Preterm Brain Injury and Neurodevelopmental Outcomes: A Meta-analysis.
Preterm brain injuries are common; neurodevelopmental outcomes following contemporary neonatal care are continually evolving. To systematically review and meta-analyze neurodevelopmental outcomes among preterm infants after intraventricular hemorrhage (IVH) and white matter injury (WMI). Published and grey literature were searched across 10 databases between 2000 and 2021. Observational studies reporting 3-year neurodevelopmental outcomes for preterm infants with IVH or WMI compared with preterm infants without injury. Study characteristics, population characteristics, and outcome data were extracted. Thirty eight studies were included. There was an increased adjusted risk of moderate-severe neurodevelopmental impairment after IVH grade 1 to 2 (adjusted odds ratio 1.35 [95% confidence interval 1.05-1.75]) and IVH grade 3 to 4 (adjusted odds ratio 4.26 [3.25-5.59]). Children with IVH grade 1 to 2 had higher risks of cerebral palsy (odds ratio [OR] 1.76 [1.39-2.24]), cognitive (OR 1.79 [1.09-2.95]), hearing (OR 1.83 [1.03-3.24]), and visual impairment (OR 1.77 [1.08-2.9]). Children with IVH grade 3 to 4 had markedly higher risks of cerebral palsy (OR 4.98 [4.13-6.00]), motor (OR 2.7 [1.52-4.8]), cognitive (OR 2.3 [1.67-3.15]), hearing (OR 2.44 [1.42-4.2]), and visual impairment (OR 5.42 [2.77-10.58]). Children with WMI had much higher risks of cerebral palsy (OR 14.91 [7.3-30.46]), motor (OR 5.3 [3-9.36]), and cognitive impairment (OR 3.48 [2.18-5.53]). Heterogeneity of outcome data. Mild IVH, severe IVH, and WMI are associated with adverse neurodevelopmental outcomes. Utilization of core outcome sets and availability of open-access study data would improve our understanding of the nuances of these outcomes.


The effects of droperidol and ondansetron on dispersion of myocardial repolarization in children.
To compare the effects of droperidol and ondansetron on electrocardiographic indices of myocardial repolarization in children. To refine understanding of the torsadogenic risk to children exposed to anti-emetic prophylaxis in the perioperative period. QT interval prolongation is associated with torsades des pointes (TdP), but is a poor predictor of drug torsadogenicity. Susceptibility to TdP arises from increased transmural dispersion of repolarization (TDR) across the myocardial wall, rather than QT interval prolongation per se. TDR can be measured on the electrocardiogram as the time interval between the peak and end of the T wave (Tp-e). Tp-e may therefore provide a readily available, noninvasive assay of drug torsadogenicity. The perioperative period is one of high risk for TdP in children with or at risk of long QT syndromes. Droperidol and ondansetron are two drugs commonly administered perioperatively, for prophylaxis of nausea and vomiting, which can prolong the QT interval. This study investigated their effects on myocardial repolarization. One hundred and eight ASA1-2 children undergoing elective day-case surgery were randomized to receive droperidol, ondansetron, both or neither. Pre- and post-administration 12-lead electrocardiogram (ECGs) were recorded. QT and Tp-e intervals were measured and compared within and between groups, for the primary endpoint of a 25 ms change in Tp-e. Eighty children completed the study. There were no demographic or baseline ECG differences between groups. QT intervals lengthened by 10-17 ms after allocated treatments, with no between-group differences. Values remained within normal limits for all groups. Tp-e intervals increased by 0-7 ms, with no between-group differences. There were no instances of dysrhythmia. Droperidol and ondansetron, in therapeutic anti-emetic doses, produce equivalent, clinically insignificant QT prolongation and negligible Tp-e prolongation, suggesting that neither is torsadogenic in healthy children at these doses.


Single injection, low volume periocular anesthesia in 1,000 cases.
Periocular anesthesia is a proven alternative to retrobulbar anesthesia. A prospective evaluation of 1,000 cases was done to study the advantages of single point, low volume periocular anesthesia. This method is efficacious and has an excellent safety profile. The small needle length and the low volume of injected anesthetic enhance the safety. Supplemental anesthesia was needed in only 0.2% of cases. Chemosis was noted in 12.7%. In no case did surgery have to be postponed because of anesthesia-related complications. We believe this method is superior to other multipoint high volume methods of periocular anesthesia.


Protective effect of Salvia plebeia R. Br ethanol extract on UVB-induced skin photoaging in vitro and in vivo.
UV exposure is one of the primary factors responsible for photoaging, causing the increase in matrix metalloproteinases (MMPs) and the reduction in collagen. Salvia plebeia R. Br (SP), as an herbaceous plant, contains abundant flavonoids and possesses excellent anti-inflammatory and antioxidant activities. This study aimed to investigate the photoprotective effects of SP on UVB-induced photodamage in immortalized human keratinocytes (HaCaTs) and Kunming mice, as well as its main active components such as homoplantaginin (HP). CCK-8 was applied to detect the cell viability in UVB-irradiated or non-irradiated HaCaTs. Commercial kits were used to evaluate the levels of ROS, MDA, SA-β-Gal, MMP-1, and IL-6. The expression of MAPK and TGF-β/Smad pathways was detected by western blot. HE and Masson's trichrome staining were performed to examine the epidermis thickness and collagen degradation of Kunming mice. Our results found that SP and HP notably decreased UVB-induced ROS, MDA, and SA-β-Gal production, and inhibited MMP-1 and IL-6 secretion by inhibiting the MAPK signaling pathway. In addition, SP and HP significantly promoted type I procollagen synthesis by activation of TGF-β/Smad pathway. Consistently, the in vivo experiments also indicated that SP and HP had a photoprotective effect, which significantly reversed UVB-induced epidermis thickness and collagen degradation. This study demonstrated that SP effectively could protect skin from UVB-induced photoaging, while HP acted as the active substance in SP. All these findings provided a new strategy for skin photoaging treatment.


EGFR inhibitors sensitize non-small cell lung cancer cells to TRAIL-induced apoptosis.
Apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be regulated by the epidermal growth factor (EGF) signaling pathway. In this study, recombinant adenoviral vectors that encode TRAIL gene from the hTERT/RGD promoter (AdTRAIL) was combined with drugs including gefitinib, elotinib, and cetuximab that inhibit EGFR and the EGF signaling pathway in non-small cell lung cancer (NSCLC) cell lines to investigate their antitumor activity. In vitro, compared to single reagent, AdTRAIL combined with EGFR inhibitors reduced proliferation and enhanced apoptosis in H460, A549, and SW1573 cell lines. Western blot results suggested that these effects were relative to up-regulation of pro-apoptosis protein BAX and down-regulation of p-AKT. In vivo, AdTRAIL combined with cetuximab resulted in a significant growth reduction in H460 xenografts without damage to the main organs of nude mice. Histological examination and TUNEL analyses of xenografts showed that cetuximab enhanced cell apoptosis induced by AdTRAIL. These results indicate that EGFR inhibitors enhanced AdTRAIL anti-tumor activity in NSCLC cell lines and that inhibiting the AKT pathway played an important role in this enhancement.


[Early hemodynamic effects of olprinone hydrochloride after coronary artery bypass grafting].
Our purpose was to evaluate the hemodynamic effects of olprinone hydrochloride early after coronary artery bypass grafting (CABG). Fifteen patients undergoing CABG were administered a constant infusion of 0.1 microgram/kg/min of olprinone and continued for 4 hours. No bolus infusion of olprinone was administered before continuous infusion. Systolic systemic arterial pressure, systolic pulmonary arterial pressure, systemic vascular resistance and pulmonary vascular resistance were significantly decreased. There were no significant changes in heart rate, mean central venous pressure, mean left atrial pressure and left ventricular stroke work index. Cardiac index was significantly increased, but a correlation between cardiac index and mixed venous blood oxygen saturation was not found. Double product was significantly decreased, which described above suggest that olprinone achieved improvement of left cardiac function without more myocardial oxygen consumption. Severe transient hypotension (systolic arterial pressure < 80 mmHg) after infusion of olprinone was observed in three patients. Olprinone administered soon after CABG surgery had beneficial effects in terms of improvement of hemodynamic status without more oxygen consumption and reduction of pulmonary vascular resistance. However transient hypotension was a serious clinical problem in patients after open heart surgery, especially in CABG patients who need suitable systolic arterial pressure to keep enough blood perfusion of arterial bypass grafts.


Willingness to pay for cataract surgery in baiyin district, northwestern China.
To investigate willingness to pay for cataract surgery, and its associations, in Northwestern China. Four hundred thirty-eight persons aged 50 years and above, diagnosed with cataract indicated for surgery, identified in an outreach screening program were included. Subjects were offered a willingness-to-pay interview for the maximal amount that the subjects would be willing to pay for a cataract surgery. Age, gender, literacy, education level, occupation, and annual household income were recorded. Among 328 (74.9%) subjects who completed the interview, 197 (60.1%) participants were willing to pay something for the cataract surgery (mean, 902.9 ± 856.7 renminbi[RMB], [US$ 145 ± 137]; median, 500RMB, US$ 78). Individuals with presenting visual acuity (PVA) in the worse eye ≤6/60 (OR: 2.1, 95% CI: 1.3-3.2) and a high annual household incomes (OR: 2.0, 95% CI: 0.9-4.6) were likely to be willing to pay for the surgery, as revealed in the regression models. Willingness to pay any amount for cataract surgery was more likely among literate persons (OR: 1.5, 95% CI: 1.0-2.4) and persons with non-agricultural occupation (OR: 1.8, 95% CI: 1.0-3.2). The amount that subjects were willing to pay is significantly less than the current cost of cataract surgery (5000 RMB, US$320) in the area. Providing low-cost cataract surgery to patients in a financially sustainable manner is important to increase uptake of cataract surgery among rural residents in Northwest China.


Cognitive mechanisms of statistical learning and segmentation of continuous sensory input.
Two classes of cognitive mechanisms have been proposed to explain segmentation of continuous sensory input into discrete recurrent constituents: clustering and boundary-finding mechanisms. Clustering mechanisms are based on identifying frequently co-occurring elements and merging them together as parts that form a single constituent. Bracketing (or boundary-finding) mechanisms work by identifying rarely co-occurring elements that correspond to the boundaries between discrete constituents. In a series of behavioral experiments, I tested which mechanisms are at play in the visual modality both during segmentation of a continuous syllabic sequence into discrete word-like constituents and during recognition of segmented constituents. Additionally, I explored conscious awareness of the products of statistical learning-whole constituents versus merged clusters of smaller subunits. My results suggest that both online segmentation and offline recognition of extracted constituents rely on detecting frequently co-occurring elements, a process likely based on associative memory. However, people are more aware of having learnt whole tokens than of recurrent composite clusters.


