Signalling mechanisms in the regulation of vascular cell migration.
The migration of arterial vascular smooth muscle cells (VSMC) is thought to play a central role in atherogenesis and restenosis. The migration of several other cell types, including monocytes, T-lymphocytes and endothelial cells is also involved in the development of the mature atherosclerotic lesion. Several defined growth factors, cytokines and extracellular matrix components which are released at the sites of lesions have been implicated in the regulation of migration of VSMC and other lesion-associated cells. Platelet-derived growth factor BB-homodimer of PDGF (PDGF-BB) is strongly implicated in neo-intima formation in vivo and is the most potent known chemoattractant for VSMC in vitro. Dynamic interactions between cell surface adhesive receptors (integrins) for ECM components, organisation of the actin cytoskeleton and the turnover of focal adhesions are all key processes in cell locomotion and migration. The signal transduction pathways which mediate the chemotactic effects of PDGF-BB and other migration factors on VSMC are unknown, but several classes of cellular components are implicated including components associated with focal adhesions, small GTP-binding proteins of the rho family, and certain substrates of the PDGF beta-receptor. Tyrosine phosphorylation of the novel focal adhesion-associated protein tyrosine kinase, p125 focal adhesion kinase (p125FAK), is regulated by integrins and by several factors which alter actin cytoskeletal organisation. Recent findings suggest that tyrosine phosphorylation of p125FAK and other focal adhesion-associated proteins may be implicated in the chemotactic response of VSMC to PDGF-BB. The migratory response to PDGF-BB may be dependent on both ligand isoform bio-availability and on receptor-isotype expression as well as on down-stream signalling events. Ultimately, cell migration in vivo will be determined by a complex array of diverse extracellular molecules organised in intercellular paracrine/autocrine networks as well as multiple interacting intracellular signal transduction pathways.


Telephone audit for monitoring stroke unit facilities: a post hoc analysis from PROSIT study.
Although several valid approaches exist to measure the number and the quality of acute stroke units, only few studies tested their reliability. This study is aimed at establishing whether the telephone administration of the PROject of Stroke unIt ITaly (PROSIT) audit questionnaire is reliable compared with direct face-to-face interview. Forty-three medical leaders in charge of in-hospital stroke services were interviewed twice using the same PROSIT questionnaire with 2 different modalities. First, the interviewers approached the medical leaders by telephone. Thereafter, they went to the hospital site and performed a direct face-to-face interview. Six independent couples of trained researchers conducted the audit interviews. The degree of intermodality agreement was measured with kappa statistic. We found a perfect agreement for stroke units identification between the 2 different audit modalities (K = 1.00; standard error [SE], 1.525). The agreement was also very good for stroke dedicated beds (K = 1.00; SE, 1.525) and dedicated personnel (K = 1.00; SE, 1.525), which are the 2 components of stroke unit definition. The agreement was lower for declared in use process of care and availability of diagnostic investigations. The telephone audit can be used for monitoring stroke unit structures. It is more rapid, less expensive, and can repeatedly be used at appropriate intervals. However, a reliable description of the process of care and diagnostic investigations indicators should be obtained by either local site audit visit or prospective stroke register based on individual patient data.


Involuting solitary cutaneous infantile myofibroma and thrombocytopaenia: a previously unreported clinical association.
Solitary and multicentric myofibromas are rare fibrous tumours with marked predilection for infants and young children. Presentation is mainly before the age of 2 and lesions are often congenital. Behaviour is usually benign, but mortality has been described in lesions with visceral involvement. We report a unique case of congenital solitary cutaneous infantile myofibroma in a neonate associated with self-limiting thrombocytopaenia. It is important to distinguish accurately these lesions from benign vascular tumours like haemangiomas, locally aggressive vascular tumours like Kaposiform haemangioendotheliomas, which are often associated with Kasabach-Merritt phenomenon and also with malignant soft tissue tumours of infancy.


DNA delivery in vitro via surface release from multilayer assemblies with poly(glycoamidoamine)s.
Localized controlled release of nucleic acid therapeutics could be an effective way to reduce the extracellular barriers associated with systemic delivery. Herein, we have used the layer-by-layer film deposition approach to construct ultrathin multilayer assemblies for in vitro controlled release of plasmid DNA (pDNA). Layer-by-layer assemblies containing alternate layers of cationic poly(l-tartaramidopentaethylenetetramine) (T4), and anionic pDNA were fabricated. The film thickness and the absorbance at 260 nm for different T4/pDNA multilayer assemblies were characterized by ellipsometry and UV-vis spectrophotometry, respectively. The results indicated an increased loading capacity of pDNA with respect to an increase in the number of T4/pDNA bilayers deposited. For the controlled-release studies we incubated the bilayers coated on quartz slides in phosphate-buffered saline (PBS) at 37 degrees C and collected the media at different incubation time points. The collected PBS samples were characterized for pDNA release by complexing solutions containing the released pDNA with Lipofectamine 2000 and following cellular pDNA uptake via flow cytometry and GFP gene expression assays with HeLa cells. The study showed that the multilayer films started to release pDNA after 1 day of incubation and increased after 7 days of incubation. Assays monitoring green fluorescent protein (GFP) expression in HeLa cells indicated that about 20% of the cells were positive for GFP expression at all sample time points up to 11 days. Although an increase in cells positive for Cy5-pDNA was found as the incubation time increased, the number of cells positive for GFP expression remained constant over the same time frame.


Prevalence of malignancy within cytologically indeterminate thyroid nodules.
The optimal management of cytologically indeterminate thyroid nodules is controversial given the variable malignancy rates reported in this patient population. We examined the prevalence of malignancy within cytologically indeterminate follicular thyroid lesions in an attempt to predict malignancy based on cytologic features. Cytopathology reports obtained after fine-needle aspiration biopsy (FNAB) examination of indeterminate follicular thyroid lesions were examined over a 4-year period. The prevalence of malignancy on final histology was determined in 4 indeterminate cytologic categories. A total of 107 records were available (91 women, 16 men). The mean patient age was 45.4 +/- 16 years. Forty-eight patients (45%) underwent surgery and had histopathologic diagnosis, while 57 patients did not have surgery. The prevalence of malignancy in patients who underwent thyroidectomy was 42% (20 of 48). The high prevalence of malignancy within indeterminate follicular lesions may necessitate thyroidectomy for patients with indeterminate follicular lesions on FNAB examination.


