surgery, urine leakage (PWT2) was reassessed and pts were classed into two main categories as 'cured' (PWT2 < or =2 g), or 'not cured' (PWT2 >2 g). Pts with lower VLPP values had significantly lower cure rates than those with higher VLPP values (43.8% vs. 81.5%, p < 0.001, respectively). Univariate logistic regresion analysis identified VLPP, PWT1, IQOL1, age, HYE, and TOT type parameters as significant factors for cure. Of these significant parameters, the multivariate logistic regresion analysis identified PWT1 and TOT type as the only independent ones. Pts with lower VLPP values are at a five-fold greater risk of not being cured than those with higher VLPP values. Preoperative urine leakage and TOT type are the only independent prognostic factors for cure after TOT implantation (Tab. 5, Fig. 3, Ref. 32).


Adrenal insufficiency.
Adrenal insufficiency can arise from a primary adrenal disorder, secondary to adrenocorticotropic hormone deficiency, or by suppression of adrenocorticotropic hormone by exogenous glucocorticoid or opioid medications. Hallmark clinical features are unintentional weight loss, anorexia, postural hypotension, profound fatigue, muscle and abdominal pain, and hyponatraemia. Additionally, patients with primary adrenal insufficiency usually develop skin hyperpigmentation and crave salt. Diagnosis of adrenal insufficiency is usually delayed because the initial presentation is often non-specific; physician awareness must be improved to avoid adrenal crisis. Despite state-of-the-art steroid replacement therapy, reduced quality of life and work capacity, and increased mortality is reported in patients with primary or secondary adrenal insufficiency. Active and repeated patient education on managing adrenal insufficiency, including advice on how to increase medication during intercurrent illness, medical or dental procedures, and profound stress, is required to prevent adrenal crisis, which occurs in about 50% of patients with adrenal insufficiency after diagnosis. It is good practice for physicians to provide patients with a steroid card, parenteral hydrocortisone, and training for parenteral hydrocortisone administration, in case of vomiting or severe illness. New modes of glucocorticoid delivery could improve the quality of life in some patients with adrenal insufficiency, and further advances in oral and parenteral therapy will probably emerge in the next few years.


Predictors of outcome for short-term medically supervised opioid withdrawal during a randomized, multicenter trial of buprenorphine-naloxone and clonidine in the NIDA clinical trials network drug and alcohol dependence.
Few studies in community settings have evaluated predictors, mediators, and moderators of treatment success for medically supervised opioid withdrawal treatment. This report presents new findings about these factors from a study of 344 opioid-dependent men and women prospectively randomized to either buprenorphine-naloxone or clonidine in an open-label 13-day medically supervised withdrawal study. Subjects were either inpatient or outpatient in community treatment settings; however not randomized by treatment setting. Medication type (buprenorphine-naloxone versus clonidine) was the single best predictor of treatment retention and treatment success, regardless of treatment setting. Compared to the outpatient setting, the inpatient setting was associated with higher abstinence rates but similar retention rates when adjusting for medication type. Early opioid withdrawal severity mediated the relationship between medication type and treatment outcome with buprenorphine-naloxone being superior to clonidine at relieving early withdrawal symptoms. Inpatient subjects on clonidine with lower withdrawal scores at baseline did better than those with higher withdrawal scores; inpatient subjects receiving buprenorphine-naloxone did better with higher withdrawal scores at baseline than those with lower withdrawal scores. No relationship was found between treatment outcome and age, gender, race, education, employment, marital status, legal problems, baseline depression, or length/severity of drug use. Tobacco use was associated with worse opioid treatment outcomes. Severe baseline anxiety symptoms doubled treatment success. Medication type (buprenorphine-naloxone) was the most important predictor of positive outcome; however the paper also considers other clinical and policy implications of other results, including that inpatient setting predicted better outcomes and moderated medication outcomes.


Cervical intraepithelial neoplasia and cancer in women 35 years and older.
To evaluate the distribution of abnormal cytohistopathology among low-income women 35 years and older compared with women younger than 35 years. This was a retrospective analysis of the 896 women who presented to the dysplasia clinic at an urban, public, tertiary care hospital with abnormal cervical cytology from September 23, 2008, to September 23, 2010. Statistical comparisons were made using t, χ(2), and Wilcoxon rank sum tests. Of the 896 patients, 460 (51%) were aged 35 years or older. Among the women 35 years and older, 56% had negative/benign histologic findings compared with 45% in women younger than 35 years. Conversely, women 35 years and older had lower rates of cervical intraepithelial neoplasia 1 (14%) than women younger than 35 years (30%). However, the prevalence of cancer diagnosis, per colposcopy, increased significantly with age, affecting 6% of women aged 50 years or older, 2% of women aged 35 to 49 years, and 1% of women younger than 35 years (p = .0008). Women older than 35 years with abnormal cytology demonstrated increased severity of cervical intraepithelial neoplasia on histology compared with younger women. Although women younger than 35 years were more likely to have transient human papillomavirus infections, a very high prevalence of severe cervical intraepithelial neoplasia and cancer was identified among women aged 35 years and older. Careful evaluation and follow-up must be performed for this group of women who may have previously been considered by some clinicians to be low risk on the basis of their age.


Molecular phylogeny and evolution of world Tachinidae (Diptera).
We reconstructed phylogenetic relationships within the diverse parasitoid fly family Tachinidae using four nuclear loci (7800 bp) and including an exceptionally large sample of more than 500 taxa from around the world. The position of the earthworm-parasitizing Polleniinae (Calliphoridae s.l.) as sister to Tachinidae is strongly supported. Our analyses recovered each of the four tachinid subfamilies and most recognized tribes, with some important exceptions in the Dexiinae and Tachininae. Most notably, the tachinine tribes Macquartiini and Myiophasiini form a clade sister to all other Tachinidae, and a clade of Palpostomatini is reconstructed as sister to Dexiinae + Phasiinae. Although most nodes are well-supported, relationships within several lineages that appear to have undergone rapid episodes of diversification (basal Dexiinae and Tachininae, Blondeliini) were poorly resolved. Reconstructions of host use evolution are equivocal, but generally support the hypothesis that the ancestral host of tachinids was a beetle and that subsequent host shifts to caterpillars may coincide with accelerated diversification. Evolutionary reconstructions of reproductive strategy using alternative methods were incongruent, however it is most likely that ancestral tachinids possessed unincubated, thick shelled eggs from which incubated eggs evolved repeatedly, potentially expanding available host niches. These results provide a broad foundation for understanding the phylogeny and evolution of this important family of parasitoid insects. We hope it will serve as a framework to be used in concert with morphology and other sources of evidence to revise the higher taxonomic classification of Tachinidae and further explore their evolutionary history and diversification.


A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD.
Cytidine deaminase (CDA) deficiency causes pyrimidine pool disequilibrium. We previously reported that the excess cellular dC and dCTP resulting from CDA deficiency jeopardizes genome stability, decreasing basal poly(ADP-ribose) polymerase 1 (PARP-1) activity and increasing ultrafine anaphase bridge (UFB) formation. Here, we investigated the mechanism underlying the decrease in PARP-1 activity in CDA-deficient cells. PARP-1 activity is dependent on intracellular NAD+ concentration. We therefore hypothesized that defects of the NAD+ salvage pathway might result in decreases in PARP-1 activity. We found that the inhibition or depletion of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage biosynthesis pathway, mimicked CDA deficiency, resulting in a decrease in basal PARP-1 activity, regardless of NAD+ levels. Furthermore, the expression of exogenous wild-type NAMPT fully restored basal PARP-1 activity and prevented the increase in UFB frequency in CDA-deficient cells. No such effect was observed with the catalytic mutant. Our findings demonstrate that (1) the inhibition of NAMPT activity in CDA-proficient cells lowers basal PARP-1 activity, and (2) the expression of exogenous wild-type NAMPT, but not of the catalytic mutant, fully restores basal PARP-1 activity in CDA-deficient cells; these results strongly suggest that basal PARP-1 activity in CDA-deficient cells decreases due to a reduction of NAMPT activity.


Mapping quantitative trait loci for principal components of bone measurements and osteochondrosis scores in a wild boar x large white intercross.
Data on osteochondrosis and femur dimensions from 195 F2 pigs from a wild boar x Large White intercross were analysed with the aim of detecting quantitative trait loci (QTLs) for normal and disturbed bone formation. The information from numerous recorded traits was summarized by principal component analysis and analysed by least-squares interval mapping. An increase in the proportion of wild boar alleles across the genome increased length versus width of femur and reduced the prevalence of osteochondrosis. The presence of QTLs with an impact on femur dimensions was indicated on chromosomes 2, 4, 16 and 17 and on osteochondrosis on chromosomes 5, 13 and 15. A substantial effect of the chromosome 5 QTL calls for further studies within commercial populations to evaluate whether marker-assisted selection could be used to reduce the prevalence of osteochondrosis.


Formation of 4-hydroxy-2-nonenal-modified proteins in ischemic rat heart.
4-Hydroxy-2-nonenal (HNE) is a major lipid peroxidation product formed during oxidative stress. Because of its reactivity with nucleophilic compounds, particularly metabolites and proteins containing thiol groups, HNE is cytotoxic. The aim of this study was to assess the extent and time course for the formation of HNE-modified proteins during ischemia and ischemia plus reperfusion in isolated rat hearts. With an antibody to HNE-Cys/His/Lys and densitometry of Western blots, we quantified the amount of HNE-protein adduct in the heart. By taking biopsies from single hearts (n = 5) at various times (0, 5, 10, 15, 20, 35, and 40 min) after onset of zero-flow global ischemia, we showed a progressive, time-dependent increase (which peaked after 30 min) in HNE-mediated modification of a discrete number of proteins. In studies with individual hearts (n = 4/group), control aerobic perfusion (70 min) resulted in a very low level (296 arbitrary units) of HNE-protein adduct formation; by contrast, after 30-min ischemia HNE-adduct content increased by >50-fold (15,356 units, P < 0.05). In other studies (n = 4/group), administration of N-(2-mercaptopropionyl)glycine (MPG, 1 mM) to the heart for 5 min immediately before 30-min ischemia reduced HNE-protein adduct formation during ischemia by approximately 75%. In studies (n = 4/group) that included reperfusion of hearts after 5, 10, 15, or 30 min of ischemia, there was no further increase in the extent of HNE-protein adduct formation over that seen with ischemia alone. Similarly, in experiments with MPG, reperfusion did not significantly influence the tissue content of HNE-protein adduct. Western immunoblot results were confirmed in studies using in situ immunofluorescent localization of HNE-protein in cryosections. In conclusion, ischemia causes a major increase in HNE-protein adduct that would be expected to reflect a toxic sequence of events that might act to compromise tissue survival during ischemia and recovery on reperfusion.