Type 2 diabetes treatment intensification in general practice in France in 2008-2009: the DIAttitude Study.
To evaluate the current procedures in French general practice of intensifying hypoglycaemic treatment in orally treated type 2 diabetic patients, according to the French recommendations. Type 2 diabetic patient characteristics, HbA(1c) values, hypoglycaemic treatment and physician characteristics were collected from the electronic records of a panel of French general practitioners. Factors associated with the time until intensification of treatment were studied with the Cox model. Among 17 493 orally treated patients with at least two available HbA(1c) values, 3118 patients (18%) required treatment intensification; 65% were on monotherapy, 31% on bitherapy and 4% on tritherapy. These patients were followed for a maximum of 14 months or until treatment was intensified. Treatment was intensified after the second high HbA(1c) value for 1212 patients (39%); this was immediate for 13% of these patients, within 6 months for 39% and within one year for 59%. Treatment intensification was less likely the older the patient, and more likely the higher the first HbA(1c) value, up to an HbA(1c) threshold of 9%. Therapeutic inertia in caring for type 2 diabetic patients in France is frequent, at least for patients treated in general practice. This inadequate glycaemic control would be expected to have significant patient and public health consequences, with higher rates of associated diabetic complications.


Separation of capsaicin from capsaicinoids by simulated moving bed chromatography.
Capsaicinoids were separated from capsicum oleoresin by solvent extraction and adsorption separation on macropore resin, and used directly as the feed of simulated moving bed. Using a mobile phase of methanol/water (75/25, v/v) and ODS columns, the two key components, capsaicin and dihydrocapsaicin, were separated completely, while part of minor weak impurities were discarded by forcing them to leak into zone I. The amount of discarded impurities increases with decreasing flow rate in zone I so that the purity of capsaicin in raffinate stream could be improved.


Selenium levels in persons with HIV/tuberculosis in India, Madurai City.
Selenium plays a vital role in the immune status of the individual. The prospective observational study was conducted from September 2009 to March 2010. The aim of the present study is to investigate the association between serum selenium levels and pulmonary tuberculosis (PTB) patients with (n = 40) and without HIV (n = 40) in comparison to healthy controls (healthy family members; n = 20) who satisfied rigid selection criteria. Standard methods were adopted to collect an early morning fasting blood sample for serum selenium concentrations, determined by atomic absorption spectrometry (AAS), and albumin, determined by the bro mocresol green method. The mean +/- SD for Body Mass Index (BMI), selenium, and albumin among the controls, HIV positive, and HIV negative patients were 19.6 +/- 0.6, 18 +/- 0.4 and 18.5 +/- 0.6 kg/m2; 113.1 +/- 4.1, 27.44 +/- 8, and 65.92 +/- 9, microg/dL; and 4.1 +/- 0.6, 2.9 +/- 0.4 and 3.6 +/- 0.7 g/dL, respectively. BMI, serum selenium, and albumin levels were found to be significantly lower (p < 0.004, p < 0.0321, and p < 0.002, respectively). Low serum selenium levels are associated with increased risk of pulmonary infection caused by mycobacteria.


Pollutant load and ecotoxicological effects of sediment from stormwater retention basins to receiving surface water on Lumbriculus variegatus.
The overflow of stormwater retention basins during intense and prolonged precipitation events may result in the direct input of particulate pollutants and remobilization of already sedimented particle-bound pollutants to receiving freshwater bodies. Particle-bound pollutants may cause adverse effects on aquatic biota, particularly sediment dwellers. Therefore, we investigated the sediment pollution load of a stream connected to the outfalls of two stormwater basins to determine the impact of the basins' discharges on the metal and organic pollutant content of the sediment. Also, the possible adverse effects of the pollutant load on benthic dwellers were evaluated in sediment toxicity tests with Lumbriculus variegatus and the effects on its growth, reproduction and the biomarkers catalase, acetylcholinesterase and metallothionein were analyzed. The results showed that the retention basins contained the highest load of pollutants. The pollutant load in the stream did not show a clear pollution pattern from the inlets. However, metal enrichment ratios revealed contamination with Cu, Pb and Zn with Pb and Zn above threshold effect concentrations in all sites. Ecotoxicity results showed that the retention basin samples were the most toxic compared to sediment from the stream. Exposure experiments with the stream sediment did not show considerable effects on reproduction, catalase activity and metallothionein concentration. However, modest inhibitions of growth and activity of acetylcholinesterase were detected. Based on the observed results, it cannot be concluded that overflows of the retention basin are responsible for the pollutant contents downstream of their inlet. Other sources that were not considered in this study, such as diffuse input, historic pollution and point sources further upstream as well as along the stream, are likely the major contributors of pollutant load in the sediment of the studied transects of the stream. Additionally, the observed results in the stormwater basin sediment further highlight their importance in retaining particle-bound pollutants and preventing ecotoxicological effects from receiving surface water bodies.


Multiple psychiatric polygenic risk scores predict associations between childhood adversity and bipolar disorder.
It remains unclear how adverse childhood experiences (ACE) and increased genetic risk for bipolar disorder (BD) interact to influence BD symptom outcomes. Here we calculated multiple psychiatric polygenic risk scores (PRS) and used the measures of ACE to understand these gene-environment interactions. 885 BD subjects were included for analyses. BD, ADHD, MDD and SCZ PRSs were calculated using the PRS-CS-auto method. ACEs were evaluated using the Children Life Event Questionnaire (CLEQ). Participants were divided into groups based on the presence of ACE and the total number of ACEs. The associations between total ACE number, PRSs and their interactions were evaluated using multiple linear and logistic regressions. Secondary analyses were performed to evaluate the influence of ACE and PRS on sub-phenotypes of BD. The number of ACEs increased with the ADHD PRS. BD participants who had ACEs showed an earlier age of BD onset and higher odds of having rapid cycling. Increased BD PRS was associated with increased odds of developing psychotic symptoms. Higher ADHD PRS was associated with increased odds of having rapid cycling. No prediction effect was observed from MDD and SCZ PRS. And, we found no significant interaction between ACE numbers and any of the PRSs in predicting any selected BD sub-phenotypes. The study was limited by sample size, ACE definition, and cross-sectional data collection method. The findings consolidate the importance of considering multiple psychiatric PRSs in predicting symptom outcomes among BD patients.


Review of Syzeuctus Frster, 1869 (Hymenoptera: Ichneumonidae: Banchinae) in Iran, with description of a new species.
A new ichneumonid species, Syzeuctus flavocephalus Zardouei Riedel sp. nov. (Hymenoptera: Ichneumonidae: Banchinae) from the Eastern high mountains of Iran (Sistan-o Baluchestan province) is described and illustrated. Together with this new species, nine previously recorded species from Iran are reviewed, and a comprehensive key of the Iranian species of Syzeuctus is provided.


Adverse impact of hyperferritinemia and transfusion dependency on treatment success in myelodysplastic syndrome.
Myelodysplastic syndrome (MDS) is characterized by peripheral cytopenias and dysplasia in one or more cell lines in the bone marrow. A significant proportion of patients require blood product support due to symptomatic anemia and/or thrombocytopenia during the course of their disease. This retrospective study was planned to evaluate the transfusion requirement of MDS patients and the role of ferritin in predicting transfusion requirement and response to treatment. We retrospectively reviewed the records of 35 MDS patients [median age: 66 (22-84); male/female: 21/14]. The World Health Organization (WHO) criteria was used for disease classification and International Prognostic Scoring System (IPSS) for risk stratification. A total of 22 patients (62.8%) required transfusions during follow-up. While all the 22 patients received packed red blood cells (PRBCs), only 8 patients (22.9%) required platelet transfusion(s). Although no significant relationship was demonstrated between transfusion dependency and disease progression, patients who responded to disease-specific treatment were exposed to less PRBC transfusions compared to non-responders (p=0.04). Treatment response was found to be better in patients who had lower serum ferritin levels at diagnosis (p=0.004). A total of 11 patients were followed for a minimum of 24months. Transfusion load was not different among these patients with respect to disease subtype, IPSS risk score and treatment protocol in the first and second 12-month interval. Median overall survival of the cohort was 26.3 (0.4-160.3) months and median progression free survival was 24.9 (0.4-160.3) months. The present report underlines the association of baseline hyperferritinemia and transfusion dependency with treatment success in MDS. Even in patients treated with new generation agents, the vicious impact of transfusion load seems to be the tender spot of the MDS puzzle. The prognostic impact of baseline hyperferritinemia should be validated with further studies.


A Timely Administration of Antenatal Steroids Is Highly Protective Against Intraventricular Hemorrhage: An Observational Multicenter Cohort Study of Very Low Birth Weight Infants.
The aim of the study is to evaluate the influence of the timing of antenatal steroids (ANSs) on neonatal outcome of very low birth weight infants (VLBWI) born before 30 weeks of gestation in the German Neonatal Network. The German Neonatal Network is a large population-based cohort study enrolling VLBWIs since 2009. We included 672 neonates, who were born between January 1, 2009 and December 31, 2019 in our analysis in 10 selected centers. Infants were divided into four subgroups based on the interval between the first steroid administration and preterm birth: (I) two doses of betamethasone, ANS-birth interval: >24 h to 7 days, n = 187, (II) only one dose of betamethasone, ANS-birth interval 0-24 h, n = 70, (III) two doses of betamethasone, ANS-birth interval >7 days, n = 177, and (IV) no antenatal steroids, n = 238. Descriptive statistics and logistic regression analyses were performed for the main neonatal outcome parameters. Group IV (no ANS) was used as a reference. An ANS-birth interval of 24 h to 7 days after the first dose was associated with a reduced risk for intraventricular hemorrhage (OR 0.17; 95% CI 0.09-0.31, p < 0.001) and mechanical ventilation (OR 0.37; 95% CI 0.23-0.61, p < 0.001), whereas the group of infants that only received a single dose of steroids reflected a subgroup at high risk for adverse neonatal outcomes; an ANS-birth interval of >7 days was still associated with a lower risk for intraventricular hemorrhage (OR 0.43; 95% CI 0.25-0.72, p = 0.002) and the need for mechanical ventilation (OR 0.43; 95% CI 0.27-0.71, p = 0.001). Our observational data indicate that an ANS-birth interval of 24 h to 7 days is strongly associated with a reduced risk of intraventricular hemorrhage in VLBWIs. Further research is needed to improve the prediction of preterm birth in order to achieve a timely administration of antenatal steroids that may improve neonatal outcomes such as intraventricular hemorrhage.