MR cholangiopancreatography at 0.5 T with a 3D inversion recovery turbo-spin-echo sequence.
The objective of this study was to assess the diagnostic value of magnetic resonance cholangiopancreatography (MRCP) at 0.5 T. The MRCP technique was performed in 28 patients with symptomatology referrable to the biliary system. A three-dimensional (3D) inversion recovery turbo-spin-echo (TSE) sequence was used to create 3D reconstructions of the bile ducts. Dilation of the biliary tree or pancreatic duct in 23 patients due to tumor, calculi, or strictures was depicted with excellent contrast resolution. The approximate level of obstruction and all calculi were accurately predicted by MRCP. In another 3 patients no cause was found for the biliary dilatation. In the last 2 cases no abnormalities were found by either MRCP or endoscopic retrograde cholangiopancreatography (ERCP). The MRCP technique at 0.5 T is an accurate method for the assessment of pathology of the biliary tree.


GHR-/- Mice are protected from obesity-related white adipose tissue inflammation.
Growth hormone (GH) excess in bovine (b)GH transgenic mice has been shown to alter white adipose tissue (WAT) immune cell populations. The present study aimed to evaluate the effects of GH resistance on WAT immune cell populations using GH receptor knockout (GHR-/- ) mice. Eight- and 24-month-old, male GHR-/- and wild-type mice were used. Body composition and tissue weights were determined, and systemic inflammation was assessed by measuring serum cytokine levels. The stromal vascular fraction (SVF) was isolated from three distinct WAT depots, and immune cell populations were quantified using flow cytometry. GHR-/- mice at both ages had decreased body weight but were obese. Although no significant changes were observed in serum levels of the measured cytokines, SVF cell alterations were seen and differed from depot to depot. Total SVF cells were decreased in epidydimal (Epi) depots, whereas SVF cells per gram adipose tissue weight were increased in mesenteric (Mes) depots of GHR-/- mice relative to controls. T cells and T helper cells were increased in Mes at 8 months old, whereas cytotoxic T cells were decreased in subcutaneous (SubQ) at 24 months old. Other cells were unchanged at both ages measured. The present study demonstrates that removal of GH action results in modest and depot-specific changes to several immune cell populations in WAT of intra-abdominal depots (Epi and Mes), which are somewhat surprising results because the SubQ has the largest change in size, whereas the Mes has no size change. Taken together with previous results from bovine GH transgenic mice, these data suggest that GH induces changes in the immune cell population of WAT in a depot-specific manner. Notably, GHR-/- mice appear to be protected from age-related WAT inflammation and immune cell infiltration despite obesity.


Diagnosis and treatment of drug and alcohol abuse in women.
The major reasons why women abuse drugs and alcohol are presented with a focus on societal and psychologic bases. A structured format is provided for eliciting a history while motivating the patient to obtain adequate treatment. A workable treatment contract is presented. A three-stage method of treatment is described, which focuses on the following: (1) achieving abstinence, (2) maintaining abstinence, and (3) achieving sobriety (advanced recovery).


Functional connectomes incorporating phase synchronization for the characterization and prediction of individual differences.
Functional connectomes have been proven to be able to predict an individual's traits, acting as a fingerprint. A majority of studies use the amplitude information of fMRI signals to construct the connectivity but it remains unknown whether phase synchronization can be incorporated for improved prediction of individual cognitive behaviors. In this paper, we address the issue by extracting phase information from the fMRI time series with a phase locking approach, followed by the construction of functional connectomes. We first examine the identification and prediction performance using phase-based profiles in comparison with amplitude-based connectomes. We then combine both phase-based and amplitude-based connectivity to extract subject-specific information enabled by the phase synchronization. Results show that high individual identification rates (from 82.7% to 92.6%) can be achieved by phase-based connectomes. Phase-based connectivity offers unique information complementary to amplitude-based signals. Intra-network phase-locking appears more informative for individual prediction. In addition, phase synchronization can be used to predict cognitive behaviors. The amplitude-based connectivity cannot capture the subject-specific information due to neural synchronization. The comparison with other phase-based methods has been involved in the discussion session. Our findings suggest that neural synchronization carries subject-specific information, which can be captured by phase locking value. The incorporation of phase information into connectomes presents a promising approach to understand each individual brain's uniqueness.


Home-made spacer as an auxiliary device in administration of beclomethasone via pressurized metered dose inhaler for asthma control. A randomized controlled pragmatic trial.
Holding chambers or spacers can enhance the efficacy of pressurized metered dose inhalers (pMDI) in delivering inhaled medications, as they reduce the need for hand-breath coordination and improve lower airways deposition. Nevertheless, their cost can be high for patients in low-income countries. To compare asthma control achieved with beclomethasone-dipropionate administered through a hydrofluoroalkane-driven pMDI (BDp-pMDI) coupled to a home-made spacer (HmS) or to a valved commercial spacer (VCS) as auxiliary devices. Sixty-three patients with poorly controlled asthma that had a BDp-pMDI prescription were randomized to use the inhaler coupled to a HmS made of 500 ml plastic bottles (Group HmS, n = 32) or to a VCS (Group VCS, n = 31) for 60 days. All were given training sessions. Asthma control was assessed through the Asthma Control Test (ACT) and forced expiratory volume in the first second (FEV1), both measured before, and 30 and 60 days after treatment began. Both groups showed significant improvement in ACT scores after 30 and 60 days compared to baseline values (an increase of 7 and 7.8 points for the HmS group and 5.9 and 7.0 points for the VCS group, respectively, p < 0.001). There was no statistically significant difference in ACT scores between groups at any observation time (P = 0.261). FEV1 showed the same behavior. A similar level of asthma control was achieved with beclomethasone-dipropionate administered through a pMDI whether the inhaler was coupled to the HmS or VCS. These results are significant for asthma control planning strategies in low-income communities. (Trial Register Number: RBR-5x4dc9).


Patterns of membrane organization in toad bladder epithelium: a freeze-fracture study.
Two cell-types of toad bladder epithelium show uncommon plasma membrane organization in freeze-fractured specimens. One type, the granular cell, contains a plasma membrane in which the A-face is poorly particulate luminally while the B-face discloses multiple large particles at this site. In contrast, the lateral and basal portions of the granular-cell membrane are typical in that more particles occupy the A-face than the B-face. In the other cell-type, which is mitochondria-rich, the plasma membrane, luminally, laterally, and basally, contains rod-shaped and a few globular particles in the A-face. We suggest that these two peculiar membrane organizations be considered in the localization of both vasopressin and aldosterone action in toad bladder.