Nano-Structured Gelatin/Bioactive Glass Hybrid Scaffolds for the Enhancement of Odontogenic Differentiation of Human Dental Pulp Stem Cells.
Tooth decay is one of the most common chronic disorders throughout the world. Regenerating decayed dentin/pulp structure requires the design of novel scaffolding materials that mimic the architecture of natural dental extracellular matrix (ECM) and provide suitable environments for the attachment, proliferation, differentiation, and biomineralization of dental pulp stem cells (DPSCs). In this work, we developed an approach to prepare three-dimensional (3D) nano-fibrous gelatin/silica bioactive glass (NF-gelatin/SBG) hybrid scaffolds that mimic the nano-structured architecture and chemical composition of natural dental ECM. This approach involved the combination of a thermally induced phase separation, sol-gel, and porogen leaching process, and synthesized hybrid scaffolds possessing natural ECM-like architecture, high porosity, well-defined pore size and interconnectivity, and improved mechanical strength. An in vitro cell culture study showed that human DPSCs had a significantly higher proliferation rate on NF-gelatin/SBG scaffolds compared to NF-gelatin scaffolds under the same conditions. Furthermore, the integration of SBG into the hybrid scaffold significantly promoted the differentiation and biomineralization of the human DPSCs. The alkaline phosphatase (ALP) activity and expressions of marker genes for odontogenic differentiation (Col I, ALP, OCN, DSPP and DMP-1) were all significantly higher in the NF-gelatin/SBG than in the NF-gelatin group. Those results were further confirmed by hematoxylin and eosin (H&E) and von Kossa staining, as evidenced by greater ECM secretion and mineral deposition in the hybrid scaffold. In summary, the biomimetic NF-gelatin/SBG hybrid scaffolds provide an excellent environment for the growth and differentiation of human DPSCs and are promising candidates for dentin/pulp tissue regeneration.


Availability of intestinal microbial lysine for whole body lysine homeostasis in human subjects.
We have investigated whether there is a net contribution of lysine synthesized de novo by the gastrointestinal microflora to lysine homeostasis in six adults. On two separate occasions an adequate diet was given for a total of 11 days, and a 24-h (12-h fast, 12-h fed) tracer protocol was performed on the last day, in which lysine turnover, oxidation, and splanchnic uptake were measured on the basis of intravenous and oral administration of L-[1-(13)C]lysine and L-[6,6-(2)H(2)]lysine, respectively. [(15)N(2)]urea or (15)NH(4)Cl was ingested daily over the last 6 days to label microbial protein. In addition, seven ileostomates were studied with (15)NH(4)Cl. [(15)N]lysine enrichment in fecal and ileal microbial protein, as precursor for microbial lysine absorption, and in plasma free lysine was measured by gas chromatography-combustion-isotope ratio mass spectrometry. Differences in plasma [(13)C]- and [(2)H(2)]lysine enrichments during the 12-h fed period were observed between the two (15)N tracer studies, although the reason is unclear, and possibly unrelated to the tracer form per se. In the normal adults, after (15)NH(4)Cl and [(15)N(2)]urea intake, respectively, lysine derived from fecal microbial protein accounted for 5 and 9% of the appearance rate of plasma lysine. With ileal microbial lysine enrichment, the contribution of microbial lysine to plasma lysine appearance was 44%. This amounts to a gross microbial lysine contribution to whole body plasma lysine turnover of between 11 and 130 mg. kg(-1). day(-1), depending on the [(15)N]lysine precursor used. However, insofar as microbial amino acid synthesis is accompanied by microbial breakdown of endogenous amino acids or their oxidation by intestinal tissues, this may not reflect a net increase in lysine absorption. Thus we cannot reliably estimate the quantitative contribution of microbial lysine to host lysine homeostasis with the present paradigm. However, the results confirm the significant presence of lysine of microbial origin in the plasma free lysine pool.


Endurance and gait in children with cerebral palsy after intensive body weight-supported treadmill training.
This study was designed to investigate changes in endurance, functional gait, and balance after intensive body weight-supported treadmill training in children with CP who were ambulatory. Six school-aged children with CP (four boys, two girls; age range: six to 14 years) participated in an intensive program of body weight-supported treadmill training 30 minutes twice daily for two weeks. Statistically significant improvement in walking velocity and energy expenditure were observed. Variability of individual outcomes was observed with some children showing positive changes, and others no change or a decline in performance. Four children showed minimal detectable changes in a positive direction on both an endurance measure and a functional gait measure. Each endurance and functional gait measure included at least one child with a positive minimal detectable change. Intensive body weight-supported treadmill training may be an effective intervention for some children with CP who are ambulatory.


Attention deficits in children with low performance IQ: arguments for right hemisphere dysfunction.
The attentional component of cognitive functioning in children might be viewed from several interrelated angles that nearly all point to right hemisphere (RH) neural circuits, subserving nonverbal attention. Neuropsychological aspects indicative of RH brain dysfunction are one aspect, studied here. Among children with learning disabilities (LD) we distinguish between LD with emphasis on nonverbal cognitive deficits and LD with verbal dysfunction. We approached this dichotomy by studying the extremes of these two LD categories (89 ss) with respect to attention deficit disorder with (ADHD) or without hyperactivity (ADD). We examined 44 children with at least average verbal IQ (VIQ > or = 95) and lower performance IQ (PIQ at least 25 points lower than VIQ), i.e. the nonverbal group, and 45 children with at least average performance IQ (PIQ > or = 95) and lower verbal IQ (VIQ at least 25 points lower than PIQ). The percentage of AD(H)D among the nonverbal LD group was more than twice as high as among the verbal LD group. Although a convincing right hemisphere (RH) syndrome could not be shown on a neurological basis in most subjects of the non-verbal LD group, a large body of evidence points on the one hand to RH dysfunction associated with nonverbal LD and on the other hand to an association between RH dysfunction and ADD. However, on clinical grounds, discussed here, we consider ADD and low visuospatial cognition, being the most important component of low PIQ, as dissociated functions, largely subserved by the RH.


Second-site reversion of a dysfunctional mutation in a conserved region of the tobacco mosaic tobamovirus movement protein.
The N-terminal two-thirds of tobamovirus movement proteins (MPs) contain two well conserved regions. Within region I (amino acids 56-96) is an area predicted by computer analysis to have loop secondary structure (amino acids 76-87). A single or two double amino acid mutations were introduced into the loop in region I of the TMV MP to destabilize the structure. The three mutant MPs were defective in movement function. The single amino acid mutation resulted in a Pro81-->Ser substitution. The mutant virus, TP81S, containing the Pro81-->Ser substitution, was propagated on a transgenic line of Nicotiana tabacum that expresses the sunn-hemp mosaic tobamovirus MP. Inoculation of virus progeny from the transgenic plants onto hypersensitive N. tabacum indicated the presence of infectious virus at a low frequency. Necrotic lesions were detected at 4 days postinoculation, 2 days later than those induced by wild-type TMV. Inoculation of virus extracted from necrotic lesions onto N. tabacum resulted in a delayed and attenuated systemic infection relative to that induced by TMV, indicating that a second-site mutation restored movement function rather than a reversion of the original mutation. Sequence analysis revealed that the revertant MP gene had two additional amino acid substitutions, a Thr104-->Ile and a Arg167-->Lys. Introduction of the amino acid substitutions individually or in combination into the MP of TP81S indicated that both substitutions were required for the revertant phenotype. The data indicate that structure within region I is important in maintaining an active conformation for functional MP, that changes outside region I can compensate for alterations within the region, and suggest that region I may interact with a distal portion of the protein.


Atom exchange between aqueous Fe(II) and structural Fe in clay minerals.
Due to their stability toward reductive dissolution, Fe-bearing clay minerals are viewed as a renewable source of Fe redox activity in diverse environments. Recent findings of interfacial electron transfer between aqueous Fe(II) and structural Fe in clay minerals and electron conduction in octahedral sheets of nontronite, however, raise the question whether Fe interaction with clay minerals is more dynamic than previously thought. Here, we use an enriched isotope tracer approach to simultaneously trace Fe atom movement from the aqueous phase to the solid ((57)Fe) and from the solid into the aqueous phase ((56)Fe). Over 6 months, we observed a significant decrease in aqueous (57)Fe isotope fraction, with a fast initial decrease which slowed after 3 days and stabilized after about 50 days. For the aqueous (56)Fe isotope fraction, we observed a similar but opposite trend, indicating that Fe atom movement had occurred in both directions: from the aqueous phase into the solid and from the solid into aqueous phase. We calculated that 5-20% of structural Fe in clay minerals NAu-1, NAu-2, and SWa-1 exchanged with aqueous Fe(II), which significantly exceeds the Fe atom layer exposed directly to solution. Calculations based on electron-hopping rates in nontronite suggest that the bulk conduction mechanism previously demonstrated for hematite1 and suggested as an explanation for the significant Fe atom exchange observed in goethite2 may be a plausible mechanism for Fe atom exchange in Fe-bearing clay minerals. Our finding of 5-20% Fe atom exchange in clay minerals indicates that we need to rethink how Fe mobility affects the macroscopic properties of Fe-bearing phyllosilicates and its role in Fe biogeochemical cycling, as well as its use in a variety of engineered applications, such as landfill liners and nuclear repositories.