Monoallelic CEBPA mutations in normal karyotype acute myeloid leukemia: independent favorable prognostic factor within NPM1 mutated patients.
We and others have shown that cytogenetically normal (CN)-AML patients with biallelic CEBPA gene mutations (biCEBPA) represent a molecularly distinct group with a favorable prognosis. Patients carrying a monoallelic CEBPA mutation (moCEBPA), however, show no different outcome compared to patients with wildtype CEBPA, and these mutations are frequently associated with mutated NPM1 or FLT3-ITD. So far, no molecular or clinical hallmark has been identified to prognostically distinguish moCEBPA patients from patients with wildtype CEBPA. Therefore, we used the data of 663 CN-AML patients treated within the AMLCG 1999 trial to explore the prognostic value of moCEBPA in the context of concomitant clinical and molecular markers (mutated NPM1, FLT3-ITD). Multiple Cox regression in 515 patients adjusting for all available potential confounders revealed that the NPM1 mutation modified the prognostic value of moCEBPA with respect to overall survival (OS, p = 0.017) and event-free survival (EFS, p = 0.011). MoCEBPA was beneficial in NPM1 mutated patients: adjusted OS-hazard ratio (HR) 0.09, 95% confidence interval (CI) 0.01-0.63, p = 0.016; EFS-HR (95% CI) 0.16 (0.04-0.65), p = 0.010. In contrast, moCEBPA had no prognostic impact in patients with wildtype NPM1: OS-HR (95% CI) 1.08 (0.59-1.97), p = 0.804; EFS-HR (95% CI) 1.12 (0.64-1.96), p = 0.682. We found no prognostic effect modification for moCEBPA by FLT3-ITD. The presence of a moCEBPA mutation was shown to be associated with prolonged survival in NPM1 mutated CN-AML patients. Confirmation of these results in larger studies will clarify whether an additional moCEBPA mutation influences the risk stratification of patients with an NPM1 mutated/FLT3-ITD positive genotype.


Enhanced epidermal localization of topically applied steroids using SPACE™ peptide.
The balance of efficacy and safety of topical corticosteroids (TCs) depends on their ability to penetrate into and be retained within the skin. Here, we evaluated the ability of SPACE™ peptide to enhance epidermal delivery and localization of three model TCs. In vitro and in vivo skin penetration studies were performed to evaluate penetration of TCs into and across the skin in the presence of various formulations of SPACE™ peptide. Topical formulations of corticosterone containing free SPACE™ peptide produced significantly enhanced epidermal penetration and localization. Ratio of drug deposition in the skin and receiver (efficacy/safety, indicative of ratio of local to systemic uptake) exhibited higher values for SPACE™ peptide-based formulation as compared to aqueous and hydroethanolic solutions and Cortizone™ cream. Mass spectrometry analysis showed that SPACE™ peptide associates with corticosterone, which may explain its enhanced retention effect. SPACE™ peptide also enhanced dermal retention of two more TCs (hydrocortisone and triamcinolone acetonide) compared to the vehicle control. An in vivo study in mice further established the ability of SPACE™ peptide to enhance skin retention of hydrocortisone without producing elevated blood concentrations. These results show that SPACE™ peptide is an effective additive to the formulation for enhanced skin localization of topical steroids.


Developmental origins of the metabolic syndrome: body clocks and stress responses.
The prevalence of the metabolic syndrome, which represents a spectrum of metabolic and cardiovascular disorders, continues to increase at an alarming rate in contemporary society. Inadequate responses of an individual to environmental challenges such as unbalanced diet or lack of physical exercise during their life course has been recognised to increase risk of this pathological condition. Recent evidence suggests that this may involve alterations in the settings of the circadian clock system, which consists of oscillating molecular pacemakers found not only in the hypothalamic region of the brain but also in most peripheral tissues, and of the hypothalamic-pituitary-adrenal (HPA) axis which regulates stress responses. These two systems are now known to interact to produce an integrated response to environmental challenges. In this review, we highlight the importance of environmental cues during early development in establishing the homeostatic set-points of the circadian clock and HPA stress systems. These effects can operate within the normal range and are not in themselves pathological, but can nevertheless affect an individual's response to environmental challenges in adult life and thus their risk of the metabolic syndrome.


Excitatory amino acid antagonists induce a phencyclidine-like catalepsy in pigeons: structure-activity studies.
The excitatory amino acid antagonists D,L-2-amino-5-phosphonovalerate (D,L-AP5), its isomers D-(-)-AP5 and L-(+)-AP5, D,L-2-amino-4-phosphonobutyrate (AP4), D,L-2-amino-7-phosphonoheptanoate (AP7), beta-D-aspartylaminomethylphosphonic acid (ASP-AMP), cis-2,3-piperidinedicarboxylic acid (cis-PDA), and gamma-D-glutamylaminomethylsulphonic acid (GAMS) were tested for their ability to produce a phencyclidine (PCP)-like catalepsy in pigeons when administered intracerebroventricularly. Each of the antagonists produced catalepsy, although L-AP5, and the non-selective antagonists GAMS and cis-PDA, produced the effect only at toxic doses. The rank order of potency to produce catalepsy was AP7 greater than D-AP5 greater than D,L-AP5 greater than cis-PDA greater than ASP-AMP greater than AP4 greater than L-AP5 greater than GAMS; there was a strong positive correlation between this rank order of potency in vivo and the potency order of these compounds in vitro as NMDA antagonists. The antagonists did not displace significant amounts of [3H]N-[1-(2-thienyl)cyclohexyl]piperidine (a congener of phencyclidine) from its recognition site in the brain of pigeon. Thus, the PCP-like catalepsy that is produced by the excitatory neurotransmission at NMDA-preferring receptors that are distinct from, but related to, PCP receptors. The results strongly support the hypothesis that a reduction of neurotransmission at excitatory synapses, utilizing NMDA-preferring receptors, may underlie catalepsy in pigeons induced by PCP.


Development of a two-stage model system to investigate the mineralization mechanisms involved in idiopathic stone formation: stage 2 in vivo studies of stone growth on biomimetic Randall's plaque.
Idiopathic stone formers often form calcium oxalate (CaOx) stones that are attached to calcium phosphate (CaP) deposits in the renal tissue, known as Randall's plaques (RP). Plaques are suggested to originate in the renal tubular basement membrane and spread into the interstitial regions where collagen fibrils and vesicles become mineralized; if the epithelium is breached, the RP becomes overgrown with CaOx upon exposure to urine. We have developed a two-stage model system of CaP-CaOx composite stones, consisting of Stage (1) CaP mineralized plaque, followed by Stage (2) CaOx overgrowth into a stone. In our first paper in this series (Stage 1), osteopontin (and polyaspartate) were found to induce a non-classical mineralization of porcine kidney tissues, producing features that resemble RP. For the Stage 2 studies presented here, biomimetic RPs from Stage 1 were implanted into the bladders of rats. Hyperoxaluria was induced with ethylene glycol for comparison to controls (water). After 4 weeks, rats were sacrificed and the implants were analyzed using electron microscopy and X-ray microanalyses. Differences in crystal phase and morphologies based upon the macromolecules present in the biomimetic plaques suggest that the plaques have the capacity to modulate the crystallization reactions. As expected, mineral overgrowths on the implants switched from CaP (water) to CaOx (hyperoxaluric). The CaOx crystals were aggregated and mixed with organic material from the biomimetic RP, along with some amorphous and spherulitic CaOx near the "stone" surfaces, which seemed to have become compact and organized towards the periphery. This system was successful at inducing "stones" more similar to human idiopathic kidney stones than other published models.


Arguments about the nature of concepts: Symbols, embodiment, and beyond.
How are the meanings of words, events, and objects represented and organized in the brain? This question, perhaps more than any other in the field, probes some of the deepest and most foundational puzzles regarding the structure of the mind and brain. Accordingly, it has spawned a field of inquiry that is diverse and multidisciplinary, has led to the discovery of numerous empirical phenomena, and has spurred the development of a wide range of theoretical positions. This special issue brings together the most recent theoretical developments from the leaders in the field, representing a range of viewpoints on issues of fundamental significance to a theory of meaning representation. Here we introduce the special issue by way of pulling out some key themes that cut across the contributions that form this issue and situating those themes in the broader literature. The core issues around which research on conceptual representation can be organized are representational format, representational content, the organization of concepts in the brain, and the processing dynamics that govern interactions between the conceptual system and sensorimotor representations. We highlight areas in which consensus has formed; for those areas in which opinion is divided, we seek to clarify the relation of theory and evidence and to set in relief the bridging assumptions that undergird current discussions.


A novel cell-stiffness-fingerprinting analysis by scanning atomic force microscopy: comparison of fibroblasts and diverse cancer cell lines.
Differing stimuli affect cell stiffness while cancer metastasis is associated with reduced cell stiffness. Cell stiffness determined by atomic force microscopy has been limited by measurement over nuclei to avoid spurious substratum effects in thin cytoplasmic domains, and we sought to develop a more complete approach including cytoplasmic areas. Ninety μm square fields were recorded from ten separate sites of cultured human dermal fibroblasts (HDF) and three sites each for melanoma (MM39, WM175, and MeIRMu), osteosarcoma (SAOS-2 and U2OS), and ovarian carcinoma (COLO316 and PEO4) cell lines, each site providing 1024 measurements as 32 × 32 square grids. Stiffness recorded below 0.8 μm height was occasionally influenced by substratum, so only stiffness recorded above 0.8 μm was analysed, but all sites were included for height and volume analysis. COLO316 had the lowest cell height and volume, followed by HDF (p < 0.0001) and then PEO4, SAOS-2, MeIRMu, WM175, U2OS, and MM39. HDF were more stiff than all other cells (p < 0.0001), while in descending order of stiffness were PEO4, COLO316, WM175, SAOS-2, U2OS, MM39, and MeIRMu (p < 0.02). Stiffness fingerprints comprised scattergrams of stiffness values plotted against the height at which each stiffness value was recorded and appeared unique for each cell type studied, although in most cases the overall form of fingerprints was similar, with maximum stiffness at low height measurements and a second lower peak occurring at high-height levels. We suggest that our stiffness-fingerprint analytical method provides a more nuanced description than previously reported and will facilitate study of the stiffness response to cell stimulation.