IMCI and ETAT integration at a primary healthcare facility in Malawi: a human factors approach.
Integrated Management of Childhood Illness (IMCI) and Emergency Triage, Assessment and Treatment (ETAT) are guidelines developed by the World Health Organization to reach targets for reducing under-5 mortality. They were set out in the Millennium Development Goals. Each guideline was established separately so the purpose of this study was to understand how these systems have been integrated in a primary care setting and identify barriers and facilitators to this integration using a systems approach. Interviews were carried out with members of staff of different levels within a primary healthcare clinic in Malawi. Along with observations from the clinic this provided a well-rounded view of the running of the clinic. This data was then analysed using the SEIPS 2.0 work systems framework. The work system elements specified in this model were used to identify and categorise themes that influenced the clinic's efficiency. A process map of the flow of patients through the clinic was created, showing the tasks undertaken and the interactions between staff and patients. In their interviews, staff identified several organisational elements that served as barriers to the implementation of care. They included workload, available resources, ineffective time management, delegation of roles and adaptation of care. In terms of the external environment there was a lack of clarity over the two sets of guidelines and how they were to be integrated which was a key barrier to the process. Under the heading of tools and technology a lack of guideline copies was identified as a barrier. However, the health passport system and other forms of recording were highlighted as being important facilitators. Other issues highlighted were the lack of transport provided, challenges regarding teamwork and attitudes of members of staff, patient factors such as their beliefs and regard for the care and education provided by the clinic. This study provides the first information on the challenges and issues involved in combining IMCI and ETAT and identified a number of barriers. These barriers included a lack of resources, staff training and heavy workload. This provided areas to work on in order to improve implementation.


Acceptability and applicability of biometric iris scanning for the identification and follow up of highly mobile research participants living in fishing communities along the shores of Lake Victoria in Kenya, Tanzania, and Uganda.
Recruitment and retention of participants in research studies conducted in fishing communities remain a challenge because of population mobility. Reliable and acceptable methods for identifying and tracking participants taking part in HIV prevention and treatment research are needed. The study aims to assess the acceptability, and technical feasibility of iris scans as a biometric identification method for research participants in fishing communities. This was a cross-sectional study conducted in eight fishing communities in Kenya, Tanzania, and Uganda, with follow-up after one month in a randomly selected subset of participants. All consenting participants had their iris scanned and then responded to the survey. 1,199 participants were recruited. The median age was 33 [Interquartile range (IQR) 24-42] years; 56% were women. The overall acceptability of iris scanning was 99%, and the success rate was 98%. Eighty one percent (n = 949) had a successful scan on first attempt, 116 (10%) on second and 113 (9%) after more than two attempts. A month later, 30% (n = 341) of participants were followed up. The acceptability of repeat iris scanning was 99% (n = 340). All participants who accepted repeat iris scanning had successful scans, with 307 (90%) scans succeeding on first attempt; 25 (7%) on second attempt, and 8 (2%) after several attempts. The main reason for refusing iris scanning was fear of possible side effects of the scan on the eyes or body. The acceptability and applicability of biometric iris scan as a technique for unique identification of research participants is high in fishing communities. However, successful use of the iris scanning technology in research will require education regarding the safety of the procedure.


Effect of cytotoxic antineoplastic chemotherapy on immunoregulatory leukocytes measured with monoclonal antibodies.
The influence of cytotoxic chemotherapy on immunoregulatory leukocyte subsets measured by monoclonal antibodies was evaluated in the peripheral blood mononuclear cells from 15 patients with nonlymphoreticular solid tumors. The results obtained were correlated to changes in sheep erythrocyte-receptor-bearing T cells, active T cells, and latex-ingesting cells; also, these leukocyte values were correlated with changes in phytohemagglutinin (PHA)-induced lymphoproliferative responses and indomethacin-sensitive suppressor cell function. The results obtained demonstrated the cytotoxic chemotherapy did not consistently influence percentages of T cells whether these were measured as sheep erythrocyte-binding cells or as OKT.3+ cells. Similarly, consistent effects on OKT4 and OKT8 cells were not observed. Chemotherapy often led to suppression of the OKT4/OKT8 ratio and tended to restore abnormal percentages of active T cells at some point following initiation of drug treatment. The effects of chemotherapy on these leukocyte values could not be consistently correlated with changes in PHA-induced lymphocyte DNA synthesis or indomethacin-sensitive regulation of PHA reactivity.


Drug-induced changes of adenylate cyclase activity in cells from asthmatic and nonasthmatic subjects.
Monolayers of adherent mononuclear leukocytes prepared from normal subjects and asthmatic children whose bronchodilater therapy did not include sympathomimetic drugs, respond to relatively low concentrations of isoproterenol (ISO) and prostaglandin E1 with increased intracellular cyclic adenosine monophosphate (cAMP) levels. The magnitude of in vitro responses to ISO is decreased by previous contact of the cells with ISO or other, orally effective, adrenergic drugs. The desensitization is rapid, concentration- and time-dependent, and is readily reversible after removal of the desensitizing drug. The phenomenon exhibits pharmacologic specificity. Cells in which the response to restimulation with ISO was decreased exhibited full sensitivity to prostaglandin E1. No differences in these behaviors were detected in cells from normal or asthmatic subjects. The results suggest that earlier observations reporting decreased responses to beta adrenergic stimulation in asthmatics may have been due to the treatment of these patients with sympathomimetic agents and not caused by a disease-related beta adrenergic receptor dysfunction.


Coexistence of a pseudolesion and a true lesion in the same location: a rare misleading imaging finding.
Congenital cholesteatoma and asymmetric fatty marrow are both common masses that appear as imaging "lesions" in the petrous apex, but their treatment modalities are very different. Accurate preoperative recognition by computed tomography and magnetic resonance imaging is, therefore, important for planning appropriate management strategies. We report a case with coexisting congenital cholesteatoma and asymmetric fatty marrow in the same petrous bone. The 2 lesions were indistinguishable on high-resolution computed tomographic images and were only identified on fat-suppressed magnetic resonance imaging sequences. This is the first report of these 2 lesions coexisting, leading to a rare misleading imaging finding.


The fate of the internalized apelin receptor is determined by different isoforms of apelin mediating differential interaction with beta-arrestin.
Internalization of the apelin receptor by apelin-13 is characterized by dissociation from beta-arrestins and rapid recycling to the cell surface. Paradoxically, the apelin receptor internalized by apelin-36 was sequestered intracellularly. The specific pathways involved in apelin receptor trafficking were resolved using beta-arrestin1 and constitutively active and dominant negative Rab proteins following activation by apelin-13 or apelin-36. beta-Arrestin1 dissociated from the apelin-13-internalized receptor while the apelin-36-internalized receptor was trafficked with beta-arrestin1 to intracellular compartments. The apelin-13-internalized receptor was rapidly recycled to the cell surface through a Rab4-dependent mechanism while Rab7 targeted the receptor to lysosomes. The internalized receptor co-expressed with dominant negative Rab4 were trafficked to lysosomes. These observations revealed a novel ligand-dependent targeting of the apelin receptor to beta-arrestin-associated and -dissociated trafficking pathways and a role for different Rab proteins to direct these pathways.