Nanoscale clustering of carbohydrate thiols in mixed self-assembled monolayers on gold.
Self-assembled monolayers (SAMs) bearing pendant carbohydrate functionality are frequently employed to tailor glycan-specific bioactivity onto gold substrates. The resulting glycoSAMs are valuable for interrogating glycan-mediated biological interactions via surface analytical techniques, microarrays, and label-free biosensors. GlycoSAM composition can be readily modified during assembly by using mixed solutions containing thiolated species, including carbohydrates, oligo(ethylene glycol) (OEG), and other inert moieties. This intrinsic tunability of the self-assembled system is frequently used to optimize bioavailability and antibiofouling properties of the resulting SAM. However, until now, our nanoscale understanding of the behavior of these mixed glycoSAMs has lacked detail. In this study, we examined the time-dependent clustering of mixed sugar + OEG glycoSAMs on ultraflat gold substrates. Composition and surface morphologic changes in the monolayers were analyzed by X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM), respectively. We provide evidence that the observed clustering is consistent with a phase separation process in which surface-bound glycans self-associate to form dense glycoclusters within the monolayer. These observations have significant implications for the construction of mixed glycoSAMs for use in biosensing and glycomics applications.


Dopaminergic and serotonergic drug use: a nationwide register-based study of over 1,300,000 older people.
To investigate the use of dopaminergic and serotonergic drugs in elderly people. We analyzed data on age, sex and dispensed drugs for individuals aged ≥65 years registered in the Swedish Prescribed Drug Register from July to September 2008 (n = 1,347,564; 81% of the total population aged ≥65 years in Sweden). Main outcome measures were dopaminergic (enhancing and/or lowering) and serotonergic (enhancing and/or lowering) drugs and combinations of these. Dopaminergic and serotonergic drugs were used by 5.6% and 13.2% the participants, respectively. Female gender was related to use of both dopaminergic and, particularly, serotonergic drugs. Higher age was associated with use of dopamine lowering drugs and serotonergic drugs, whereas the association with use of dopamine enhancing drugs declined in the oldest old. The occurrence of combinations of dopaminergic and serotonergic drugs was generally low, with dopamine lowering + serotonin lowering drug the most common combination (1.6%). Female gender was associated with all of the combinations of dopaminergic and serotonergic drugs, whereas age showed a mixed pattern. Approximately one out of ten older patients uses serotonergic drugs and one out of twenty dopaminergic drugs. The frequent use of dopaminergic and serotonergic drugs in the elderly patients is a potential problem due to the fact that aging is associated with a down-regulation of both these monoaminergic systems. Future studies are needed for evaluation of the impact of these drugs on different cognitive and emotional functions in old age.


[Tumors of the gastrointestinal system in the rainbow trout].
Gastrointestinal tumours occurring in rainbow trout were investigated histologically and virologically. Neoplasms in stomach, medium and posterior intestine mainly in distal parts of these organs were found. Histologically the tumours are benign adenomatous polyps, differentiated adenocarcinomas, poorly differentiated adenocarcinomas, and poorly differentiated or entirely anaplastic adenocarcinomas. The last two types of tumours produced metastases into pancreas, pyloric caeca, and the liver. Virological investigations failed to confirm the presence of any oncoviral particles in these tumours. Aflatoxin analysis of fish foodstuffs gave negative results.


Characterization of advanced glycation end products and their receptor (RAGE) in an animal model of myocardial infarction.
Circulating advanced glycation end products (AGE) and their receptor, RAGE, are increased after a myocardial infarction (MI) episode and seem to be associated with worse prognosis in patients. Despite the increasing importance of these molecules in the course of cardiac diseases, they have never been characterized in an animal model of MI. Thus, the aim of this study was to characterize AGE formation and RAGE expression in plasma and cardiac tissue during cardiac remodeling after MI in rats. Adult male Wistar rats were randomized to receive sham surgery (n = 15) or MI induction (n = 14) by left anterior descending coronary artery ligation. The MI group was stratified into two subgroups based on postoperative left ventricular ejection fraction: low (MIlowEF) and intermediate (MIintermEF). Echocardiography findings and plasma levels of AGEs, protein carbonyl, and free amines were assessed at baseline and 2, 30, and 120 days postoperatively. At the end of follow-up, the heart was harvested for AGE and RAGE evaluation. No differences were observed in AGE formation in plasma, except for a decrease in absorbance in MIlowEF at the end of follow-up. A decrease in yellowish-brown AGEs in heart homogenate was found, which was confirmed by immunodetection of N-ε-carboxymethyl-lysine. No differences could be seen in plasma RAGE levels among the groups, despite an increase in MI groups over the time. However, MI animals presented an increase of 50% in heart RAGE at the end of the follow-up. Despite the inflammatory and oxidative profile of experimental MI in rats, there was no increase in plasma AGE or RAGE levels. However, AGE levels in cardiac tissue declined. Thus, we suggest that the rat MI model should be employed with caution when studying the AGE-RAGE signaling axis or anti-AGE drugs for not reflecting previous clinical findings.


Cardiovascular and perceptual responses to isometric exercise.
The purpose of this study was to investigate the effects of 3 intensities of isometric handgrip contractions on selected cardiovascular parameters and perception of effort, and to determine the relationship of these cardiovascular parameters to perception of effort. Seven healthy subjects were instructed to maintain 3-minute contractions in a randomized sequence, at 15, 25, and 35% of their maximal voluntary contractions (% MVC) while heart rate, systolic blood pressure, diastolic blood pressure and perception of effort were measured at 1-minute intervals. All 4 parameters were found to significantly increase (p less than 0.05) both as a function of contraction intensity (% MVC) and time. Correlation coefficients relating perception of effort to systolic blood pressure, diastolic blood pressure, and heart rate were 0.76, 0.64, and 0.63, respectively, suggested that perception of effort was a better predictor of systolic blood pressure than of diastolic blood pressure or heart rate. A 3-step multiple regression resulted in a cumulative r value of 0.82. Recommendations were made that perception of effort be further explored for clinical use during exercise prescription as an indicator of cardiovascular stress. By using a technique of perception of effort, patients could be taught to restrict activity to within a safe range of cardiovascular variability, rather than totally refrain from all forms of isometric activity.


Clinical evaluation of a new computerized arrhythmia monitoring system.
A study has been made of the accuracy of a computerized system of arrhythmia monitoring in the coronary-care unit of the Palo Alto Veterans Administration Hospital. The system provides beat-to-beat analysis of cardiac rhythm and QRS morphology and stores information for display of incidence of abnormalities and trend curves. The variables monitored by the system include: (1) heart rate, (2) early beats, (3) late beats, (4) abnormal QRS waveforms, and combinations of 2, 3, and 4. Accuracy analysis was performed using a standard ECG trace with a simultaneous record of computer classification of each QRS complex on a dual-channel recorder. Thirty-four patients with various cardiac arrhythmias were studied and 188,000 QRS complexes were evaluated. The number of true abnormal beats (abnormal in timing or waveform) recorded by the ECG was 12,194 out of 188,000 or 6.5 per cent. Computer classification accuracy was as follows: false positives (computer diagnosis abnormal but ECG diagnosis normal), 0.10 per cent (191 complexes) of all complexes and 1.56 per cent of true positives. False negatives (computer diagnosis normal but ECG diagnosis abnormal), 0.70 per cent (84 complexes) of abnormal beats. Computer monitoring and analysis of seven variables in cardiac rhythm and QRS waveform abnormalities can be performed with a high degree of accuracy using a compact computer system suitable for intensive-care units.


Rab-subfamily-specific regions of Ypt7p are structurally different from other RabGTPases.
The GTPase Ypt7p from S. cerevisiae is involved in late endosome-to-vacuole transport and homotypic vacuole fusion. We present crystal structures of the GDP- and GppNHp-bound conformation of Ypt7p solved at 1.35 and 1.6 A resolution, respectively. Despite the similarity of the overall structure to other Ypt/Rab proteins, Ypt7p displays small but significant differences. The Ypt7p-specific residues Tyr33 and Tyr37 cause a difference in the main chain trace of the RabSF2 region and form a characteristic surface epitope. Ypt7p*GppNHp does not display the helix alpha2, characteristic of the Ras-superfamily, but instead possess an extended loop L4/L5. Due to insertions in loops L3 and L7, the neighboring RabSF1 and RabSF4 regions are different in their conformations to those of other Ypt/Rab proteins.


Counterpropagating solitons at boundary of photonic lattices.
We study numerically the interaction of two counterpropagating (CP) optical beams near the boundary of a truncated one-dimensional photonic lattice. We demonstrate that the mutual coupling of beams suppresses the effective repulsion from the lattice edge, resulting in the formation of CP surface solitons. Such localized beams may propagate in the same, as well as in neighboring, waveguides. We also reveal that the lattice disorder reduces substantially the threshold power for the formation of CP surface states.


From phase to microphase separation in flocking models: the essential role of nonequilibrium fluctuations.
We show that the flocking transition in the Vicsek model is best understood as a liquid-gas transition, rather than an order-disorder one. The full phase separation observed in flocking models with Z(2) rotational symmetry is, however, replaced by a microphase separation leading to a smectic arrangement of traveling ordered bands. Remarkably, continuous deterministic descriptions do not account for this difference, which is only recovered at the fluctuating hydrodynamics level. Scalar and vectorial order parameters indeed produce different types of number fluctuations, which we show to be essential in selecting the inhomogeneous patterns. This highlights an unexpected role of fluctuations in the selection of flock shapes.