A case of dermoid cyst of the floor of the mouth: ultrasonography was more useful than computed tomography and magnetic resonance imaging in the preoperative diagnosis.
Dermoid cysts are rare in the floor of the mouth. This report presents a case of dermoid cyst (dermoid type) of the floor of the mouth in a 21-year-old man. The preliminary preoperative assessment was made by using three modalities: computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography (US). CT depicted the lesion as a well-circumscribed, unilocular, homogeneous low-density mass. MRI showed a mass lesion located in the submental region between the geniohyoid and mylohyoid muscles. The lesion exhibited homogeneous intermediate signal intensity on T1-weighted images and homogeneous high signal intensity on T2-weighted images. The wall of the lesion was well enhanced on gadolinium-enhanced MRI. CT and MRI could not demonstrate any fatty components within the lesion and only indicated that the lesion was cystic in nature. In contrast, on US, multiple echogenic foci that seemed to be caused by keratin and sebaceous material were detected within the lesion, and this US finding was useful information for the differential diagnosis. In this case, of the three modalities, only US suggested that the lesion might be a dermoid cyst.


Effect of BOF-4272 on the oxidation of allopurinol and pyrazinamide in vivo. Is xanthine dehydrogenase or aldehyde oxidase more important in oxidizing both allopurinol and pyrazinamide?
Allopurinol or pyrazinamide was administered to rats treated with BOF-4272 (a potent xanthine oxidase inhibitor) to investigate to what degree xanthine dehydrogenase participates in the oxidation of these agents. BOF-4272 markedly decreased the plasma concentration and the urinary excretion of both oxypurinol and 5-hydroxypyrazinamide. It also decreased the sum of the urinary excretion of allopurinol and oxypurinol and that of pyrazinamide and its metabolites, although it did not affect the sum of the plasma concentrations of allopurinol and oxypurinol at 105 min after administration of allopurinol or the plasma concentration of pyrazinamide during the period after the administration of pyrazinamide. These results suggested that BOF-4272 almost completely inhibited the oxidation of allopurinol and pyrazinamide and had some effect on the excretion and/or the tissue incorporation of these two compounds. Since the in vitro study demonstrated that BOF-4272 did not inhibit the activity of aldehyde oxidase, which oxidized both allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide, the results suggested that xanthine dehydrogenase was the more important enzyme in converting allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide.


Active inhibition of the first over the second ear implanted sequentially.
To identify the influence of the first implanted ear on the performance of the delayed sequentially implanted ear in pediatric patients. Retrospective case series review. Outpatient Cochlear Implant (CI) center. Congenitally deaf children who underwent unilateral implant at various ages followed by sequential implant of the contralateral ear with various delays were enrolled in the study. Children were divided into two groups based on the retention of the first implant or its removal, creating a sequential unilateral user group (USG) and a sequential bilateral user group (BSG). Both groups reflect differing durations of auditory deprivation in each ear, being relatively longer for the USG group for each ear than for the BSG group. Rehabilitative. All patients underwent periodic speech recognition testing for two years after the second surgery. The results for each implanted ear in both groups were evaluated and an index score representing the Difference Between the Ears, (DBE), was calculated. A statistically significant difference results was obtained between the groups. Both groups reached interaural equivalence (i.e. DBE=0%), after two years post-sequential implant. The USG patients achieved interaural equivalence at a faster rate than the BSG patients with 85% USG subjects demonstrating it at 6months compared to the majority of BSG patients demonstrating equivalence at one-year post-sequential implant. The performance of the sequentially implanted ear depends to an extent on a negative influence, which could be considered as a type of inhibition, of the first implanted ear over the second ear. It appears that the role of the unilateral auditory deprivation is not the primary influencing factor. These findings have driven us clinically to redefine some important considerations for rehabilitation management of the deaf children in the cases of delayed sequential implant.


Fixed behaviours and migration in parasitic flatworms.
This paper considers how fixed behaviours may play a role in post-larval migrations of Entobdella soleae. A general argument is that a shift away from the paradigm of orientation is required to elucidate the mechanisms that parasites use to navigate on the surface of their hosts. Some migrations may rely on fixed behaviours (genetically programmed stereotyped behaviours) that often evolve under predictable environmental conditions with reliable signals. In turbulent and stochastic free-living environments, homeostatic hosts present very predictable topological substrates and physico-chemical characteristics to their parasites. Over the course of evolution on these predictable host substrates, adaptive behaviours in the parasites can become fixed. Examples of endoparasite migration behaviour, particularly that of the common liver fluke, Fasciola hepatica, will be used to develop an approach based on the perceptual worlds of migrating parasites. An important conclusion is that multi-disciplinary approaches, firmly rooted in an understanding of each parasite's natural history, are requisite to successful interpretation of migration behaviours on the host.


Changes in VEGF expression and in the vasculature during the growth of early-stage ethylnitrosourea-induced malignant astrocytomas in rats.
Vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, may be important as a mediator of brain tumour progression. However, it is still not clear whether VEGF plays a causative role in the early stage of glioma development. We investigated the relationship between VEGF protein expression (as assayed by immunohistochemistry) and different morphological parameters reflecting tumour progression (tumour diameter, vascular density and vascular diameter) in tumours at various stages. As a tumour model, ethylnitrosourea (ENU)-induced rat malignant astrocytoma was used. Tumours were classified by size and level of vascularity estimated by the von Willebrand factor (vWF) staining. Tumours less than 10 mm in diameter were designated early stage neoplastic lesions. All 34 early astroglial tumours were found to be VEGF positive. Increase in the VEGF immunopositive rate of tumour cells correlated significantly with increase in vascular density and vascular diameter. We suggest that VEGF induces angiogenesis and growth of microvessels, promoting growth of the early stage malignant astrocytoma.


Use of gonococcal W serogrouping in the evaluation of a clinical trial of rosoxacin.
Serogrouping by co-agglutination was used for the characterization of isolates of Neisseria gonorrhoeae in a clinical trial of rosoxacin in Stockholm. Twenty-four isolates (56%) belonged to serogroup WI, 17 (40%) to WII, and two (5%) to WIII. The proportion of WI isolates in Stockholm was reported in earlier studies to be approximately 40%. On the basis of serogrouping data and clinical information, five (10%) of 48 patients in this study were classified as therapeutic failures. Of the initial WI isolates, 22 (92%) of 24 were inhibited by less than or equal to 0.03 microgram of rosoxacin/ml, as compared with ten (59%) of 17 of the initial WII isolates (.05 greater than P greater than .01). Thus, this study might underestimate the failure rate as compared with that for patient populations in which WII isolates are more prevalent, since WI isolates are more susceptible to rosoxacin than WII isolates. A certain WII serovar was correlated with decreased susceptibility to rosoxacin (P less than .001). Correlations were found between decreased susceptibility to rosoxacin and decreased susceptibility to other antibiotics (P less than or equal to .01). A high frequency of side effects (40%) was seen among the patients studied.


EEG sleep and affective psychoses: I. Schizoaffective disorders.
The sleep electroencephalogram (EEG) was studied in 41 depressed inpatients. EEG sleep records were compared for two diagnostic subgroups; patients with psychotic depression (n = 29) or with schizoaffective disorders (n = 12). As was true in the previous pilot study, no major EEG sleep variables distinguished the patients with psychotic depression from those with schizoaffective disorders. These data are consistent with the theory that all psychotic depressive states may have certain common psychobiologic features such as shortened rapid eye movement (REM) sleep latency.


Treatment of urinary tract infections with varying regimens of sulfisoxazole.
Four therapeutic regimens of sulfisoxazole were compared and contrasted with the antibody-coated bacteria test in patients with acute urinary tract infections. Of 158 college coeds who entered the study 146 completed the randomly assigned regimen. All 146 patients received 2 gm. sulfisoxazole initially and 1 gm. 4 times daily for 3 days in 44 patients (group 1), 7 days in 51 (group 2), 14 days in 29 (group 3) and 21 days in 22 (group 4). The presumptive sites of infection by the antibody-coated bacteria test were kidney (positive test) in 43 per cent of the patients and bladder (negative test) in 51.3 per cent. There was no correlation between the results of the antibody-coated bacteria test with either the presenting symptoms or the therapeutic responses. The bacteriologic cure rates at 2 days after therapy were 100 per cent in all groups and at 4 weeks after therapy they were 88.6 per cent in group 1, 86.3 per cent in group 2, 86.2 per cent in group 3 and 91 per cent in group 4. A 3-day course of sulfisoxazole was as effective as the longer regimens.


Relationships between the epiphysis and hippocampus during formation of a stress response.
Lesions to the dorsal hippocampus and removal of the epiphysis had differently-directed effects on behavior in rats in conditions of a conflict situation and on the temporal dynamics of forced swimming. The combination of both operative procedures resulted in weakening of the behavioral changes typical of hippocampus deficiency. It is suggested that the anti-stress properties of epiphyseal factors may be mediated by changes in the functional state of the hippocampus.


Critical links between biodiversity and health in wild bee conservation.
Wild bee populations are declining due to human activities, such as land use change, which strongly affect the composition and diversity of available plants and food sources. The chemical composition of food (i.e., nutrition) in turn determines the health, resilience, and fitness of bees. For pollinators, however, the term 'health' is recent and is subject to debate, as is the interaction between nutrition and wild bee health. We define bee health as a multidimensional concept in a novel integrative framework linking bee biological traits (physiology, stoichiometry, and disease) and environmental factors (floral diversity and nutritional landscapes). Linking information on tolerated nutritional niches and health in different bee species will allow us to better predict their distribution and responses to environmental change, and thus support wild pollinator conservation.