A European household waste management approach: Intelligently clean Ukraine.
The European-wide environmental obstacles of inefficient and unsustainable recycling systems and flows constrain household waste (HW) management, endangering the circular economy. The European 2020 strategy and ongoing environmental disasters indicate the ineffectiveness of the current HW sustainability practices. This paper introduces an artificial intelligence (AI) approach for calculating urban residual waste, based on its generation level. It reforms the current diverse and high discrepancy levels of HW residual for EU-countries and Ukraine. Adopting a k-means clustering method with a multi-criteria taxonomic development level index (TIDL), it produces uniform clusters with higher accuracy and manageability. Findings discover and remedy opaque managerial practices, enabling sustainable and environment-friendly development at national and regional levels for EU-countries. Results reveal an increased number of clusters in crisis, contributing to a methodological reference for environmental planning. In conclusion, this AI approach could have a European-wide impact on sustainable economic value-chain, converging toward an eco-friendly economy.


A novel hydrazone-based fluorescent "off-on-off" probe for relay sensing of Ga3+ and PPi ions.
A novel hydrazone-based fluorescent probe (E)-3-((2-(benzo[d]thiazol-2-yl)hydrazono)methyl)-4H-chromen-4-one (BTC) has been rationally designed and synthesized. BTC can subsequently detect Ga3+ and PPi ions through the absorption and emission off-on-off response with high specificity. Importantly, fluorescent probe BTC can well discriminate Ga3+ from Al3+ and In3+. The association constant (K) was calculated as 2.06 × 104M-1, and the limit of detection (LOD) was calculated as 4.88 × 10-2μM. Competitive binding studies also illustrated good results of the probe BTC towards Ga3+. Job's plot and HRMS results substantiated the 1:1 stoichiometry between BTC and Ga3+ ion. The interaction binding mode of BTC with Ga3+ was proposed by HRMS, 1H NMR spectral titration, UV-vis absorption and fluorescence spectral measurements. The combination of the restraint of the photo-induced electron transfer (PET) process and the chelation enhanced fluorescence (CHEF) process is responsible for the fluorescence enhancement of this probe. The in situ chelated BTC-Ga3+ could further monitor pyrophosphate ion (PPi) by demetallization process with quenching fluorescence emission. Additionally, the BTC and BTC-Ga3+ showed good cell permeability and could detect Ga3+ and PPi ions in onioninner epidermal cells, respectively.


Echo-Doppler evaluation of acute flow changes in portal hypertensive patients: flow velocity as a reliable parameter.
In order to evaluate the behavior of the portal vein cross-sectional area during changes in portal flow, two groups of subjects were analyzed in two blinded cross-over studies using echo-Doppler flowmetry. The first group (I) consisted of 21 patients with cirrhosis and 16 controls. They received a standardized meal which is known to increase portal flow. The second group (II) consisted of 31 patients with cirrhosis who received a dose of propranolol which is known to decrease portal flow. In Group I, 30 min after the meal, the portal vein blood velocity increased by 35 +/- 6% (p less than 0.01) in cirrhotic patients and by 55 +/- 5% (p less than 0.01), in normal subjects. The portal vein cross-sectional area increased significantly in normal subjects (22 +/- 2%, p less than 0.01) but not in cirrhotic patients (4 +/- 2%, n.s.). In Group II, 2 h after propranolol, there was a significant decrease in portal blood velocity (-14 +/- 2%), whereas the portal vein cross-sectional area did not show any significant changes. These data demonstrate that, in portal hypersensitive patients, the portal area measured by echo-Doppler flowmetry can be assumed to be constant and hence its calculation to estimate changes in portal blood flow can be omitted. Therefore, the use of blood velocity alone is suggested to monitor acute changes in flow in portal hypertension using Doppler flowmetry. The elimination of the portal vein cross-sectional area measurement simplifies the quantitative calculation of portal hemodynamics and increases the reliability of the technique by avoiding a source of error.


Patterns of change in endoneurial capillary permeability and vascular space during nerve regeneration.
In frog sciatic nerve crushed and allowed to regenerate, an in situ perfusion technique was used to measure the permeability coefficient-surface area product (PS) of endoneurial capillaries to [14C]sucrose and endoneurial vascular space (V) at intervals of 3 days to 12 weeks post-crush. Additionally, the amplitude and latency of the compound action potential (CAP) of the regenerating nerve were also monitored. There was a delayed increase of both PS and V which peaked at 2-3 weeks after the crush and then declined. This is strikingly similar to the pattern seen in transected nerves. Whereas both PS and V reached near normal levels 6 weeks after transection, in regenerating nerves V continued toward normal levels but PS increased again to peak around 9 weeks post-crush. This second peak of PS coincided with a rapid increase of the CAP amplitude and a sharp decline of its latency. As is the case for transected nerves, the initial increase of PS is probably induced by breakdown products of axons or chemical signals from attendant Schwann cells and related to the clearance of debris from the endoneurium. The later increase of PS may be an endoneurial homeostatic mechanism to increase blood-nerve exchange during rapid axonal growth and remyelination.


Temperature dependence of fast carbonyl backbone dynamics in chicken villin headpiece subdomain.
Temperature-dependence of protein dynamics can provide information on details of the free energy landscape by probing the characteristics of the potential responsible for the fluctuations. We have investigated the temperature-dependence of picosecond to nanosecond backbone dynamics at carbonyl carbon sites in chicken villin headpiece subdomain protein using a combination of three NMR relaxation rates: (13)C' longitudinal rate, and two cross-correlated rates involving dipolar and chemical shift anisotropy (CSA) relaxation mechanisms, (13)C'/(13)C'-(13)C(α) CSA/dipolar and (13)C'/(13)C'-(15)N CSA/dipolar. Order parameters have been extracted using the Lipari-Szabo model-free approach assuming a separation of the time scales of internal and molecular motions in the 2-16°C temperature range. There is a gradual deviation from this assumption from lower to higher temperatures, such that above 16°C the separation of the time scales is inconsistent with the experimental data and, thus, the Lipari-Szabo formalism can not be applied. While there are variations among the residues, on the average the order parameters indicate a markedly steeper temperature dependence at backbone carbonyl carbons compared to that probed at amide nitrogens in an earlier study. This strongly advocates for probing sites other than amide nitrogen for accurate characterization of the potential and other thermodynamics characteristics of protein backbone.


In situ condensation of an anti-cancer drug into fibrin gel enabling effective inhibition of tumor cell growth.
We show herein the highly effective inhibition of tumor cell growth using a gel consisting of a fibrin polymer formed with the in situ condensation of a camptothecin (CPT) derivative as an anti-cancer drug, which is efficiently conveyed with a carrier aptamer from a solution to the gel in a phenomenon, called selective oligonucleotide entrapment in fibrin polymers (SOEF).