Fractional flow reserve versus intravascular imaging to guide decision-making for percutaneous coronary intervention in intermediate lesions: A meta-analysis.
Both fractional flow reserve (FFR) and intravascular imaging (IVI) have been used to guide the decision-making for percutaneous coronary intervention (PCI) in intermediate coronary stenosis. Nevertheless, studies that directly compared the prognostic significance of these two strategies are scarce. The aim of this meta-analyses was to evaluate the impact of FFR versus IVI to guide the decision-making in PCI for intermediate stenosis on clinical outcomes. We systematically searched PubMed, Embase, Cochrane, and relevant database from inception date to September 2022 for observational studies and randomized clinical trials (RCTs) which compared FFR and IVI-based decision-making in PCI for intermediate stenosis. The primary outcome was a composite of major adverse cardiac event (MACE). Pooled risk ratios (RR) were calculated using random effects models and heterogeneity were evaluated with the I2 statistic. We identified 5 studies (3 RCTs and 2 observational studies) with 3208 patients. The follow-up duration ranged from 12 to 24 months. Among five studies, four compared FFR with intravascular ultrasound while one compared FFR with optical coherence tomography. There was no statistically difference between FFR and IVI in the incidence of MACE (RR: 1.19; 95% confidence interval: 0.85-1.68; p = 0.31) and its individual components. These results were consistent regardless of various cut-off value of PCI across the studies. Compared with IVI, FFR was associated with a lower PCI rate (37.0% vs. 60.3%; p < 0.001). The decision to perform PCI for intermediate stenosis guided by FFR or IVI showed a similar clinical outcome. The use of FFR significantly reduced the need for PCI.


EuroSCORE performance in valve surgery: a meta-analysis.
The European System for Cardiac Operative Risk Evaluation (EuroSCORE) was developed to predict immediate outcomes after adult cardiac operations, but less than 30% of the cases used to develop this score were valve procedures. We studied EuroSCORE performance in valve procedures. We performed a meta-analysis of published studies reporting the assessment of discriminatory power of the EuroSCORE by receiver operating characteristics (ROC) curve analysis in adult valve operations. A comparison of observed and predicted mortality rates was also performed. A literature search identified 37 potentially eligible studies, and 12 were selected for meta-analysis comprising 26,621 patients with 1250 events (mortality rate, 4.7%). Meta-analysis of these studies provided an average area under the curve (AUC) value of 0.730 (95% confidence interval [CI], 0.717 to 0.743). The same results were obtained when meta-analyses were performed separately in studies categorized on reliability of uncertainty estimation: in the seven studies reporting reliable uncertainty estimation (8175 patients with 358 events; mortality rate, 4.4%), the ROC curve provided an average AUC value of 0.724 (95% CI, 0.699 to 0.749). The five studies not reporting reliable uncertainty estimation (18,446 patients with 892 events; mortality rate, 4.8%) had an average AUC of 0.732 (95% CI, 0.717 to 0.747). We documented a constant trend to overpredict mortality by EuroSCORE, both in the additive and especially in the logistic form. The EuroSCORE has low discrimination ability for valve surgery, and it sensibly overpredicts risk. Alternative risk scoring algorithms should be seriously considered.


The determination of the infectious status and prevalence of motile Aeromonas species isolated from disease cases in rainbow trout (Oncorhynchus mykiss) and aquarium fish.
The aims of this study were to determine the prevalence and phylogenetic relationship of motile Aeromonas spp. that might be pathogenic species for rainbow trout in infected/mix infection cases (based upon different outbreaks on fish farms). A total of 99 motile Aeromonas isolates (and three reference strains) were analysed that were isolated from four different fish species in different sizes of fish (0.1-3,000 g), different months and water temperatures (6.1-21.2°C). The biochemical characteristics of the isolates were determined using conventional tests and a rapid test kit. Additionally, molecular identification was performed using the gyrB housekeeping gene region and with glycerophospholipid-cholesterol acyltransferase polymerase chain reaction (GCAT-PCR). The sequencing results obtained from the gyrB gene region were deposited in the GenBank database, and phylogenetic relationships were determined with the BioNumerics 7.6 database. Nearly half of the Aeromonas isolates that were isolated from rainbow trout showing signs of disease were determined to be possible infectious agents. Aeromonas species exhibit biochemical variability for many characters, so some Aeromonas species tested negative for GCAT-PCR despite that this test was created especially for Aeromonas identification. The phylogenetic tree based upon gyrB contained 10 different phylogroups that were based on 96% cut-off value in gyrB gene region.


Non-uniform distribution of passive muscle stiffness within hamstring.
Limited information is available on whether stiffness is different within and between the constituents of the hamstring, that is, the biceps femoris long head (BFlh), semitendinosus (ST), and semimembranosus (SM). Therefore, understanding of hamstring injuries and stretching effect on hamstring stiffness is difficult. The present study primarily aimed to identify whether passive muscle stiffness differs between the BFlh, ST, and SM and between the proximal, middle, and distal sites within each muscle. Secondly, the effect of stretching exercise on the heterogeneity in passive muscle stiffness was examined. In the lengthened hamstring positions by extending the knee joint or flexing the hip joint, passive muscle shear modulus (a measure of stiffness) at the proximal, middle, and distal sites of the BFlh, ST, and SM was measured by using ultrasound shear wave elastography. Furthermore, before and after five repetitions of 90-seconds static stretching for the hamstring, passive muscle shear modulus at the proximal and distal sites of the SM was measured. The shear modulus was significantly higher in the SM than in the BFlh and ST and higher at the distal site than the proximal site in all muscles. After the stretching, the higher shear modulus at the distal site of the SM compared to the proximal site was still observed (pre-stretching: +80%, post-stretching: +81%). These findings indicate that passive muscle stiffness varies within the hamstring regardless of performing stretching exercise and that passive muscle stiffness is not highest at the proximal site of the SM where a stretching-type hamstring strain typically occurs.


Oral delivery of xenon for cardiovascular protection.
Cardiac hypertrophy often causes impairment of cardiac function. Xenon (Xe), a naturally occurring noble gas, is known to provide neurological and myocardial protection without side effects. The conventional method of Xe delivery by inhalation is not feasible on a chronic basis. We have developed an orally deliverable, effective Xe formulation for long-term administration. We employed 2-hydroxypropyl)-β-cyclodextrin (HPCD), which was dissolved in water to increase the Xe concentration in solution. The beneficial effects of long-term oral administration of Xe-enriched solutions on cardiovascular function were evaluated in vivo. HPCD increased Xe solubility from 0.22 mM to 0.67 mM (3.8-fold). Aged ApoE knockout mice fed high-fat diet for 6 weeks developed hypertension, and myocardial hypertrophy with impaired cardiac function. Oral Xe prevented this ischemic damage, preserving normal blood pressure, while maintaining normal left ventricular mass and wall thickness. This novel formulation allows for gastrointestinal delivery and cardiovascular stabilization.


[SCP Phosphatases and Oncogenesis].
Small SCP phosphatases CTDSP1, CTDSP2, and CTDSPL specifically dephosphorylate serine and threonine residues in protein molecules. The enzymes are involved in regulating activity of RNA polymerase II at the transition from transcription initiation to elongation, regulating expression of neuron-specific genes, and activating the key cell-cycle protein pRb at the G1/S boundary. In addition, the substrates of SCP phosphatases include SMAD transcription modulators; AKT1 protein kinase, which regulates the cell cycle, apoptosis, and angiogenesis; the TWIST1 and c-MYC transcription factors; Ras family proteins, which are involved in signaling pathways regulating the cell growth and apoptosis; CDCA3, which is associated with cell division; the cyclin-dependent kinase inhibitor p21; and the promyelocytic leukemia protein (PML), which is involved in regulation of the tumor suppressors p53, PTEN, and mTOR. Dysfunction or inactivation of SCP phosphatases leads to various diseases, including cancer. Recently the increase in interest to SCP phosphatases is due to their their tumor growth-inhibiting properties or role in the development of malignant tumors of various etiology and localization. The review discusses the properties of SCP phosphatases and their role in oncogenesis. Understanding the functions of SCP phosphatases and their regulatory mechanisms can be useful in searching for efficient targets for tumor therapy.


Expression of BrpA in Streptococcus mutans is regulated by FNR-box mediated repression.
Our previous studies showed that brpA in Streptococcus mutans, which encodes a member of the LytR-CpsA-Psr family of proteins, can be co-transcribed with brpB upstream as a bicistronic operon, and the intergenic region also has strong promoter activity. To elucidate how brpA expression is regulated, the promoter regions were analyzed using polymerase chain reaction-based deletions and site-directed mutagenesis and a promoterless luciferase gene as a reporter. Allelic exchange mutagenesis was also used to examine genes encoding putative trans-acting factors, and the impact of such mutations on brpA expression was analyzed by reporter assays. Multiple elements in the short brpA promoter (nucleotide -1 to -344 relative to start cordon ATG) were shown to have a major impact on brpA expression, including an FNR-box, for a putative binding site of an FNR-type of transcriptional regulator. When compared with the intact brpA promoter, mutations of the highly conserved nucleotides in FNR-box from TTGATgtttAcCtt to TTACAgaaaGtTac resulted in 1362-fold increases of luciferase activity (P < .001), indicative of the FNR-box-mediated repression as a major mechanism in regulation of brpA expression. When luciferase reporter was fused to the upstream brpBA promoter (nucleotides -784 to -1144), luciferase activity was decreased by 4.5-fold (P < .001) in the brpA mutant, TW14D, and by 67.7-fold (P < .001) in the brpB mutant, JB409, compared with the wild-type, UA159. However, no such effects were observed when the reporter gene was fused to the short brpA promoter and its derivatives. These results also suggest that brpA expression in S. mutans is auto-regulated through the upstream brpBA promoter.