Almost 100 % Peroxymonosulfate Conversion to Singlet Oxygen on Single-Atom CoN2+2 Sites.
Single-atom CoN4 active sites have demonstrated excellent efficiency in peroxymonosulfate activation. However, the identification of CoN4 active sites and the detailed singlet oxygen generation mechanism in peroxymonosulfate activation remains ambiguous. We demonstrate a strategy to regulate the generation of reactive oxygen species by atomically dispersed cobalt anchored on nitrogen-doped carbon. As indicated by experiment and DFT calculations, CoN2+2 was the active site and singlet oxygen was the predominant reactive oxygen species with a proportion of 98.89 %. Spontaneous dissociation of adsorbed peroxymonosulfate on the CoN2+2 active sites was energetically unfavorable because of the weakly positive Co atoms and CoN2+2 coordination, which directed PMS oxidation by a non-radical pathway and with simultaneous singlet oxygen generation. The generated singlet oxygen degraded several organic pollutants with high efficiency across a broad pH range.


Effectiveness of case management performed by nurses for blood pressure control in adults with hypertension: a systematic review protocol.
The question of this review is: what is the effectiveness of nurse case management in primary healthcare for improving blood pressure, in adults over 18 years with hypertension?The objective of this review is to synthesize the best available evidence regarding the effectiveness of nurse case management in primary healthcare, compared to usual care, in improving blood pressure in adults over 18 years with hypertension.


Ethanol reinforced responding in the rat: relation of ethanol introduction to later ethanol responding.
Rats, maintained on ad lib food and water, were trained to lever press on a concurrent schedule using water and sucrose (10% w/v) as the fluids presented contingent on responding. Each fluid was associated with a lever and available on a fixed ratio eight (FR8) response requirement. The lever with which each fluid was paired was alternated daily. When stable responding occurred, ethanol was substituted for water, first at low concentrations, and then slowly increased to 5% (v/v). When stable sucrose-ethanol responding was reached, the response requirement for sucrose was altered to fixed ratio requirements of either FR32 or FR64. Moderate, but unstable increments in the number of ethanol responses occurred during the increased sucrose response requirements. Following the sucrose response requirement manipulation, water was substituted for the sucrose. Ethanol responding was found to fall to or below prior baseline levels. Weight reduction by food restriction failed to increase ethanol responding. The levels of ethanol responding resulting from this introduction procedure were always much lower independent of body weight than previously reported levels found in rats trained to respond for ethanol using a different procedure of initial ethanol introduction.


Oropharyngeal dysphagia and associated factors among individuals living in nursing homes in northern Sweden in 2007 and 2013.
Swallowing difficulties in the oral cavity or pharynx (i.e., oropharyngeal dysphagia) are a common problem in the aging population, which may result in severe consequences, such as malnutrition, aspiration pneumonia, and mortality. Identifying oropharyngeal dysphagia and its associated factors is essential for establishing better healthcare policies in nursing homes. In this study, we aimed to describe the oropharyngeal dysphagia prevalence among nursing home residents, and to investigate the association between dysphagia and potentially related factors in a large survey of nursing home residents in Sweden, including individuals with various degrees of cognitive impairment. A secondary aim was to compare findings between years on oropharyngeal dysphagia and its associated factors. This study is based on two cross-sectional surveys performed in 2007 and 2013, including 4,995 individuals living in nursing homes in the Region of Västerbotten, Sweden. Data were collected from caregivers' reports regarding swallowing ability, nutritional status, chewing ability, and other baseline characteristics, such as cognitive function and activity of daily living (ADL). Data were analyzed using logistic regression models to calculate the odds of the association between oropharyngeal dysphagia and associated factors. Oropharyngeal dysphagia was reported in 14.9% (95% CI: 13.9-16.0) of the nursing home residents. An adjusted model revealed that oropharyngeal dysphagia was associated by severe cognitive impairment (OR: 1.56, 95% CI: 1.14-2.12) and ADL independence (OR: 0.81 95% CI: 1.82-2.66) among nursing home residents. We also identified the following as independently associated factors of dysphagia: reduced nutritional status (OR: 1.84, 95% CI: 1.49-2.27), artificial nutrition (OR: 6.33, 95% CI: 2.73-14.71), and clinical signs of aspiration (OR: 10.89, 95% CI: 8.40-14.12). Oropharyngeal dysphagia was reported among approximately 15% nursing home residents and was associated with cognitive impairment and ADL capability. Furthermore, reduced nutritional status and artificial nutrition were also associated with oropharyngeal dysphagia. Implementing routine protocols in nursing homes may help detect oropharyngeal dysphagia and manage oropharyngeal dysphagia among residents.


Effect of present versus previous smoking on non-invasive haemodynamics.
We examined cardiovascular function in 637 volunteers (19-72 years) without antihypertensive medication in never smokers (n = 365), present smokers (n = 81) and previous smokers (n = 191, median abstinence 10 years). Haemodynamics during passive head-up tilt were recorded using whole-body impedance cardiography and radial pulse wave analysis. Results were adjusted for age, sex, body mass index, LDL cholesterol and alcohol use. Systolic and diastolic blood pressure, heart rate, and pulse wave velocity were not different between the groups. Supine aortic reflection times did not differ, while upright values were shorter in present versus previous smokers (p = 0.04). Heart rate adjusted augmentation index was increased in the supine position in present smokers versus controls (p = 0.045), and in present (p < 0.001) and previous (p = 0.031) smokers versus controls in the upright position. Supine and upright cardiac output was higher (p ≤ 0.016) and systemic vascular resistance lower (p ≤ 0.001) in present versus previous smokers. In spite of the long abstinence, in the upright position previous smokers had lower cardiac output (p = 0.032) and higher systemic vascular resistance (p = 0.014) than never smokers. In the absence of differences in blood pressure and arterial stiffness, present smokers presented with hyperdynamic circulation and enhanced wave reflection compared with previous smokers.


Oxytocin Exerts Antidepressant-like effect by potentiating dopaminergic synaptic transmission in the mPFC.
Oxytocin (OT) and dopamine (DA) are two important elements that are closely related to mental and reward processes in the brain. OT controlled DA functional regulation contributes to various behaviours such as social reward, social cognition and emotion-related behaviours. Previous studies indicated that diminished dopaminergic transmission in the medial prefrontal cortex (mPFC) is correlated with the pathophysiology of depression. However, the interaction of OT and DA and their roles in antidepressant effects still require further exploration. Here, we investigated the antidepressant effect of OT through local mPFC administration, and further explored the underlying mechanisms that indicated that OT could strengthen dopaminergic synaptic transmission with OT receptor (OTR) activation dependent in the mPFC. Our results showed that local administration of OT in the mPFC exerts antidepressant (-like) effects in both naïve and social defeat stress (SDS) depressive animal model. Mechanism study suggested that OT enhances DA level with OTR activation dependent, and elevated mPFC DA levels might further enhance excitatory synaptic transmission by activating the D1/PKA/DARPP32 intracellular signalling pathway in the mPFC. Hence, our study revealed that the activation of OTR strengthens excitatory synaptic transmission via the potentiation of dopaminergic synaptic transmission, especially via D1R activation dependent, in the mPFC, which may be the underlying mechanism of antidepressant (-like) effects mediated by OT. With specifically activation of the D1/PKA/DAPRR32 signalling pathway, our results may augment the important role of OT in reward circuits in the central nervous system.


Analysis of substrate interactions of the Rous sarcoma virus wild type and mutant proteases and human immunodeficiency virus-1 protease using a set of systematically altered peptide substrates.
In the preceding study, mutant Rous sarcoma virus (RSV) proteases are described in which three amino acids found in the human immunodeficiency virus-1 (HIV-1) protease (PR) were substituted into structurally comparable positions (Grinde, B., Cameron, C.E., Leis, J., Weber, I., Wlodawer, A., Burstein, H., Bizub, D., and Skalka, A. M. (1992) J. Biol. Chem. 267, 9481-9490). In this report, the activity of the wild type and these mutant PRs are compared using a set of RSV NC-PR peptide substrates with single amino acid substitutions in each of the P4 to P3' positions. With most substrates, the relative activities of the two active mutants followed that of the RSV PR. Substitutions in the P1 and P1' positions were an exception; in this case, the mutants behaved more like the HIV-1 PR. These results confirm predictions from structural analyses which indicate that residues 105 and 106 of the RSV PR are important in forming the S1 and S1' binding subsites. These results, further analyzed with the aid of computer modeling of the RSV PR with different substrates, provide an explanation for why only partial HIV-1 PR-like behavior was introduced into the above RSV PR mutants.


Culture of rat cerebellar granule neurons and application to identify neuroprotective agents.
In primary culture of the early postnatal cerebellum, glutamatergic granule cells are highly enriched and recapitulate many properties characteristic of developing granule neurons in vivo. For example, withdrawal of K(+) from differentiated rat primary cerebellar granule neurons results in the apoptotic death of the majority of cells after 48 h. Removal of cerebellar granule neurons from depolarizing culture conditions with high K(+) is thought to reflect the regulation of trophic action of neuronal activity and has found widespread application as a model for studying the mechanisms of survival factor withdrawal-induced neuronal cell apoptosis and the neuroprotective action of trophic agents. This chapter presents a protocol for the culture of postnatal rat cerebellar granule neurons and results in a preparation containing 95% glutamatergic granule cells and its application to the evaluation of corticotropin receptor agonists as neuroprotective agents.


Using bear rub data and spatial capture-recapture models to estimate trend in a brown bear population.
Trends in population abundance can be challenging to quantify during range expansion and contraction, when there is spatial variation in trend, or the conservation area is large. We used genetic detection data from natural bear rubbing sites and spatial capture-recapture (SCR) modeling to estimate local density and population growth rates in a grizzly bear population in northwestern Montana, USA. We visited bear rubs to collect hair in 2004, 2009-2012 (3,579-4,802 rubs) and detected 249-355 individual bears each year. We estimated the finite annual population rate of change 2004-2012 was 1.043 (95% CI = 1.017-1.069). Population density shifted from being concentrated in the north in 2004 to a more even distribution across the ecosystem by 2012. Our genetic detection sampling approach coupled with SCR modeling allowed us to estimate spatially variable growth rates of an expanding grizzly bear population and provided insight into how those patterns developed. The ability of SCR to utilize unstructured data and produce spatially explicit maps that indicate where population change is occurring promises to facilitate the monitoring of difficult-to-study species across large spatial areas.