Renal outcomes of idiopathic and atypical membranous nephropathy in adult Chinese patients: a single center retrospective cohort study.
Membranous nephropathy (MN) is mainly classified into idiopathic MN (iMN) and secondary MN in etiology. In recent years, a new kind of membranous nephropathy, atypical membranous nephropathy (aMN) which shows "full house" in immunofluorescence but without definite etiology was paid more attention. In a single center cohort, the renal outcomes of iMN and aMN were compared. iMN and aMN patients were selected from renal pathology databank from January 2006 to December 2015. Patients' demographics, laboratory values, induction regimens and patients' responses were recorded. Specially, creatinine, eGFR, albumin and 24 h urinary protein excretion were recorded at 6th month after the induction of immunosuppressive (IS) treatment and at the end of follow up. Complete proteinuria remission was defined as urinary protein < 0.3 g/d, partial proteinuria remission was defined as urinary protein between 0.3 g/d ~ 3.5 g/d and decreased > 50 % from the baseline. The primary outcome was worsening renal function, defined as a 30 % or more decrease in eGFR or end-stage renal disease (eGFR < 15ml/min/1.73m2). COX proportional hazard models were used to test if aMN was a risk factor of worsening renal function compared with iMN. There were 298 patients diagnosed with MN and followed in our center for 1 year or more, including 145 iMN patients with an average follow-up time of 4.5 ± 2.6 years, and 153 aMN patients with 4.1 ± 2.0 years (p = 0.109). The average age of iMN patients was older than aMN patients (56.1 ± 12.2 versus 47.2 ± 16.2 years old, p < 0.001). There were 99 iMN patients and 105 aMN patients with nephrotic range proteinuria and without previous immunosuppressive treatment. 93 (93.9 %) and 95 (90.5 %) patients underwent immunosuppressive treatment in iMN and aMN group, and there was no significant difference of the overall proteinuria remission rates at 6th month (59.1 % vs. 52.0 %, p = 0.334) and endpoint (73.7 % vs. 69.5 %, p = 0.505) between the two groups. 25 (25.3 %) patients in iMN group and 21 (20.0 %) patients in aMN group reached primary endpoint (X2 = 0.056, p = 0.812). Multivariate COX regression showed that after demographics, baseline laboratory values and remission status at 6th month were adjusted, aMN group had similar renal outcome compared with iMN group, the HR of primary outcome was 0.735 (95 % CI 0.360 ~ 1.503, p = 0.399). The proteinuria remission rates and renal outcomes were similar in iMN and aMN patients after covariables were adjusted.


Increased serum cancer antigen-125 is a marker for severity of deep endometriosis.
To determine whether cancer antigen-125 (CA-125) levels are increased in women with endometriosis, especially in those with endometriomas (OMAs), deep infiltrating lesions (DIE), and superficial endometriosis (SUP) compared with controls without endometriosis in a large cohort of operated women. Cross-sectional study (Canadian Task Force classification II-2). Tertiary-care university hospital. Four hundred six women with histologically proven endometriosis and 279 women without endometriosis. Surgical examination of the abdomino-pelvic cavity. Preoperative serum CA-125 antigen levels were evaluated by electrochemoluminescence immunoassay in women with endometriosis and controls. Correlations between serum CA-125 levels and clinical and anatomical characteristics of disease severity were examined. Women with endometriosis displayed higher mean serum CA-125 levels compared with disease-free controls (50.1 ± 62.4 U/mL vs 22.5 ± 25.2 U/mL; p ≤ .001). CA-125 levels were significantly increased in women with OMA (60.8 ± 63.5 U/mL) and DIE (55.2 ± 68.7 U/mL) compared with women with SUP (23.2 ± 24.5 U/mL) and controls (22.5 ± 25.2 U/mL). There was no difference in CA-125 levels between patients with SUP and controls and between patients with OMA and DIE. CA-125 serum levels were correlated with DIE severity: the mean number of DIE lesions and worst DIE lesion. Serum CA-125 levels were significantly increased in women with severe forms of endometriosis, OMA, and DIE lesions. In addition, elevated serum Ca-125 levels were associated with more severe and extended DIE lesions. In women with superficial peritoneal lesions, CA-125 levels were not different from women without endometriosis.


Optimization of heterologous Darobactin A expression and identification of the minimal biosynthetic gene cluster.
Darobactin A (DAR) is a ribosomally synthesized and post-translationally modified peptide (RiPP) antibiotic, which was initially identified from bacteria belonging to the genus Photorhabdus. In addition, the corresponding biosynthetic gene cluster (BGC) was identified and subsequently detected in several bacteria genera. DAR represents a highly promising lead structure for the development of novel antibacterial therapeutic agents. It targets the outer membrane protein BamA and is therefore specific for Gram-negative bacteria. This, together with the convincing in vivo activities in mouse infection models, makes it a particular promising candidate for further research. To improve compound supply for further investigation of DAR and to enable production of novel derivatives, establishment of an efficient and versatile microbial production platform for these class of RiPP antibiotics is highly desirable. Here we describe design and construction of a heterologous production and engineering platform for DAR, which will ensure production yield and facilitates structure modification approaches. The known Gram-negative workhorses Escherichia coli and Vibrio natriegens were tested as heterologous hosts. In addition to that, DAR producer strains were generated and optimization of the expression constructs yielded production titers of DAR showing around 10-fold increase and 5-fold decrease in fermentation time compared to the original product description. We also report the identification of the minimal DAR BGC, since only two genes were necessary for heterologous production of the RiPP.


Quantitation of deoxyribonucleoside 5'-triphosphates by a sequential boronate and anion-exchange high-pressure liquid chromatographic procedure.
A rapid method for the quantitative determination of cellular deoxyribonucleoside 5'-triphosphates is described. Cell extracts are first separated by boronate chromatography at pH 8.9, which removes 99% of the ribonucleoside triphosphate (rNTPs) from the deoxyribonucleoside triphosphates (dNTPs). The resulting dNTP fraction is analyzed by gradient high-pressure liquid chromatography utilizing a strong anion-exchange column, which can separate minor rNTP peaks from the corresponding dNTPs. This sequential procedure, which requires less than 1 h per sample for both chromatographic steps, results in the quantitative recovery of greater than 98% of the dNTPs from cell extracts. Nucleotide analogs, such as 1-beta-D-arabinofuranosylcytosine-5'-triphosphate and 5-bromo-2'-deoxyuridine-5'-triphosphate, can also be quantitated efficiently by this method.