to investigate clinical properties of course and outcomes of infective endocarditis (IE) depending on source of infection, to find predictors of mortality in a Moscow general hospital. We included in this study 176 patients with definite and possible infective endocarditis (the Duke criteria), admitted in our hospital in 2010-2017. Patients were divided in three groups according to source of infection. All patients underwent standard clinical and laboratory assessment, echocardiography, blood culture test combined with blood PCR with sequencing. Inhospital and 1-year outcome were evaluated. Among 176 patients with IE 65.3 % were men (median age 57 [35-72] years), most patients (n=149, 84.7 %) had native valve IE. Etiological factor was identified in 127 (72.2 %) cases. Gram-positive infective agents prevailed (54 %). Surgery in active phase of the disease was performed in 30 (17 %) patients. Among patients with healthcare-associated IE (n=76, 43.9 %) prevailed those older than 60 years, with high Charlson comorbidity index, with culture-negative IE, and complicated clinical course (mainly progressing heart failure). Patients with intravenous drug use associated IE (n=50, 28.4 %) had low Charlson index, association with hepatitis C viral infection, involvement of tricuspid valve with big vegetations, high frequency of embolic complications, and low inhospital mortality. Group of patients with community acquired IE (n=50, 28.4 %) more often had uncommon causative microorganisms, and had better long-term outcome. In-hospital mortality was 30.1 % (n=53) mostly due to sepsis with multi-organ failure, and heart failure. Risk factors of inhospital death were history of cardiovascular diseases, old age, kidney damage, methicillin-resistant Staphylococcus aureus (MRSA) infection, uncontrolled infection, and embolic events. Risk factors of 1-year mortality were history of stroke, and heart failure as IE complication. Independent predictors of in-hospital death were MRSA infection (odds ratio [OR] 50.32, 95 % confidence interval [CI] 1.66-213.92; p=0.002), persistent infection (OR 18.6, 95 %CI 5.37-64.40; p=0.001), duration of fever >7 days after initiation of antibacterial therapy (OR 13.41, 95 %CI 3.51-51.24; p=0.001); and of death during first year - history of cerebral infarction (OR 4.39, 95 %CI 1.32-14.70; p=0.016)), and heart failure as IE complication (OR 8.1, 95 %CI 1.97-67.09; p=0.016). Among patients subjected to surgery there were no fatal outcomes during 1 year after hospital discharge, while among conservatively treated patients were 21 (14.4 %) deaths (p<0.009). Main clinical features of IE course in patients urgently admitted to a general hospital was dominance of healthcare-associated IE among patients, who were older than 60 years with severe comorbidities. These patients had more complications and worse outcome. Modeling of prognosis identified uncontrolled infection as key factor of unfavorable outcome. Surgery significantly reduced long-term mortality.


Nucleic binding affinity of bacteriophage T4 gene 32 protein in the cooperative binding mode.
This study reports on various parameters which affect the binding stoichiometry for complexes of bacteriophage T4 gene 32 protein (P32) and single stranded polynucleotides (determined by UV absorbance and fluorescence quenching) and presents results of a quantitative electron spin resonance assay to determine physiologically effective binding affinity differences of nucleic acid binding proteins. The assay employs macromolecular spin probes (spin-labeled nucleic acids) which are used to determine the fraction of saturation in competition experiments with unlabeled nucleic acids. It was found that the fraction of complexed spin-labeled polynucleotides can be directly monitored by ESR with a two-component analysis approach when ligands such as poly(L-lysine), gene 5 protein (P5) of filamentous bacteriophage fd, and gene 32 protein (P32) of bacteriophage T4 are used. The ESR data unequivocally show that: 1) the binding stoichiometry for poly(L-lysine), P5 and P32 is nucleotide/lysine, 4 nucleotides/P5 monomer, and 10 nucleotides/P32 monomer, respectively; and 2) under physiologically relevant buffer conditions the relative affinity of P32 in the cooperative binding mode for polythymidylic acid is about 4 times greater than for polydeoxyinosinic acid and about 12 times greater than for polyinosinic acid, and the relative affinity of P32 for polydeoxyinosinic acid is about 3 times greater than for polyinosinic acid.


The role of Fibroscan in predicting the presence of varices in patients with cirrhosis.
Transient elastography is a relatively new, noninvasive method of measuring liver stiffness. This study aimed to evaluate the diagnostic accuracy of transient elastography and other noninvasive methods for the diagnosis of esophageal varices (EV) in patients with cirrhosis. This cross-sectional study graded EV according to size in 145 consecutive patients with cirrhosis who underwent endoscopy, Fibroscan, and other noninvasive diagnostic methods. The accuracy of these diagnostic methods in diagnosing EV was evaluated on the basis of area under receiver operating characteristic (AUROC) curves. Elastography was successful in 123 patients. Of these, 54.5% had hepatitis C and 10.6% had hepatitis B. EV were absent in 39.8%, small EV was present in 24.4%, and large EV was present in 35.8% of patients. Fibroscan, aspartate aminotransferase-to-platelet ratio index, and international normalized ratio showed low accuracy in diagnosing EV in non-viral-related cirrhosis patients (AUROCs 0.66, 0.68, and 0.67, respectively). Fibroscan and aspartate aminotransferase-to-platelet ratio index were more accurate in measuring EV with a viral etiology (AUROCs 0.704 and 0.703, respectively). A cutoff value of 16.9 kPa was 83.8% sensitive in diagnosing EV in non-viral-cirrhotic patients, whereas a cutoff value of 19.9 kPa was 83.4% sensitive in diagnosing EV in patients with viral hepatitis. Fibroscan was moderately accurate in diagnosing grade I EV and less accurate in diagnosing grades II and III EV in all cirrhotic patients, irrespective of the underlying etiology. Fibroscan might be useful in predicting the presence of EV in patients with cirrhosis with a viral etiology. However, endoscopy remains the gold standard for EV screening.


Unmet need for eyeglasses: results from the 1994 Robert Wood Johnson Access to Care Survey.
Although poor access to general medical care services has been documented widely, the unmet need for supplemental health care services--such as eyeglasses--has been largely ignored. This article documents the inability to obtain eyeglasses on the national level and for various subpopulations using the 1994 Robert Wood Johnson Foundation National Access to Care Survey. The Survey, a followup to the 1993 National Health Interview Survey, collected data on respondents' inability to obtain health care services due to access barriers. The sample comprised 3,480 observations, weighted to represent the U.S. civilian non-institutionalized population. More than 5% of the U.S. population reported an unmet need for eyeglasses, and of these, more than 80% cited financial reasons as the primary barrier. Persons in poor health and blacks were most likely to face barriers to obtaining eyeglasses. Understanding this under-served population and their unmet needs can help policymakers formulate new initiatives. The focus on preventive care within managed care organizations may ease some barriers for the insured population. Policy should focus on uninsured and underinsured working individuals who cannot afford and do not receive public assistance for needed eye care.


Person-centred communication: design, implementation and evaluation of a communication skills module or undergraduate nursing students - an Irish context.
Despite wide agreement about the importance of effective communication in nursing there is continuing evidence of the need for nurses to improve their communication skills. Consequently, there is a growing demand for more therapeutic and person-centred communication courses. Studies on communication education reveal considerable variability on the design and operationalisation of these programmes. Additionally, the literature highlights that nurse educators are continually challenged with developing and implementing these programmes. Communication skills are generally taught in years one and two of undergraduate nursing degree programmes. This is a stage when students have minimal contact with patients and clients. We suggest that a communication skills module should be included in all final years of undergraduate nursing programmes. With an array of clinical experiences to draw from, final year nursing students are better placed to apply the skills of effective communication in practice. In this paper, we present the design, implementation and evaluation of an advanced communication skills module undertaken by fourth year undergraduate nursing students completing a Bachelor of Science (BSc) degree - nursing programme at one university in the Republic of Ireland.


Hyaluronic acid-based nanoplatforms for Doxorubicin: A review of stimuli-responsive carriers, co-delivery and resistance suppression.
An important motivation for the use of nanomaterials and nanoarchitectures in cancer therapy emanates from the widespread emergence of drug resistance. Although doxorubicin (DOX) induces cell cycle arrest and DNA damage by suppressing topoisomerase activity, resistance to DOX has severely restricted its anti-cancer potential. Hyaluronic acid (HA) has been extensively utilized for synthesizing nanoparticles as it interacts with CD44 expressed on the surface of cancer cells. Cancer cells can take up HA-modified nanoparticles through receptor-mediated endocytosis. Various types of nanostructures such as carbon nanomaterials, lipid nanoparticles and polymeric nanocarriers have been modified with HA to enhance the delivery of DOX to cancer cells. Hyaluronic acid-based advanced materials provide a platform for the co-delivery of genes and drugs along with DOX to enhance the efficacy of anti-cancer therapy and overcome chemoresistance. In the present review, the potential methods and application of HA-modified nanostructures for DOX delivery in anti-cancer therapy are discussed.


Tyrosine phosphorylation regulates cell cycle-dependent nuclear localization of Cdc48p.
Cdc48p from Saccharomyces cerevisiae and its highly conserved mammalian homologue VCP (valosin-containing protein) are ATPases with essential functions in cell division and homotypic fusion of endoplasmic reticulum vesicles. Both are mainly attached to the endoplasmic reticulum, but relocalize in a cell cycle-dependent manner: Cdc48p enters the nucleus during late G1; VCP aggregates at the centrosome during mitosis. The nuclear import signal sequence of Cdc48p was localized near the amino terminus and its function demonstrated by mutagenesis. The nuclear import is regulated by a cell cycle-dependent phosphorylation of a tyrosine residue near the carboxy terminus. Two-hybrid studies indicate that the phosphorylation results in a conformational change of the protein, exposing the nuclear import signal sequence previously masked by a stretch of acidic residues.


Pharmacokinetics of the potent redox-modulating manganese porphyrin, MnTE-2-PyP(5+), in plasma and major organs of B6C3F1 mice.
Mn(III) tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+), a potent catalytic superoxide and peroxynitrite scavenger, has been beneficial in several oxidative stress-related diseases thus far examined. Pharmacokinetic studies are essential for the better assessment of the therapeutic potential of MnTE-2-PyP(5+) and similar compounds, as well as for the modulation of their bioavailability and toxicity. Despite high hydrophilicity, this drug entered mitochondria after a single 10 mg/kg intraperitoneal injection at levels high enough (5.1 muM; 2.95 ng/mg protein) to protect against superoxide/peroxynitrite damage. Utilizing the same analytical approach, which involves the reduction of MnTE-2-PyP(5+) followed by the exchange of Mn(2+) with Zn(2+) and HPLC/fluorescence detection of ZnTE-2-PyP(4+), we measured levels of MnTE-2-PyP(5+) in mouse plasma, liver, kidney, lung, heart, spleen, and brain over a period of 7 days after a single intraperitoneal injection of 10 mg/kg. Two B6C3F1 female mice per time point were used. The pharmacokinetic profile in plasma and organs was complex; thus a noncompartmental approach was utilized to calculate the area under the curve, c(max), t(max), and drug elimination half-time (t(1/2)). In terms of levels of MnTE-2-PyP(5+) found, the organs can be classified into three distinct groups: (1) high levels (kidney, liver, and spleen), (2) moderate levels (lung and heart), and (3) low levels (brain). The maximal levels in plasma, kidney, spleen, lung, and heart are reached within 45 min, whereas in the case of liver a prolonged absorption phase was observed, with the maximal concentration reached at 8 h. Moreover, accumulation of the drug in brain continued beyond the time of the experiment (7 days) and is likely to be driven by the presence of negatively charged phospholipids. For tissues other than brain, a slow elimination phase (single exponential decay, t(1/2)=60 to 135 h) was observed. The calculated pharmacokinetic parameters will be used to design optimal dosing regimens in future preclinical studies utilizing this and similar compounds.


Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients.
Adefovir monotherapy is an established treatment modality for lamivudine-experienced patients with chronic hepatitis B, but it carries a significant risk of resistance in the long term. We assessed whether this risk could be overcome by adefovir-lamivudine combination therapy. A total of 145 lamivudine-resistant patients with chronic hepatitis B (73% cirrhotics, 86% hepatitis B e antigen negative, 92% genotype D) were treated with adefovir 10 mg in addition to lamivudine 100 mg. Liver function tests and hepatitis B virus (HBV) DNA (Versant 3.0) were assessed bimonthly, whereas adefovir-related mutations were searched by INNO-LiPA assay at baseline and at yearly intervals. During 42 months (range, 12-74), 116 patients (80%) cleared serum HBV DNA, 67 (84%) had normalized alanine aminotransferase levels, and 145 (100%) remained free of virologic and clinical breakthroughs, independently of the degree of HBV suppression. The rtA181V/T was the only adefovir-related mutation detected, which occurred in 6 patients at baseline (4%; 1 rtA181V and 5 rtA181T) and in an additional 3 patients (2%; all rtA181T) during treatment. In all these 9 patients, HBV DNA levels progressively declined during therapy to become undetectable in 7 (78%). The 1-, 2-, 3-, and 4-year cumulative rates of de novo rtA181T were 1%, 2%, 4%, and 4%, respectively. None of the cirrhotic patients clinically decompensated, but 11 (12%) developed hepatocellular carcinoma. Under prolonged adefovir-lamivudine therapy, patients with lamivudine-resistant hepatitis B were unlikely to develop genotypic resistance to adefovir and had durable prevention of virologic and clinical breakthrough.


PF74 Inhibits HIV-1 Integration by Altering the Composition of the Preintegration Complex.
The HIV-1 capsid protein (CA) facilitates reverse transcription and nuclear entry of the virus. However, CA's role in post-nuclear entry steps remains speculative. We describe a direct link between CA and integration by employing the capsid inhibitor PF74 as a probe coupled with the biochemical analysis of HIV-1 preintegration complexes (PICs) isolated from acutely infected cells. At a low micromolar concentration, PF74 potently inhibited HIV-1 infection without affecting reverse transcription. Surprisingly, PF74 markedly reduced proviral integration owing to inhibition of nuclear entry and/or integration. However, a 2-fold reduction in nuclear entry by PF74 did not quantitatively correlate with the level of antiviral activity. Titration of PF74 against the integrase inhibitor raltegravir showed an additive antiviral effect that is dependent on a block at the post-nuclear entry step. PF74's inhibitory effect was not due to the formation of defective viral DNA ends or a delay in integration, suggesting that the compound inhibits PIC-associated integration activity. Unexpectedly, PICs recovered from cells infected in the presence of PF74 exhibited elevated integration activity. PF74's effect on PIC activity is CA specific since the compound did not increase the integration activity of PICs of a PF74-resistant HIV-1 CA mutant. Sucrose gradient-based fractionation studies revealed that PICs assembled in the presence of PF74 contained lower levels of CA, suggesting a negative association between CA and PIC-associated integration activity. Finally, the addition of a CA-specific antibody or PF74 inhibited PIC-associated integration activity. Collectively, our results demonstrate that PF74's targeting of PIC-associated CA results in impaired HIV-1 integration.IMPORTANCE Antiretroviral therapy (ART) that uses various combinations of small molecule inhibitors has been highly effective in controlling HIV. However, the drugs used in the ART regimen are expensive, cause side effects, and face viral resistance. The HIV-1 CA plays critical roles in the virus life cycle and is an attractive therapeutic target. While currently there is no CA-based therapy, highly potent CA-specific inhibitors are being developed as a new class of antivirals. Efforts to develop a CA-targeted therapy can be aided through a clear understanding of the role of CA in HIV-1 infection. CA is well established to coordinate reverse transcription and nuclear entry of the virus. However, the role of CA in post-nuclear entry steps of HIV-1 infection is poorly understood. We show that a CA-specific drug PF74 inhibits HIV-1 integration revealing a novel role of this multifunctional viral protein in a post-nuclear entry step of HIV-1 infection.


Expanding role of cyclin dependent kinases in cytokine inducible gene expression.
The Positive Transcriptional Elongation Factor b (P-TEFb), a heterodimer of CDK9 and Cyclin T1, is widely implicated in control of basal gene expression. Here, P-TEFb is involved in transitioning paused RNA polymerase II to enter productive transcriptional elongation mode by phosphorylating negative elongation factors and Ser(2) of the heptad repeat in the RNA Pol II COOH terminal domain (CTD). This perspective will examine recent work in two unrelated inducible signaling pathways that illustrate the central role of P-TEFb in mediating cytokine inducible transcription networks. Specifically, P-TEFb has been recently discovered to play a key role in TNF-inducible NFkappaB activation and IL-6-inducible STAT3 signaling. In these signaling cascades, P-TEFb forms protein complexes with the activated nuclear RelA and STAT3 transcription factor in the cellular nucleoplasm, an association important for P-TEFb's promoter targeting. Studies using siRNA-mediated knockdown and/or selective CDK inhibitors show that P-TEFb plays a functional role in activation of a subset of NFkappaB-dependent targets and all STAT3-dependent genes studied to date. Interestingly, cytokine inducible genes that are sensitive to P-TEFb inhibition share an induction mechanism requiring inducible RNA Pol II recruitment. Chromatin immunoprecipitation studies have preliminarily indicated that this recruitment is dependent on CDK enzymatic activity. The potential of inhibiting P-TEFb as an anti-inflammatory therapy in innate immunity and systemic inflammation will be discussed.


Experimental Pain and Auditory Sensitivity in Overactive Bladder Syndrome: A Symptoms of the Lower Urinary Tract Dysfunction Research Network (LURN) Study.
The objective of this study was to investigate the presence of nonbladder sensory abnormalities in participants with overactive bladder syndrome (OAB). Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) study participants with OAB symptoms and controls were recruited from 6 U.S. tertiary referral centers. Quantitative sensory testing (QST) was performed to determine pressure pain sensitivity at the thumbnail bed and auditory sensitivity. Fixed and mixed effect multivariable linear regressions and Weibull models were used to compare QST responses between groups. Pearson correlations were used to assess the relationship between QST measures. Associations between QST and self-reported symptoms were explored with linear regression. A total of 297 participants were analyzed (191 OAB, 106 controls; 76% white, 51% male). OAB cases were older than controls (57.4 vs 52.2 years, p=0.015). No significant differences in experimental thumbnail (nonbladder) pain or auditory sensitivity were detected between OAB cases and controls. Correlations between pressure and auditory derived metrics were weak to moderate overall for both groups, with some significantly stronger correlations for cases. Exploratory analyses indicated increased pressure pain and auditory sensitivity were modestly associated with greater self-reported bladder pain and pain interference with physical function. As a group, no significant differences between OAB cases and controls were observed in experimental nonbladder pain or auditory sensitivity during QST. Associations between QST outcomes and clinical pain raise the possibility of centrally mediated sensory amplification in some individuals with OAB.


Complex Molecules That Fold Like Proteins Can Emerge Spontaneously.
Folding can bestow macromolecules with various properties, as evident from nature's proteins. Until now complex folded molecules are the product either of evolution or of an elaborate process of design and synthesis. We now show that molecules that fold in a well-defined architecture of substantial complexity can emerge autonomously and selectively from a simple precursor. Specifically, we have identified a self-synthesizing macrocyclic foldamer with a complex and unprecedented secondary and tertiary structure that constructs itself highly selectively from 15 identical peptide-nucleobase subunits, using a dynamic combinatorial chemistry approach. Folding of the structure drives its synthesis in 95% yield from a mixture of interconverting molecules of different ring sizes in a one-step process. Single-crystal X-ray crystallography and NMR reveal a folding pattern based on an intricate network of noncovalent interactions involving residues spaced apart widely in the linear sequence. These results establish dynamic combinatorial chemistry as a powerful approach to developing synthetic molecules with folding motifs of a complexity that goes well beyond that accessible with current design approaches. The fact that such molecules can form autonomously implies that they may have played a role in the origin of life at earlier stages than previously thought possible.


Discovery of Novel Marine-Derived Phidiandine/Lipoic Acid Hybrid as a Potential Anti-atherosclerosis Agent: Design, Synthesis and in Vitro/in Vivo Evaluation.
In the present study, a novel derivative, IOP-LA, was prepared by hybridizing antioxidant lipoic acid (LA) and our recently reported antioxidative marine phidianidine B-inspired indole/1,2,4-oxadiazole derivative. Our results demonstrated that IOP-LA could protect vascular endothelial cells (VECs) from oxidized low-density lipoprotein (oxLDL)-induced oxidative stress by activating the Nrf2 pathway, inhibit the production of atherosclerotic plaque, and promote the stability of atherosclerotic plaque in apoE-/- mice. Moreover, the protective effect of IOP-LA was superior to LA at the same concentration. Mechanistic studies revealed that IOP-LA significantly inhibited the increase of reactive oxygen species (ROS) levels and the translocation of nuclear factor kappa-B (NF-κB) nuclear induced by oxLDL through the nuclear factor erythroid2-related factor 2 (Nrf2) pathway. In summary, the data demonstrate that IOP-LA, as a new antioxidant, protects VECs from oxLDL-induced oxidative stress by activating the Nrf2 pathway. It is worth noting that this study provides a promising lead compound for the prevention and treatment of atherosclerosis.