Vocally disruptive behavior (VDB) in the institutionalized elderly: a naturalistic multiple case report.
Employing a naturalistic multiple case study approach, we investigated the current clinical practice in the treatment and care of VDB among a convenience sample of 85 patients cared for in specialized old age psychiatric clinics and nursing homes in French and German-speaking Switzerland. We wished to clinically characterize VDB patients, to identify common approaches used to treat VDB in everyday practice, and to explore how the efficiency of the interventions employed was judged by the responsible carers. Data were collected by means of a questionnaire. Most patients with VDB in this study had dementia, of whom 75% had at least one current or premorbid psychiatric disorder and 25% had premorbid personality disorder. A majority of patients received multiple psychosocial care interventions that were often judged to be effective, but the potential of psychosocial interventions is underused. Many patients did not receive psychotropic medication specifically targeted at VDB, but about 70% of all prescriptions were judged to have positive effects. Premorbid psychiatric and personality disorders or traits are likely candidates to be entered into the etiopathogenic equation of VDB and set a new frame for approaches used to treat these underlying disorders.


An optimized transformation protocol for Lipomyces starkeyi.
We report the development of an efficient genetic transformation system for Lipomyces starkeyi based on a modified lithium acetate transformation protocol. L. starkeyi is a highly lipogenic yeast that grows on a wide range of substrates. The initial transformation rate for this species was extremely low, and required very high concentrations of DNA. A systematic approach for optimizing the protocol resulted in an increase in the transformation efficiency by four orders of magnitude. Important parameters included cell density, the duration of incubation and recovery periods, the heat shock temperature, and the concentration of lithium acetate and carrier DNA within the transformation mixture. We have achieved efficiencies in excess of 8,000 transformants/µg DNA, which now make it possible to screen libraries in the metabolic engineering of this yeast. Metabolic engineering based on this transformation system could improve lipogenesis and enable formation of higher value products.


The unexpected beneficial role of smoking in preeclampsia.
We have recently investigated the association between the risk of developing PE and clinical, hemostatic, inflammatory and genetic parameters of 108 severe preeclamptic women. A multivariate logistic regression analysis was performed to assess what variables are independent risk factors for PE. Univariate analysis was performed including the variables in age, smoking condition, multiple pregnancy, blood group, phenotypes and alleles of IL-4, IL-5, IL-10, IL-6, IL-8, IL-12, IL-1β, IFN-γ, TNF-α, and the plasma levels of FVII, FVIIa, FVIIa-AT, FVIII, FVW, ADAMTS13, D-Di, PAI-1, ADMA. Those variables whose P<0.20 (smoking, multiple pregnancy, blood group, phenotype IL-6, IFN-γ allele, IL-10 allele and FVII) were selected to the multivariate logistic regression. In the final model, only FVII, IFN-γ allele and smoking were independently associated to severe PE (P<0.0001, P<0.0001 and P=0.008, respectively). Increased FVII plasma levels and IFN-γ "T" allele were associated to an increased probability of developing PE (OR 1.001, 95% CI [1.001-1.002], and OR 4.81 95% CI [2.42-9.60], respectively). On the other hand, smoker status was associated with a 4.72 decreased chance of PE occurrence (OR 4.72, 95% CI [1.51-14.75]). In this article we also reviewed the studies that investigate the risk of PE in pregnant women who smoked, as well as the effect of tobacco extract in cells or animal models. The hypotheses proposed to explain the biological mechanism by which smoking during pregnancy reduces the risk of PE was also discussed.


Improving the care of patients with cystic fibrosis (CF).
The West Midlands Adult Cystic Fibrosis (CF) Centre based at Birmingham Heartlands Hospital provides care for adults with CF in the West Midlands. People with CF are prone to pulmonary exacerbations, which often require inpatient admission for intravenous antibiotics. We observed that the admission process was efficient during working hours (9:00-17:00, Monday-Friday) when the CF team are routinely available, but out-of-working hours, there were delays in these patients being clerked and receiving their first antibiotic dose. We were concerned that this was resulting in quality and potential safety issues by causing delays in starting treatment and prolonging hospital inpatient stays. We therefore undertook a quality improvement project (QIP) aimed at addressing these issues. An initial survey showed median time to clerk of 5 hours, with 60% of patients missing their first dose of antibiotics and mean length of stay of 16 days. We applied the Plan-Do-Study-Act (PDSA) cycle approach, with the first PDSA cycle involving raising awareness of the issue through education to doctors, nurses and patients. This led to a reduction of median time to clerk from 5 to 2 hours with 23% of patients missing their first antibiotic dose and mean length of stay reducing to 14 days. The second cycle involved introducing an admissions checklist and displaying education posters around the hospital, resulting in median time to clerk remaining at 2 hours but only 20% of patients missing their first antibiotic dose and the mean length of stay remaining at 14 days. This QIP has improved the out-of-hours admissions process for adults with CF in our centre. We plan to review the longer term effects of the project including sustainability, effects on clinical outcomes and patient satisfaction.


Guidelines on the Use of Systemic Therapy in Patients with Advanced Thyroid Cancer.
With increasing understanding of the molecular alterations leading to thyroid cancers in recent years we have seen a rapid increase in the number of effective targeted systemic therapies available for patients with advanced thyroid cancer; firstly with the advent of the multi-kinase inhibitors and more recently with more specific RET, BRAF, MEK, ALK and NTRK inhibitors. Although these developments are very welcome, they have resulted in a paradigm shift in the management of advanced thyroid cancer to which thyroid oncologists have had to rapidly adapt, learning how to supervise treatment safely with novel agents, the management of novel toxicities, when and how to arrange molecular genetic testing of cancers and, perhaps most importantly, determining when the optimum time is to start these treatments in what can often be a relatively indolent, if progressive, disease. We hope that these guidelines will support clinicians in making these decisions with their patients, as well as signposting and providing useful supporting information both for patients and clinicians.


Feeding skill milestones of preterm infants born with extremely low birth weight (ELBW).
To compare the feeding development of preterm infants with that of full-term infants. Nineteen preterm infants with extremely low birth weight, and 11 healthy full-term infants. Intensive follow-up study. Feeding situations were analyzed by NOMAS (Neonatal Oral Motor Assessment Scale) and by an oral motor patterns checklist based on video recorded sessions. Most of the preterm infants showed a disorganized sucking pattern and most of the full-term infants a normal sucking pattern, as long as suckling was present. However, the early suckling pattern did not predict the schedule of later feeding development. Preterm infants seemed to learn the various feeding skills at the same corrected ages as full-term infants, with the exception of munching, which they learned earlier than the full-term infants. However, the age range for gaining these skills was wider for the preterm infants. Preterm infants also seemed to have feeding problems more often than full-term infants when qualitative features of feeding were considered. Feeding was prolonged and messy, and the preterm infants were sensitive to different qualities of food. Feeding development of preterm and full-term infants is similar except for suckling, when only oral motor skills are concerned. When the qualitative characteristics of feeding are taken into account, the preterm infants suffer from feeding problems that create a risk for early interaction and communication.


Cytosolic delivery of a p16-peptide oligoarginine conjugate for inhibiting proliferation of MCF7 cells.
One of the major limitations in protein and peptide therapeutics is the requirement of delivery to the cytosol or nucleus of cells. It has recently been shown that a small peptide derived from the p16 protein is able to inhibit cell cycle progression when delivered to the cytosol after conjugation to cell penetrating peptides, however the correlation between delivery efficiency and biological activity has not been made. Additionally, whether or not the biological activity attained was due to membrane transduction has not been established. In this paper, the total internalization, and internalization via endocytosis and transduction of 125I-p16, 125I-p16-C(R)9, and 125I-p16-C(K)9 were determined in MCF7 cultured cell monolayers. The results showed that while p16 and p16-oligopeptide conjugates have similar total internalization, 125I-p16-C(R)9 is predominantly internalized via membrane transduction, while p16 and p16-oligolysine are primarily endocytosed. Therefore, the amount of 125I-p16-C(R)9 delivered to the cytosol is significantly higher than both 125I-p16-C(K)9 and 125I-p16. These results show that biological activity is correlated with membrane transduction efficiency, and not total internalization. Additionally, the biological activity and delivery to the cytosol were not sensitive to endocytic inhibitors, verifying that the biological effect is due to membrane transduction, and not endocytosis.


Molecular comparison of the sampling efficiency of four types of airborne bacterial samplers.
In the present study, indoor and outdoor air samples were collected using four types of air samplers often used for airborne bacterial sampling. These air samplers included two solid impactors (BioStage and RCS), one liquid impinger (BioSampler), and one filter sampler with two kinds of filters (a gelatin and a cellulose acetate filter). The collected air samples were further processed to analyze the diversity and abundance of culturable bacteria and total bacteria through standard culture techniques, denaturing gradient gel electrophoresis (DGGE) fingerprinting and quantitative polymerase chain reaction (qPCR) analysis. The DGGE analysis indicated that the air samples collected using the BioStage and RCS samplers have higher culturable bacterial diversity, whereas the samples collected using the BioSampler and the cellulose acetate filter sampler have higher total bacterial diversity. To obtain more information on the sampled bacteria, some gel bands were excised and sequenced. In terms of sampling efficiency, results from the qPCR tests indicated that the collected total bacterial concentration was higher in samples collected using the BioSampler and the cellulose acetate filter sampler. In conclusion, the sampling bias and efficiency of four kinds of air sampling systems were compared in the present study and the two solid impactors were concluded to be comparatively efficient for culturable bacterial sampling, whereas the liquid impactor and the cellulose acetate filter sampler were efficient for total bacterial sampling.


Rotating three-dimensional dynamic culture of adult human bone marrow-derived cells for tissue engineering of hyaline cartilage.
The method of constructing cartilage tissue from bone marrow-derived cells in vitro is considered a valuable technique for hyaline cartilage regenerative medicine. Using a rotating wall vessel (RWV) bioreactor developed in a NASA space experiment, we attempted to efficiently construct hyaline cartilage tissue from human bone marrow-derived cells without using a scaffold. Bone marrow aspirates were obtained from the iliac crest of nine patients during orthopedic operation. After their proliferation in monolayer culture, the adherent cells were cultured in the RWV bioreactor with chondrogenic medium for 2 weeks. Cells from the same source were cultured in pellet culture as controls. Histological and immunohistological evaluations (collagen type I and II) and quantification of glycosaminoglycan were performed on formed tissues and compared. The engineered constructs obtained using the RWV bioreactor showed strong features of hyaline cartilage in terms of their morphology as determined by histological and immunohistological evaluations. The glycosaminoglycan contents per microg DNA of the tissues were 10.01 +/- 3.49 microg/microg DNA in the case of the RWV bioreactor and 6.27 +/- 3.41 microg/microg DNA in the case of the pellet culture, and their difference was significant. The RWV bioreactor could provide an excellent environment for three-dimensional cartilage tissue architecture that can promote the chondrogenic differentiation of adult human bone marrow-derived cells.