Selective transport of ions and molecules across layer-by-layer assembled membranes of polyelectrolytes, p-sulfonato-calix[n]arenes and Prussian Blue-type complex salts.
Our recent studies in the field of ultrathin membranes prepared upon layer-by-layer assembly of various polyionic compounds such as polyelectrolytes, calixarenes and polyelectrolytes, and metal hexacyanoferrate salts such as Prussian Blue are reviewed. It is demonstrated that polyelectrolyte multilayers can be used (a) as nanofiltration and reverse osmosis membranes suitable for water softening and seawater desalination and (b) as molecular sieves and ion sieves for size-selective separation of neutral and charged aromatic compounds. Furthermore, hybrid membranes of p-sulfonato-calixarenes and cationic polyelectrolytes showing specific host-guest interactions with permeating ions are described. The membranes exhibit high selectivities for distinct metal ions. Finally, it is demonstrated that purely inorganic membranes of Prussian Blue (PB) and analogues can be prepared upon multiple sequential adsorption of transition metal cations and hexacyanoferrate anions. Due to the porous lattice of PB, the membranes are useful as ion filters able to separate cesium from sodium ions, for example.


Novel magnetically retrievable In2O3/MoS2/Fe3O4 nanocomposite materials for enhanced photocatalytic performance.
The current work involves synthesis of hybrid nanomaterial of In2O3/MoS2/Fe3O4 and their applications as photocatalysts for disintegration of esomeprazole under visible light illumination. The data emerged from various analyses testified to the successful construction of the desired nano-scaled hybrid photocatalyst. Tauc plot gave the band gap of In2O3/MoS2/Fe3O4 to be ~ 2.15 eV. Synergistic effects of the integrant components enabled efficacious photocatalytic performances of the nanocomposite. The nanohybrid photocatalyst In2O3/MoS2/Fe3O4 showed photodecomposition up to ~ 92.92% within 50 min. The current work realizes its objective of constructing metal oxide based hybrid nano-photocatalyst supported on MoS2 sheets for activity in the visible spectrum, which displayed remarkable capacity of disintegrating emerging persistent organic contaminants and are magnetically recoverable.


Clinical significance of late potential in patients with Duchenne muscular dystrophy.
The relationship between late ventricular potentials (LP) and myocardial ischemic changes or ventricular arrhythmias was investigated in patients with Duchenne muscular dystrophy (DMD). Twenty-six DMD patients aged 10-33 years (mean 18.2 years) and 27 age-matched healthy volunteers were studied. Ventricular arrhythmias were detected by 24-h Holter ECGs and LPs were determined using signal-averaged ECGs. In DMD patients filtered QRS duration, late duration, and low-amplitude signal under 40 microV were significantly prolonged compared with those of the controls. The root mean square voltage of the f-QRS complex in the last 40 ms was lower in DMD patients than in the controls. None of the control subjects had LP. However, LP was detected in 8 (31%) of the 26 DMD patients. The patients with LP had more frequent ST-T depression and ventricular arrhythmias than the patients without LP. LP had 60% sensitivity and 87% specificity for documented ventricular arrhythmias. It is concluded that LP in DMD patients indicates the presence of substrate for ventricular arrhythmias associated with local myocardial fibrosis, and is useful in identifying those at high risk for malignant ventricular arrhythmias.


Cumulative organic anion transporter-mediated drug-drug interaction potential of multiple components in salvia miltiorrhiza (danshen) preparations.
To evaluate organic anion transporter-mediated drug-drug interaction (DDI) potential for individual active components of Danshen (Salvia miltiorrhiza) vs. combinations using in vitro and in silico approaches. Inhibition profiles for single Danshen components and combinations were generated in stably-expressing human (h)OAT1 and hOAT3 cells. Plasma concentration-time profiles for compounds were estimated from in vivo human data using an i.v. two-compartment model (with first-order elimination). The cumulative DDI index was proposed as an indicator of DDI potential for combination products. This index was used to evaluate the DDI potential for Danshen injectables from 16 different manufacturers and 14 different lots from a single manufacturer. The cumulative DDI index predicted in vivo inhibition potentials, 82% (hOAT1) and 74% (hOAT3), comparable with those observed in vitro, 72 ± 7% (hOAT1) and 81 ± 10% (hOAT3), for Danshen component combinations. Using simulated unbound Cmax values, a wide range in cumulative DDI index between manufacturers, and between lots, was predicted. Many products exhibited a cumulative DDI index > 1 (50% inhibition). Danshen injectables will likely exhibit strong potential to inhibit hOAT1 and hOAT3 function in vivo. The proposed cumulative DDI index might improve prediction of DDI potential of herbal medicines or pharmaceutical preparations containing multiple components.


Enhanced acquisition of reversal training in a spatial learning task in rats treated with chronic nimodipine.
Nimodipine levels were measured in blood and brain of rats implanted SC with sustained-release pellets of nimodipine (0, 10, 20, or 40 mg). Dose-dependent levels of nimodipine were detected in both plasma and brain. These results indicated the possible usefulness of these pellets in behavioral studies where long-term treatment is required. Therefore, the effects of chronic nimodipine, using 40-mg pellets, were examined on the performance of young, middle-aged, and aged rats in the Morris water maze. Following implantation of either nimodipine or placebo pellets, rats were trained for 6 days (three sessions/day) followed by 6 days of reversal training. During both initial and reversal training, every sixth trial was a probe trial. During initial training, there were clear age-related acquisition deficits in place training, with no effects of chronic nimodipine. Nimodipine did, however, enhance performance of rats during the first and second probe trials of reversal training. Time spent in the training quadrant by nimodipine-treated rats was approximately 30% longer on the first reversal probe and 35% longer on the second reversal probe than time spent in this quadrant by placebo-treated animals. These results indicate that chronic nimodipine enhances the performance of normal animals in reversal training on a spatial learning task.


The emergence of rare nocardiosis following allogeneic hematopoietic stem cell transplantation in the era of molecular taxonomy.
The purpose of this study was to describe the clinical features of nocardiosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT), focusing on new Nocardia species. We retrospectively reviewed data from patients with nocardiosis after allo-HSCT treated at our hospital and documented cases in the medical literature. Fifty-seven cases were identified from our institution and the literature review. Although 51 patients (89.5%) responded to initial treatment, 28 (49.1%) patients were switched over to other treatment regimens due to the recurrence of nocardiosis or adverse events of antimicrobials. Nocardiosis-attributed mortality occurred in ten patients (17.5%). Antimicrobial susceptibilities varied among intra- and inter-species except linezolid (LZD). In the present study, five species were newly discovered after 2000, including N. cyriacigeorgica, N. veterana, N. abscessus, N. aobensis, and N. mexicana. All isolates of N. cyriacigeorgica, N. veterana, N. abscessus, and N. aobensis were sensitive to trimethoprim/sulfamethoxazole, amikacin (AMK), imipenem (IPM), and LZD; however, N. mexicana was resistant to AMK and IPM. Newly identified Nocardia species have various antimicrobial susceptibility patterns. Long-term maintenance therapy could be challenging due to the adverse events of antimicrobials, especially in the allo-HSCT setting. Prudent evaluation is crucial for selecting a second-line or further treatment options.