Oxolinic acid-resistant mutants of Bacillus subtilis.
Two mutants of Bacillus subtilis have been independently selected for resistance to oxolinic acid, and inhibitor of DNA gyrase. The mutations, designated oxr-1 and oxr-2, map very close to one another but are clearly separated from mutations in the genes for DNA gyrase. Many of the phenotypic properties of the mutants differ from those of a strain containing the gyrA mutation described by other workers. In particular, the oxr strains are as sensitive as the wild-type to inhibition by nalidixic acid on solid medium. In addition, experiments with DNA synthesis in toluenized cells show that the enzyme of the gyrA mutant is resistant to oxolinic acid, whereas DNA synthesis in the oxr mutants is as sensitive as it is in wild-type preparations. It is concluded that resistance to oxolinic acid is not due to an alteration in the DNA gyrase, but is more probably the result of an impaired uptake of the inhibitor. Although growth of the mutants on agar plates is inhibited at high concentrations of oxolinic acid, lower concentrations (1-2 microgram ml-1) can be used to distinguish them from the wild-type. The oxr-1 and oxr-2 mutations define a new genetic locus and can be used as genetic markers in B. subtilis.


Radiology capital asset management.
Radiology administrators are expected not only to take on the ultimate accountability for meeting the needs and challenges of present day-to-day operations, but also to plan for the future. Computer Aided Facility Management (CAFM), as a tool, enables radiology managers to obtain up-to-date data to manage their services. Using Autocad on a unix-based minicomputer as the graphical base generator and integrating information from a MUMPS-based minicomputer, the CAFM process can define areas to be studied for productivity and life cycle costs. From an analysis of radiology service, management was able to make solid judgement calls for equipment replacement and facility project renovation to effectively manage radiology resources.


The paradoxical cyanide-stimulated respiration of Zymomonas mobilis: cyanide sensitivity of alcohol dehydrogenase (ADH II).
The respiratory inhibitor cyanide stimulates growth of the ethanologenic bacterium Zymomonas mobilis, perhaps by diverting reducing equivalents from respiration to ethanol synthesis, thereby minimizing accumulation of toxic acetaldehyde. This study sought to identify cyanide-sensitive components of respiration. In aerobically grown, permeabilized Z. mobilis cells, addition of 200 microM cyanide caused gradual inhibition of ADH II, the iron-containing alcohol dehydrogenase isoenzyme, which, in aerobic cultures, might be oxidizing ethanol and supplying NADH to the respiratory chain. In membrane preparations, NADH oxidase was inhibited more rapidly, but to a lesser extent, than ADH II. The time-course of inhibition of whole-cell respiration resembled that of NADH oxidase, yet the inhibition was almost complete, and was accompanied by an increase of intracellular NADH concentration. Cyanide did not significantly affect the activity of ADH I, the zinc-containing alcohol dehydrogenase isoenzyme. When an aerobic batch culture was grown in the presence of 200 microM cyanide, cyanide-resistant ADH II activity was observed, its appearance correlating with the onset of respiration. It is concluded that the membrane-associated respiratory chain, but not ADH II, is responsible for the whole-cell cyanide sensitivity, while the cyanide-resistant ADH II is needed for respiration in the presence of cyanide, and represents an adaptive response of Z. mobilis to cyanide, analogous to the induction of alternative terminal oxidases in other bacteria.


Resistance of human immunodeficiency virus type 1 to protease inhibitors: selection of resistance mutations in the presence and absence of the drug.
Inhibitors of the human immunodeficiency virus (HIV) protease are a promising class of antiviral agents that dramatically reduce HIV replication both in culture and in infected patients. However, as for many other antiviral compounds, long-term efficacy of these agents is impeded by the emergence of virus variants with increased resistance to their inhibitory action, following selection of specific mutations in the protease coding sequence. We have studied HIV-1 variants that emerged at different stages of selection in the presence of the C2-symmetrical protease inhibitor ABT-77003. The selection of variants was a gradual process during which mutations accumulated at different sites in the protease, generating virus populations with increasing levels of resistance to the drug. The initially selected viruses had a low level of resistance as well as a markedly reduced replicative capacity. Further accumulation of mutations at secondary sites led to an improvement in both drug resistance and replication. In spite of their reduced infectivity, partially selected virus populations did not readily revert to wild-type when serially passaged in drug-free conditions. Instead, even in the absence of drug, secondary mutations identical to those selected in the presence of the inhibitor continued to emerge. These mutations improved both the intrinsic replicative capacity of the virus and its level of resistance to the inhibitor, suggesting that once committed to drug resistance, readaptation of the enzyme to its natural substrate leads to a reduction of its sensitivity to the inhibitor.


Hyalinizing trabecular tumors of the thyroid gland are almost all benign.
In 1987, Carney et al reported 11 thyroid tumors with the following features: circumscription or encapsulation, trabecular architecture with intratrabecular hyalin and colloid, polygonal and spindle cells, nuclei with frequent grooves and cytoplasmic inclusions, occasional psammoma bodies, and a low mitotic rate. The neoplasms did not recur or metastasize during a follow-up period that averaged 10 years, and they were titled hyalinizing trabecular adenomas. Subsequently, the nuclear features of the neoplasm led to the introduction of 2 modified titles for it, hyalinizing trabecular tumor and hyalinizing trabecular neoplasm. Later, discovery of RET/PTC mutations in the tumor resulted in it being designated as a type of papillary thyroid carcinoma. We studied 119 neoplasms of the type outlined, collected over a 20-year period, for invasion, recurrence and metastasis, and obtained follow-up in 96% of the cases. One hundred eighteen tumors showed no evidence of aggressive behavior (capsular, vascular, and parenchymal invasion), local recurrence, or metastasis. One tumor showed vascular and capsular invasion, and pulmonary metastasis. We conclude that the overwhelming majority of hyalinizing trabecular tumors of the thyroid behave as benign neoplasms and that, at this time, hyalinizing trabecular adenoma is the most appropriate title for them.


Unsupervised 3D Local Feature Learning by Circle Convolutional Restricted Boltzmann Machine.
Extracting local features from 3D shapes is an important and challenging task that usually requires carefully designed 3D shape descriptors. However, these descriptors are hand-crafted and require intensive human intervention with prior knowledge. To tackle this issue, we propose a novel deep learning model, namely circle convolutional restricted Boltzmann machine (CCRBM), for unsupervised 3D local feature learning. CCRBM is specially designed to learn from raw 3D representations. It effectively overcomes obstacles such as irregular vertex topology, orientation ambiguity on the 3D surface, and rigid or slightly non-rigid transformation invariance in the hierarchical learning of 3D data that cannot be resolved by the existing deep learning models. Specifically, by introducing the novel circle convolution, CCRBM holds a novel ring-like multi-layer structure to learn 3D local features in a structure preserving manner. Circle convolution convolves across 3D local regions via rotating a novel circular sector convolution window in a consistent circular direction. In the process of circle convolution, extra points are sampled in each 3D local region and projected onto the tangent plane of the center of the region. In this way, the projection distances in each sector window are employed to constitute a novel local raw 3D representation called projection distance distribution (PDD). In addition, to eliminate the initial location ambiguity of a sector window, the Fourier transform modulus is used to transform the PDD into the Fourier domain, which is then conveyed to CCRBM. Experiments using the learned local features are conducted on three aspects: global shape retrieval, partial shape retrieval, and shape correspondence. The experimental results show that the learned local features outperform other state-of-the-art 3D shape descriptors.


Use of Polyglycolic Acid Sheets for the Prevention of Pancreatic Fistula after Laparoscopic Gastrectomy: A Single-Center Retrospective Study.
Laparoscopic gastrectomy (LG) indications have been extended to advanced gastric cancer requiring expansive lymph node dissection. Despite the huge benefits of this minimally invasive surgery, major complications such as postoperative pancreatic fistula (POPF) remain a concern. With technical advances in surgical procedures, the treatment outcomes of gastric cancer surgery have improved. However, effective methods for preventing POPF have not yet been established. Herein, we examined the usefulness of polyglycolic acid (PGA) sheets for preventing POPF after LG. We retrospectively assessed 142 patients who underwent curative LG at our institution between January 2017 and August 2022. The 142 patients were divided into 2 groups; PGA group (n = 61): the site of lymph node dissection at the superior margin of the pancreas and pancreatic head was covered with PGA sheets, and nPGA group (n = 81): the site was not covered. We retrospectively compared the short-term surgical outcomes including POPF incidence. There was no significant difference in the background factors between the 2 groups and in the incidence of Grade II or higher postoperative complications according to the Clavien-Dindo (CD) classification. However, the incidence of CD Grade II or higher POPF was significantly lower in the PGA group than in the nPGA group (.0% vs 2.3%, respectively, P = .007). There was no POPF in any of the 61 patients in the PGA group. This outcome suggests that POPF incidence may be reduced by covering the lymph node dissection site with PGA sheets after LG.


Recent advances in the laboratory detection of Mycobacterium tuberculosis complex and drug resistance.
The global control of tuberculosis remains a challenge from the standpoint of diagnosis, detection of drug resistance, and treatment. Because treatment can only be initiated when infection is detected and is based on the results of antimicrobial susceptibility testing, there recently has been a marked increase in the development and testing of novel assays designed to detect Mycobacterium tuberculosis complex, with or without simultaneous detection of resistance to isoniazid and/or rifampin. Both nonmolecular and molecular assays have been developed. To a large extent, the nonmolecular methods are refinements or modifications of conventional methods, with the primary goal of providing more-rapid test results. Evaluations of molecular assays have generally shown that these assays have variable sensitivity for detecting the presence of M. tuberculosis complex and, in particular, are insensitive when used with smear-negative specimens; high sensitivity for detecting resistance to rifampin; and variable sensitivity for detecting resistance to isoniazid.