Pharmacokinetics of clarithromycin in bronchial epithelial lining fluid.
BAL is an established technique for measuring antibiotic concentrations in the epithelial lining fluid (ELF) of the bronchiolar-alveolar regions. However, the results may not reflect concentrations in bronchial regions. Bronchoscopic microsampling (BMS) is a technique for repeated sampling of bronchial ELF. The objective of the present study was to determine the time versus concentration profile of clarithromycin and its active metabolite, 14-hydroxy-clarithromycin, in bronchial ELF, as determined by BMS. BMS was performed at 1, 2, 3, 5 and 10 h after a single oral administration of 200 mg clarithromycin in five healthy volunteers. BAL was performed 3 h after administration to determine clarithromycin concentrations in alveolar ELF and alveolar macrophages (AM). The maximum concentration (C(max)) of clarithromycin was 0.36 +/- 0.07 mg/L in serum and 1.44 +/- 0.49 mg/L in bronchial ELF (P < 0.01). C(max) for 14-hydroxy-clarithromycin was 0.34 +/- 0.13 mg/L in serum and 0.68 +/- 0.34 mg/L in bronchial ELF. The area under the concentration-time curve from 0 to 10 h (AUC(0-10)) for clarithromycin was 2.10 +/- 0.49 mg.h/L for serum and 7.37 +/- 2.07 mg.h/L for bronchial ELF (P < 0.01). The concentrations of clarithromycin in alveolar ELF and AM, 3 h after oral administration, were 4.84 +/- 3.39 mg/L and 10.7 +/- 8.7 mg/L, respectively. A single oral dose of clarithromycin produces a significantly higher C(max) and AUC(0-10) for clarithromycin in bronchial ELF than in serum, and higher concentrations in alveolar ELF and AM than in serum. BMS might be useful for measuring the pharmacokinetic profile of clarithromycin in bronchial ELF.


Trampoline and minitrampoline injuries to the cervical spine.
The purpose of this paper is to (1) examine the world's literature documenting cervical spine injuries; (2) attempt to identify common factors regarding patient characteristics, environment, injury mechanisms, and pathology; (3) review policy statements and safety guidelines of various medical and athletic administrative bodies; and (4) evaluate what effect, if any, these policies and guidelines have had on documented injuries. On the basis of this review, we believe that the American Academy of Pediatrics was ill-advised in altering its position on the use of trampolines. It is our opinion that both the trampoline and the minitrampoline are dangerous devices when used in the best of circumstances, and their use has no place in recreational, educational, or competitive gymnastics.


An assessment of Nurses' knowledge, attitude and practice of emergency care related to road traffic accident victims at three selected hospitals in Rwanda.
Quality emergency nursing care is an important variable in reducing death and disability due to road traffic accidents (RTA), yet little is known about emergency nursing care within the Rwandan context. This study aims to describe the knowledge, attitude and practice (KAP) of nurses of the emergency care of RTA patients. We employed a cross sectional design to survey the full cohort of nurses working in Accident and Emergency (A&E) units in three selected Rwandan hospitals (N = 51). This study revealed that the knowledge and practice of nurses is either high or very high and the majority of them (73.657%) had a positive attitude towards emergency management of RTA patients. Being trained before working in A&E units was associated with a significant increase in the likelihood of being at the level of practice which is (1) very high (OR = 5.35, 95%, CI = 5.20-5.50), (2) high (OR = 1.60, 95%, CI = 1.17-2.19) (3), moderate (OR = 5.35,95%, CI = 4.15-6.88) and (4) low (OR = 1.33,95%, CI = 1.33-133) and it decreased more than 99.9% the likelihood of being at low level of practice in all levels. The study showed that training had a significant effect on practice and this is supported by previous studies. Training interventions to improve the management of RTA patients by nurses working in A&E should be regularly audited to ensure ongoing quality of care.


The effect of mycophenolate mofetil on podocytes in nephrotoxic serum nephritis.
Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca2+-actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca2+ concentration ([Ca2+]i), the experimental design was repeated in mice expressing podocyte-specific Ca2+ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca2+ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca2+]i imaging in podocytes showing decreased Ca2+ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca2+]i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.


Crystallization and preliminary crystallographic data for class I deoxyribose-5-phosphate aldolase from Escherichia coli: an application of reverse screening.
X-ray quality crystals of class I-deoxyribose-5-phosphate aldolase from Escherichia coli have been obtained for the unliganded enzyme and in complex with its substrate, 2-deoxyribose-5-phosphate. The enzyme catalyzes the reversible cleavage of 2-deoxyribose-5-phosphate to acetaldehyde and D-glyceraldehyde-3-phosphate. The unliganded and complex crystals are prismatic long rods and belong to the orthorhombic space group P2(1)2(1)2(1) with cell dimensions a = 183.1 A, b = 61.4 A, c = 49.3 A and a = 179.2 A, b = 60.5, A, c = 49.1 A, respectively. Two molecules in the asymmetric unit are related by a noncrystallographic 2-fold axis. The crystals are stable in the X-ray beam and diffract to at least 2.6 A. A new method, reverse screening, designed to minimize protein utilization during the screening process was used to determine supersaturation and crystallization conditions.


If Proust had whiskers: Recalling locations with smells.
Recent research suggests that the piriform cortex simultaneously represents spatial and olfactory information. These findings may provide further insight into the non-topographic principles of odor coding.


Abundance and seasonality of phoronid larvae in coastal temperate waters: More abundant than previously thought?
In zooplankton surveys, many smaller taxa or species considered less important are often overlooked. One such example is the actinotrocha larvae of phoronid worms that are rarely quantified in zooplankton samples yet may play important roles in marine food webs. To gain a better understanding of phoronid ecology in coastal waters, we retrospectively analysed 145 plankton samples collected from two coastal sites in Ireland (Lough Hyne and Bantry Bay). Samples were collected using plankton nets from depths of 20 and 40 m. Phoronids were present in 37.7% and 38.2% of samples, with mean abundances of 0.3 ± 0.5 ind. m-3 and 1.2 ± 2.8 ind. m-3, respectively, and were identified as Phoronis muelleri and Phoronis hippocrepia. Phoronids were present consistently each year from April to October at Lough Hyne and from February to October at Bantry Bay. Comparisons with other taxa in Lough Hyne show that abundances are similar to those of fish larvae (1.1 ± 1.8 ind. m-3) and echinoderm larvae (2.3 ± 4.4 ind. m-3). Examination of these samples from Irish waters suggests that phoronids are more abundant in temperate waters than previously reported. The online version contains supplementary material available at 10.1007/s10452-022-09982-6.


The SUMOylation and ubiquitination crosstalk in cancer.
The cancer occurrence and progression are largely affected by the post-translational modifications (PTMs) of proteins. Currently, it has been shown that the relationship between ubiquitination and SUMOylation is highly complex and interactive. SUMOylation affects the process of ubiquitination and degradation of substrates. Contrarily, SUMOylation-related proteins are also regulated by the ubiquitination process thus altering their protein levels or activity. Emerging evidence suggests that the abnormal regulation between this crosstalk may lead to tumorigenesis. In this review, we have discussed the study of the relationship between ubiquitination and SUMOylation, as well as the possibility of a corresponding application in tumor therapy. The relevant literatures from PubMed have been reviewed for this article. The interaction between ubiquitination and SUMOylation is crucial for the occurrence and development of cancer. A greater understanding of the crosstalk of SUMOylation and ubiquitination may be more conducive to the development of more selective and effective SUMOylation inhibitors, as well as a promotion of synergy with other tumor treatment strategies.


Nanotechnology based therapeutic application in cancer diagnosis and therapy.
Due to the lack of early diagnosis, cancer remains as one of the leading cause of human mortality. Inability to translate research into clinical trials and also inability of chemotherapeutics delivery to targeted tumor sites are major drawbacks in cancer therapeutics. With the emergence of nanomedicine, several nanoprobes (conjugated with targeting ligands and chemotherapeutic drugs) are developed. It can interact with biological system and thus sense and monitor the biological events with high efficiency and accuracy along with therapy application. Nanoparticles like gold and iron oxide are frequently used in the computed tomography and magnetic resonance imaging applications, respectively. Moreover, enzymatic activity of gold and iron oxide nanoparticles enables the visible colorimetric diagnostic of cancer cells, whereas, fluorescence property of quantum dots and upconversion nanoparticles helps in in vivo imaging application. Other than this, drug conjugation with nanoparticles also reduces the systemic toxic effect of chemotherapeutic drugs. Due to their several unique intrinsic properties, nanoparticles itself can also be employed as therapeutics in cancer treatment by photothermal therapy (PTT) and photodynamic therapy (PDT). Thus, the main focus of this review is to emphasize on current progress in diagnostic and therapeutic application of nanoprobes in cancer.


Ventilator-induced lung-injury in mouse models: Is there a trap?
Ventilator-induced lung injury (VILI) is a serious acute injury to the lung tissue that can develop during mechanical ventilation of patients. Due to the mechanical strain of ventilation, damage can occur in the bronchiolar and alveolar epithelium resulting in a cascade of events that may be fatal to the patients. Patients requiring mechanical ventilation are often critically ill, which limits the possibility of obtaining patient samples, making VILI research challenging. In vitro models are very important for VILI research, but the complexity of the cellular interactions in multi-organ animals, necessitates in vivo studies where the mouse model is a common choice. However, the settings and duration of ventilation used to create VILI in mice vary greatly, causing uncertainty in interpretation and comparison of results. This review examines approaches to induce VILI in mouse models for the last 10 years, to our best knowledge, summarizing methods and key parameters presented across the studies. The results imply that a more standardized approach is warranted.