Anastomotic compression button: a new mechanical device for sutureless bowel anastomosis.
The anastomotic compression button is a new mechanical device that uses three interlocking polypropylene buttons to produce a sutureless bowel anastomosis. The device is unique in that it allows application of the buttons via a device similar to the popular intraluminal stapler, but it leaves no staples or foreign body of any kind in the bowel wall. The authors compared the 25-mm anastomotic compression button with the 25-mm intraluminal stapler in the colon of dogs. After 28 days, the mucosal blood flow, burst pressure, and anastomotic indices were found to be identical between the anastomotic compression button and the stapler. The anastomotic compression button was easier to use, and microscopic examination showed less ulceration, fibrosis, and inflammation, and better re-epithelialization at the anastomotic compression button site. The anastomotic compression button appears to have the potential to be a superior method compared with stapled anastomoses in the colon.


Accuracy and reproducibility of conclusions by forensic bloodstain pattern analysts.
Although the analysis of bloodstain pattern evidence left at crime scenes relies on the expert opinions of bloodstain pattern analysts, the accuracy and reproducibility of these conclusions have never been rigorously evaluated at a large scale. We investigated conclusions made by 75 practicing bloodstain pattern analysts on 192 bloodstain patterns selected to be broadly representative of operational casework, resulting in 33,005 responses to prompts and 1760 short text responses. Our results show that conclusions were often erroneous and often contradicted other analysts. On samples with known causes, 11.2% of responses were erroneous. The results show limited reproducibility of conclusions: 7.8% of responses contradicted other analysts. The disagreements with respect to the meaning and usage of BPA terminology and classifications suggest a need for improved standards. Both semantic differences and contradictory interpretations contributed to errors and disagreements, which could have serious implications if they occurred in casework.


Body mass index, functional disability and all-cause mortality in 330 000 older adults: The Shizuoka study.
A J-shaped association has been observed between body mass index (BMI) and all-cause mortality, but its relationship with functional disability is uncertain. We aim to clarify the association between BMI and functional disability, as well as all-cause mortality, by analyzing prefecture-wide annual health checkup data, and health and care insurance data. The dataset analyzed in this study consisted of 332 405 community residents aged ≥65 years who subscribed to the National Health Insurance. Basic clinical information was obtained from the annual health checkup data. The presence of comorbidities at baseline and the incidence of functional disability and all-cause mortality were obtained from the health insurance data. The mean age and standard deviation of the study participants was 73.5 ± 6.0 years. During a 4-year follow-up period, we observed 31 508 incident cases of functional disability and 16 640 deaths. The incidence rates of functional disability and all-cause mortality were higher in both lower and higher BMI subgroups, and the lowest risk was observed in the range of 21-27 kg/m2 in men and 20-25 kg/m2 in women. These associations were independent of age, sex, current smoking and possible confounding factors, including a cardiovascular diseases history, hospitalization during the half-year period before baseline, and baseline comorbidities. A similar association was observed between BMI and all-cause mortality even when individuals who developed functional disabilities before death were excluded from the analysis. Maintaining the bodyweight within the recommended range could be an effective method of reducing the risk of functional disability and mortality. Geriatr Gerontol Int 2021; 21: 1040-1046.


Effects of donor age on osteogenic cells of rat bone marrow in vitro.
The effect of donor age on the production of bone-like tissue and expression of cellular alkaline phosphatase was examined in cultures of cells obtained from rat bone marrow. Stromal cells were obtained from the bone marrow of young (5-6 weeks) and old (18 months) rats and cultured in vitro. After 28 days in first subculture, the following were quantified: (1) the total number of mineralised nodules and the size distribution of nodules and (2) the density of osteoblasts and osteocytes associated with nodules in histological sections. The doubling times of the cultures and the numbers of cells in cultures which expressed alkaline phosphatase activity were determined in separate experiments. Cells from young cultures produced three times more bone-like nodules than old cultures, although no differences were seen in the size distribution of nodules, or on osteoblast and osteocyte density. Doubling times for both groups were similar. The numbers of alkaline phosphatase (AP) positive cells was reduced by half in old cultures. These data show that this model may be useful for the study of the mechanisms of ageing on osteogenesis, and demonstrate a reduced osteogenic capacity in old cultures. The results suggest that this effect may be due to a reduction in the generation of cells of osteoblast lineage during ageing.


4'-epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data.
4'-epi-doxorubicin (4'-epi-DX) is a new anthracycline antibiotic. It differs from doxorubicin (DX) by the epimerization of the OH group in position 4' of the aminosugar moiety, and was synthesized in an effort to find agents with a superior therapeutic index to the parent compound doxorubicin (DX). 4'-epi-doxorubicin binds to DNA and inhibits nucleic acid synthesis and function. The antitumor activity of 4'-epi-DX in several experimental tumors (Leukemias L 1210, P 388, Gross Leukemia, Sarcoma 180 ascitic and solid, C3H/HE mammary carcinoma) is similar to that of DX. However, 4'-epi-doxorubicin has greater antitumor activity than doxorubicin in Lewis lung carcinoma, MS-2 sarcoma lung metastasis, and human melanoma in athymic mice. In chronic toxicity studies there were no qualitative differences between 4'-epi-DX and DX; quantitatively, however, 4'-epi-DX was less toxic. In different experimental models 4'-epi-DX has been shown to be less cardiotoxic than its parent compound. In chronic toxicity studies in the rabbit, histopathologic findings revealed the same pattern of cardiotoxicity for both drugs but less marked with 4'-epi-DX. Distribution studies in mice with tumors showed a lower concentration of 4'-epi-DX in the heart, spleen and kidneys; the hepatobiliary metabolism and excretion of 4'-epi-DX investigated in the rat, indicated that the new analogue was more extensively metabolized than the parent compound. Pharmacokinetics of 4'-epi-DX in humans showed a multiexponential decrease of plasma levels; the same pattern was observed for the metabolite 13-OH epidoxorubicinol but with lower concentrations than the unchanged drug. A high plasma clearance (0.9-1.41/min), a terminal half-life of about 30-40 hr and a large volume of distribution were the main pharmacokinetic characteristics of 4'-epi-DX. A reduction of the dose appears to be appropriate in patients with liver function impairment. Phase II studies with 4'-epi-DX have indicated that the drug produces a pattern of acute toxicity, including acute cardiac toxicity, qualitatively similar to that of DX at identical doses but quantitatively lower, with particular regard to leukopenia and gastrointestinal toxicity. The range of single active doses is between 60 and 90 mg/m2, the most frequently employed doses schedules being 75 or 90 mg/m2 i.v. every 3 weeks. 4'-epi-DX has shown activity in a variety of tumors such as breast carcinoma, soft tissues sarcomas, NH lymphomas, leukemias, ovarian cancer and gastric cancer. Preliminary evidence of activity has been found in melanoma, rectal cancer and pancreatic cancer suggesting a broad spectrum of activity. As to chronic cardiac toxicity up to now only 2 mild to moderate and reversible CHF have been observed at doses of 1120 and 1235 mg/m2 in about 700 treated patients. Specific and comparative studies are in progress: preliminary findings from a randomized comparison of 4'-epi-DX vs DX in breast cancer indicated that 4'-epi-DX may have a lower cumulative cardiotoxicity.