Multiple cholesterol emboli syndrome simulating systemic necrotizing vasculitis.
The multiple cholesterol emboli syndrome associated with severe atherosclerotic vascular disease may clinically simulate systemic necrotizing vasculitis. Widespread visceral infarctions in conjunction with potential leukocytosis, eosinophilia, thrombocytopenia, hypocomplementemia and an elevated sedimentation rate may be present. It frequently occurs after intraarterial procedures such as cardiac catheterization and aortography. Diagnosis is made by biopsy of involved tissue. It is essential to establish a proper diagnosis to avoid inappropriate use of steroid and cytotoxic treatment measures.


Effects of Alcohol on Inhibitory Avoidance Learning in Zebrafish (Danio rerio).
The zebrafish (Danio rerio) can be used in studies addressing the effects of drugs on learning, memory, and anxiety. In the present study, we investigated the effect of different alcohol treatments (chronic and acute) on the learning and anxiety response of zebrafish in an inhibitory avoidance paradigm. Zebrafish were initially exposed to different alcohol treatments and submitted to an inhibitory avoidance protocol, where an electroshock was applied to the fish as they swam from the white to the black side of a shuttle box tank (naturally preferred environment of zebrafish). Animals from the control and 0.5% acute alcohol groups exhibited high latency to enter the black side of the tank after the first exposure to electroshock, in addition to higher freezing and a shorter distance from the bottom of the tank, suggesting acute alcohol exposure did not affect aversive learning in zebrafish. However, chronic exposure and alcohol withdrawal impaired the fish's capacity to properly respond to the aversive stimulus. Overall, our results show the harmful effects of chronic alcohol exposure, both continued intake and its cessation, but avoidance behavior persisted and anxiety increased following acute alcohol exposure.


Optical and electronic properties of air-stable organoboron compounds with strongly electron-accepting bis(fluoromesityl)boryl groups.
Three compounds with phenyl (1), 4-tert-butylphenyl (2) and 4-N,N-diphenylaminophenyl (3) groups attached to bis(fluoromesityl)boryl ((FMes)2B) through B-C bonds have been prepared. The restricted rotation about the B-C bonds of boron-bonded aryl rings in solution has been studied by variable-temperature 19F NMR spectroscopy, and through-space F-F coupling has been observed for 3 at low temperature. Steric congestion inhibits binding of 1 by Lewis bases DABCO and tBu3P and the activation of H2 in their presence. Photophysical and electrochemical studies have been carried out on 2, 3, and an analogue of 3 containing a bis(mesityl)boryl ((Mes)2B) group, namely 4. Both 2 and 3 show bright emission in nonpolar solvents and in the solid-state, very strong electron-accepting ability as measured by cyclic voltammetry, and good air-stability. In addition, 2 displayed unusually long-lived emission (τ = 2.47 s) in 2-MeTHF at 77 K. The much stronger acceptor strength of (FMes)2B than (Mes)2B leads to significantly red-shifted emission in solution and the solid state, stronger emission solvatochromism, and significantly lower reduction potentials. Theoretical calculations confirm that 2 and 3 tend to form highly twisted excited states with good conjugation between one FMes group and the boron atom, which correlate well with their blue-shifted solid-state emissions and low kr values in solution.


Molecular dynamics simulations provide insights into ULK-101 potency and selectivity toward autophagic kinases ULK1/2.
Kinase domains are highly conserved within protein kinases in both sequence and structure. Many factors, including phosphorylation, amino acid substitutions or mutations, and small molecule inhibitor binding, influence conformations of the kinase domain and enzymatic activity. The serine/threonine kinases ULK1 and ULK2 are highly conserved with N- and C-terminal domains, phosphate-binding P-loops, -αC-helix, regulatory and catalytic spines, and activation loop DFG and APE motifs. Here, we performed molecular dynamics (MD) simulations to understand better the potency and selectivity of the ULK1/2 small molecule inhibitor, ULK-101. We observed stable bound states for ULK-101 to the adenosine triphosphate (ATP)-binding site of ULK2, coordinated by hydrogen bonding with the hinge backbone and the catalytic lysine sidechain. Notably, ULK-101 occupies a hydrophobic pocket associated with the N-terminus of the -αC-helix. Large movements in the P-loop are also associated with ULK-101 inhibitor binding and exit from ULK2. Our data further suggests that ULK-101 could induce a folded P-loop conformation and hydrophobic pocket reflected in its nanomolar potency and kinome selectivity.


Can the Children's Communication Checklist differentiate between children with autism, children with ADHD, and normal controls?
The Children's Communication Checklist (CCC; Bishop, 1998) is a questionnaire that was developed to measure pragmatic language use and may be completed by parents and teachers. Two studies are reported, which were designed to investigate: (1) whether children with Attention Deficit Hyperactivity Disorder (ADHD) encounter pragmatic language problems in comparison with normal controls (NC), (2) whether children with ADHD and children with High Functioning Autism (HFA) can be differentiated using the CCC, (3) the usefulness of the CCC for parents and teachers in a clinical and in a research setting, and (4) the role of age in pragmatic language use in ADHD and HFA. In the first study (clinical sample) 50 children with ADHD, 50 children with HFA, and 50 NC were compared to each other using the CCC. In the second study (research sample) CCC data was gathered on 23 children with ADHD (without co-morbid disorders), 42 children with HFA, and 35 NC. Compared to NC, children with HFA showed pragmatic deficits on all CCC scales. Children with ADHD demonstrated deficits compared to NC as well. Moreover, the ADHD and HFA groups differed from each other on most of the scales. Discriminant analyses showed that CCC scales were relevant for case identification in these samples. Furthermore, profiles of impairment seen in children with HFA and ADHD did not vary with age. Pragmatic difficulties do occur in both HFA and ADHD. The present studies indicate that the CCC is a useful instrument to obtain information concerning pragmatic language use in both a clinical and a research setting. Although the information of parents is more tightly linked to the diagnosis, combining the information of both parent and teacher slightly improves case identification.


Induction of anaesthesia with desflurane and isoflurane in the rabbit.
The characteristics of two techniques of face-mask induction of desflurane anaesthesia (rapid or slow) were compared with the effects of slow isoflurane induction in five New Zealand White (NZW) rabbits. Slow induction used stepwise increments in vapour setting of 2% for desflurane and 0.5% for isoflurane at 30 s intervals. All animals were anaesthetized using each technique according to a randomized block design with one week between treatments. Observations were made of the quality of induction (any struggling or periods of apnoea) and the latency to, and the duration of loss of the righting and toe pinch reflexes recorded. Changes in respiratory rate, arterial blood gas and cardiovascular parameters were also recorded. Induction and recovery times were shorter with rapid desflurane induction in comparison to isoflurane (loss of righting reflex: 139+/-27 s cf. 205+/-48 s), but both techniques were associated with struggling and long periods of apnoea (> 1 min) during the first 4 min after administration. During this period a significant degree of bradycardia, hypercapnia and hypoxaemia occurred with both techniques, but these and the subsequent effects of rapid desflurane administration were less severe than with isoflurane. Slow induction with desflurane was tolerated best, with little or no deleterious behavioural or physiological effects, however excessively prolonged induction times (loss of righting reflex 337+/-160 s) limits the application of this method. Desflurane, administered rapidly, appears to be a more suitable agent than isoflurane. However, as with isoflurane, anaesthesia should only be induced following oxygen supplementation.


The chicken IL-1 family: evolution in the context of the studied vertebrate lineage.
The interleukin-1 gene family encodes a group of related proteins that exhibit a remarkable pleiotropy in the context of health and disease. The set of indispensable functions they control suggests that these genes should be found in all eukaryotic species. The ligands and receptors of this family have been primarily characterised in man and mouse. The genomes of most non-mammalian animal species sequenced so far possess all of the IL-1 receptor genes found in mammals. Yet, strikingly, very few of the ligands are identifiable in non-mammalian genomes. Our recent identification of two further IL-1 ligands in the chicken warranted a critical reappraisal of the evolution of this vitally important cytokine family. This review presents substantial data gathered across multiple, divergent metazoan genomes to unambiguously trace the origin of these genes. With the hypothesis that all of these genes, both ligands and receptors, were formed in a single ancient ancestor, extensive database mining revealed sufficient evidence to confirm this. It therefore suggests that the emergence of mammals is unrelated to the expansion of the IL-1 family. A thorough review of this cytokine family in the chicken, the most extensively studied amongst non-mammalian species, is also presented.


Effectiveness of expedient sheltering in place in a residence.
The objective of this study was to evaluate the effectiveness of expedient sheltering in place in a residence for protection against airborne hazards, as outlined in the U.S. Department of Homeland Security (DHS) guidance to the public. An improved method was developed to determine the air flow rate for a shelter inside a house. Expedient sheltering measures (plastic sheeting and duct tape) were applied to a room inside a test house by participants who followed the DHS guidance. Measured air flow rates were used to determine protection factors for various scenarios. Protection factors were calculated for the house and shelter under various occupancy times, weather conditions, and outdoor exposure times for hazardous agents. Protection factors ranged from 1.3 to 539, depending on the conditions. Results indicate that proper sealing can make a substantial difference in the effectiveness of the shelter. Sheltering in place can be most beneficial if people enter shelters before the arrival of a cloud of hazardous agent, and people exit shelters as soon as the cloud passes over. However, sheltering in place can be detrimental if people enter or exit shelters too late. CO2 and O2 concentrations inside the shelter are not likely to reach dangerous levels under most scenarios, but concentrations could reach dangerous levels under certain conditions, and concentration levels could affect individuals with respiratory problems.


Specific fluorogenic probes for ozone in biological and atmospheric samples.
Ozone exposure is a growing global health problem, especially in urban areas. While ozone in the stratosphere protects the earth from harmful ultraviolet light, tropospheric or ground-level ozone is toxic and can damage the respiratory tract. It has recently been shown that ozone may be produced endogenously in inflammation and antibacterial responses of the immune system; however, these results have sparked controversy owing to the use of a non-specific colorimetric probe. Here we report the synthesis of fluorescent molecular probes able to unambiguously detect ozone in both biological and atmospheric samples. Unlike other ozone-detection methods, in which interference from different reactive oxygen species is often a problem, these probes are ozone specific. Such probes will prove useful for the study of ozone in environmental science and biology, and so possibly provide some insight into the role of ozone in cells.