Rat ovary glucocorticoid receptor: identification and characterization.
A soluble, thermolabile protein with characteristics typical of glucocorticoid receptors has been identified in the ovaries of estrogen-stimulated hypophysectomized immature rats. After the incubation of 3H- dexamethasone with ovarian cytosol, fractionation on a Sephadex G-200 column reveals a peak of radioactivity which elutes at the void volume. This peak, which represents saturable 3H-dexamethasone binding, disappears following heating (4 degrees C X 15 min) or treatment of the cytosol with pronase. Scatchard analysis of the 3H-dexamethasone binding to cytosol shows it to be high affinity (Kd=5.1 nM) and saturable, with 327 fmol binding sites/mg cytosol protein. Binding site number rises linearly with increasing cytosol protein concentrations. The relative abilities of various steroids to inhibit 3H-dexamethasone binding are: triamcinolone acetonide greater than or equal to dexamethasone greater than cortisol = progesterone greater than dihydro-testosterone greater than estradiol. This binding protein sediments at 9 S on a sucrose gradient, has a mean Stokes radius of 105 A on gel exclusion chromatography, and has a calculated molecular weight of 388,000 daltons and a frictional ratio of 2.1. 3H-Dexamethasone is not metabolized and does not bind specifically to serum. We have identified a protein in the rat ovary with characteristics of a glucocorticoid receptor and propose that this protein may be responsible for mediating direct effects of glucocorticoids on the ovary.


Analgesic, anti-inflammatory, antipyretic and toxicological evaluation of some newer 3-methyl pyrazolone derivatives.
In this paper, we described the pharmacological and toxicological studies of three pyrazolone derivatives namely PYZ1: 4-[4-N dimethylamino benzylidine]-3-methyl pyrazolin-5(4H)-one, PYZ2: 4-[2-chlorobenzylidine]-3-methylpyrazolin-5(4H)-one and PYZ3: 4-[benzylidine]-3-methylpyrazolin-5(4H)-one derivatives. Analgesic, anti-inflammatory and antipyretic studies of 3-methyl pyrazolone derivatives at 400 mg/kg, p.o. have shown significant activity as compared to control. Amongst three pyrazolone derivatives, PYZ2 was found to be more active. Based on the result of pharmacological studies, PYZ2 was selected for toxicological studies. Acute toxicity studies revealed that methyl pyrazolone derivatives are non-toxic in rats up to 5000 mg/kg, p.o. The subacute toxicity study of PYZ2 showed that decrease in Hb content, RBC and WBC count. In biochemical analysis level of blood glucose and bilirubin reduced where as AST, ALT and alkaline phosphatase level elevated. Histopathological studies revealed that there was mild toxicity on liver and kidney at 1000 mg/kg, p.o.


Sub-millisecond closed-loop feedback stimulation between arbitrary sets of individual neurons.
We present a system to artificially correlate the spike timing between sets of arbitrary neurons that were interfaced to a complementary metal-oxide-semiconductor (CMOS) high-density microelectrode array (MEA). The system features a novel reprogrammable and flexible event engine unit to detect arbitrary spatio-temporal patterns of recorded action potentials and is capable of delivering sub-millisecond closed-loop feedback of electrical stimulation upon trigger events in real-time. The relative timing between action potentials of individual neurons as well as the temporal pattern among multiple neurons, or neuronal assemblies, is considered an important factor governing memory and learning in the brain. Artificially changing timings between arbitrary sets of spiking neurons with our system could provide a "knob" to tune information processing in the network.


Management of severe subarachnoid hemorrhage; significance of assessment of both neurological and systemic insults at acute stage.
In order to elucidate mutual interrelationship between neurological and systemic dysfunctions in patients with subarachnoid hemorrhage (SAH) at acute stage, neurological condition, systemic complications and plasma catecholamine (CA) level were studied in 1431 consecutive cases admitted within 72 hours after the onset. Five hundred and twenty-four cases with Glasgow Coma Scale (GCS) score 8 or less were assigned to the group of severely ill cases (G-ill), 907 cases with GCS score 9 or more to that of the less ill group (G-well). Plasma CA level was extremely high at super-acute stage within an hour after bleeding and lowered fairly quickly within 24 hours to the normal range. Assuming the value obtained from a formula of [blood sugar level (mg/dl)/serum potassium concentration (mEq/L)] as stress index (SI), SI correlates well (r = 0.4-0.6) with serum catecholamine level at acute stage. Thus, sympathetic hyperactivity after SAH can be grossly estimated with SI. SI over 40 means that patients might have considerable neurological insults as well as systemic ones. For patients in G-well, SI over 50 means that there may be risks for systemic complications even in cases with good neurological condition.


Temporary arterial shunt in the severely injured limb.
Silicone rubber tubing and matching vessel tips are available in any hospital with a renal dialysis unit. These materials may be used as a temporary measure to restore distal circulation in the severely injured limb. The operative technique and postoperative management of a case in which this manoeuvre was used are presented.


Toxicity of prolonged high dose inhaled PGE1 in ventilated neonatal pigs.
To study the toxicity of inhaled PGE1 (IPGE1) in healthy ventilated piglets. Mechanically ventilated anesthetized piglets received either high dose IPGE1 (IPGE1 group) or nebulized saline (control group) continuously for 24h. Cardio-respiratory parameters, complete blood counts and serum electrolytes were monitored. Lung histology was evaluated by a masked pathologist for the severity (minimal, moderate, and severe) and extent (focal, multifocal, and diffuse) of histologic injury. Ten neonatal pigs were instrumented. Four received nebulized saline and six received high dose IPGE1. There was no evidence of adverse cardio-respiratory effects, bronchial irritation or hypernatremia related to IPGE1. Diffuse/multifocal alveolar edema and focal polymorphonuclear infiltration was observed in both the control and IPGE1 groups suggesting that alveolar alterations may be secondary to effects of mechanical ventilation. The most distinct histomorphological abnormalities observed in the IPGE1 animals were focal ulceration, flattening of the bronchial epithelium and loss of cilia of moderate to severe degree in the trachea and bronchi. In healthy piglets, inhalation of high dose IPGE1 was not associated with adverse cardiorespiratory effects, bronchial irritation, or hypernatremia and produced minimal signs of pulmonary toxicity even after 24h. Prolonged inhalation of high dose PGE1 therefore appears safe in newborn piglets.


Erythrocytes as markers of oxidative stress related pathologies.
Erythrocytes are deeply sensitive cells and important health indicators. During inflammatory response RBC, as a part of haematological system, are exposed to circulating inflammatory mediators and related oxidative stress. They present a highly specialized and organized cell membrane that interacts with inflammatory mediators and oxidative agents, leading to a variety of structural changes that promptly signal an abnormal situation. This review is aimed to provide an overview on erythrocyte involvement in physiological and pathological processes related to oxidative stress, such as aging, Down syndrome, neurodegenerative diseases, for instance Alzheimer Disease, erectile dysfunction and cardiovascular diseases. In particular this review will focus on the effects of oxidative stress on structural changes in the cell membrane and also on in the activity of erythrocyte enzymes such as membrane-bound, cytosolic glycohydrolases and RBC-eNOS. This review also underlines the potential clinical application of erythrocyte specific related parameters, which can be important tools not only for the study but also for the monitoring of several oxidative stress related diseases.


The interaction of CFLAR with p130Cas promotes cell migration.
CASP8 and FADD Like Apoptosis Regulator (CFLAR) is a key anti-apoptotic regulator for resistance to apoptosis mediated by Fas and TRAIL. In addition to its anti-apoptotic function, CFLAR is also an important mediator of tumor growth. High level of CFLAR expression correlates with a more aggressive tumor. However, the mechanism of CFLAR signaling in malignant progression is not clear. Here we report a novel CFLAR-associated protein p130Cas, which is a general regulator of cell growth and cell migration. CFLAR-p130Cas association is mediated by the DED domain of CFLAR and the SD domain of p130Cas. Immunofluorescence observation showed that CFLAR had the colocalization with p130Cas at the focal adhesion of cell membrane. CFLAR overexpression promoted p130Cas phosphorylation and the formation of focal adhesion complex. Moreover, the enhancement of cell migration induced by CFLAR overexpression was obviously inhibited by p130Cas siRNA. In silico analysis on human database suggests high expressions of CFLAR or/and p130Cas are associated with poor prognosis of patients with lung cancer. Together, our results suggest a new mechanism for CFLAR involved in tumor development via association with p130Cas.


Ideogram writing in a disconnection syndrome.
A case of disconnection-type agraphia coupled with alexia was reported. The patient showed several asymmetrical manual capacities between the two hands, i.e., dissociated difficulty of Kanji (ideogram) writing between the two hands, left unilateral difficulty of Kana (phonogram) writing, right unilateral dyscopia of letters as well as geometrical figures, and right unilateral difficulty in drawing without a model. Anatomically, lesions involved most of the corpus callosum in its posterior portion including the splenium and the left medial occipital lobe. From these data, a possible linguistic capacity of the right hemisphere was suggested.


FOLR2+ Macrophages Are Associated with T-cell Infiltration and Improved Prognosis.
FOLR2+ macrophages are associated with improved survival in patients with breast cancer.


Liver stiffness by two-dimensional shear wave elastography for screening high-risk varices in patients with compensated advanced chronic liver disease.
To investigate the usefulness of the criteria with liver stiffness (LS) measured by two-dimensional shear wave elastography (2D-SWE) and platelet count (PLT) for ruling out high-risk varices in patients with compensated advanced chronic liver disease (cACLD). A total of 661 patients with cACLD had successfully undergone 2D-SWE and endoscopy screening. We analyzed risk factors for the presence of high-risk varices and compared proportions of patients who were spared endoscopy when used the predicting criteria with LS (ranged from 16 to 25 kPa) and PLT (ranged from 80 × 109/L to 150 × 109/L). PLT, albumin, LS were found to be independent predictors of high-risk varices. The LS values for ruling out and ruling in high-risk varices were 14.0 kPa and 24.8 kPa, respectively. When the Baveno VI criteria LS < 20 kPa and PLT > 150 × 109/L were used, the high-risk varices miss rate was 2.1%, while the saved endoscopy rate only was 19.2%. The new criteria that LS < 16 kPa and PLT > 100 × 109/L saved 30.4-34.6% endoscopy with 0-3.2% high-risk varices miss rate in the subgroup analysis stratified according to the types of underlying liver disease. The Baveno VI criteria can be applied to LS measurement by 2D-SWE. The new criteria that LS < 16 kPa and PLT > 100 × 109/L could be a potential model to spare more endoscopy screening with < 5% high-risk varices miss rate. • LS measured by 2D-SWE is reliable predictive factor for predicting all-size varices and high-risk varices in patients with compensated advanced chronic liver disease. • LS measured by 2D-SWE < 16 kPa and PLT > 100 × 109 /L, which can spare more endoscopy than Baveno VI criteria with < 5% high-risk varices miss rate. • The Baveno VI criteria can be applied to LS measurement by 2D-SWE.