Housing crowding effects on children's wellbeing.
The degree to which children grow up in crowded housing is a neglected but potentially important aspect of social inequality. Poor living conditions can serve as a mechanism of social stratification, affecting children's wellbeing and resulting in the intergenerational transmission of social inequality. This paper reports an investigation of housing crowding on children's academic achievement, behavior, and health in the US and Los Angeles, a city with atypically high levels of crowding. We use data from the Panel Study of Income Dynamics' Child Development Supplement and the Los Angeles Family and Neighborhood Survey to explore the effect of living in a crowded home on an array of child wellbeing indicators. We find that several dimensions of children's wellbeing suffer when exposed to crowded living conditions, particularly in Los Angeles, even after controlling for socioeconomic status. The negative effects on children raised in crowded homes can persist throughout life, affecting their future socioeconomic status and adult wellbeing.


Polypeptides specified by the mercuric resistance (mer) operon of plasmid R100.
Overlapping deletion mutations were constructed in chimaeric plasmids carrying the mer operon of plasmid R100. Polypeptides specified by the mutant plasmids in Escherichia coli minicells correlated with the mer genes as follows: merT, 17- and 16-kDa polypeptides; merP, 9.8- and 9.5-kDa polypeptides; merC, a 14-kDa polypeptide; merA, 65- and 62-kDa polypeptides. The products of the merR and merD genes were not identified. The revised nomenclature of the mer genes is explained.


Response to immunosuppressive therapy and an HLA-DRB1 allele in patients with aplastic anaemia: HLA-DRB1*1501 does not predict response to antithymocyte globulin.
HLA-DRB1*1501, a subtype of HLA-DR2, has been shown to be closely associated with a good response to cyclosporine (CyA) therapy in patients with aplastic anaemia (AA). To determine whether this DRB1 allele can also predict a response to antithymocyte globulin (ATG) therapy in AA patients, we analysed the results of HLA-DRB1 typing in 59 Japanese patients who received ATG within 2 years after diagnosis of AA and also in 52 patients treated with CyA. All patients were divided into three groups: those with DRB1*1501, those with DRB1*1502, and those without either of these two alleles (DR2-). The response rate to ATG in DRB1*1501+ patients (56%) was not significantly higher than that in DRB1*1502+ patients (47%) and in the other DR2- patients (54%). In contrast, the response rate to CyA therapy in DRB1*1501+ patients (92%) was significantly higher than that in the DRB1*1502+ (41%) and in DR2- patients (57%). Multivariate analysis revealed that possessing DRB1*1501 was an independent factor significantly predictive of a good response to CyA. These results indicate that although identifying the DRB1*1501 allele in AA patients prior to therapy is predictive of a good response to CyA therapy, it does not have a predictive value for ATG therapy.


Histamine is not released in acute thermal injury in human skin in vivo: a microdialysis study.
Animal models have shown histamine to be released from the skin during the acute phase of a burn injury. The role of histamine during the early phase of thermal injuries in humans remains unclear. The objectives of this trial were to study histamine release in human skin during the acute phase of a standardized thermal injury in healthy volunteers. Histamine concentrations in human skin were measured by skin microdialysis technique. Microdialysis fibers were inserted into the dermis in the lower leg in male healthy volunteers. A standardized superficial thermal injury was elicited by a heating thermode (49 degrees C) applied to the skin for 5 min. Histamine in dialysate was analyzed for up to 2 h after the injury using two different analytical methods. Spectrofluorometric assay of histamine showed no histamine release in separate studies using 2-min samples over 20 min (n = 6) and 5-10-min samples over 120 min (n = 8). The histamine values were at the limits of the quantification limit of the spectrofluorometric assay. Confirmatory studies using a sensitive radioimmunoassay confirmed no histamine release within the first hour of a thermal injury (baseline 11.6 +/- 1.8 nM vs. post-burn values of 14.8 +/- 1.8 nM, n = 8). Histamine is not released in human skin during the acute phase of a thermal injury.


Behavioral sensitization to cocaine: cooperation between glucocorticoids and epinephrine.
Stressful life experiences facilitate responsiveness to psychostimulant drugs. While there is ample evidence that adrenal glucocorticoids mediate these effects of stress, the role of the sympatho-adrenal system in the effects of psychostimulants is poorly understood. The present study investigated the role of the two adrenal stress hormones, corticosterone and epinephrine, in sensitization to the locomotor stimulant effects of cocaine. The DBA/2 mouse strain was used, as behavioral sensitization in this strain critically depends on adrenal hormones. Animals were subjected to adrenalectomy ("ADX", surgical removal of the adrenals) or SHAM surgery, and ADX mice were given replacement of epinephrine (5 x 10(-3) mg/kg subcutaneously (s.c.) just prior to each drug administration), corticosterone (20%, s.c., pellet), or both. Mice were subjected to a cocaine sensitization regimen (15.0 mg/kg cocaine on nine consecutive days followed by a 7.5 mg/kg cocaine challenge after a 5-day withdrawal). In agreement with our previous observations, ADX prevented initiation and expression of cocaine-induced locomotor sensitization. Whereas neither corticosterone nor epinephrine alone were sufficient to reverse the ADX effect, both hormones were necessary to fully restore initiation and retention of sensitization to levels observed in SHAM animals. The present findings indicate that corticosterone and epinephrine cooperate to facilitate behavioral responsiveness to cocaine. These data emphasize that in addition to the hypothalamic-pituitary-adrenal axis, the sympathetic nervous system plays a critical role in psychostimulant sensitivity.


Automatable downstream purification of the benzohydroxamic acid D-DIBOA from a biocatalytic synthesis.
Herbicides play a vital role in agriculture, contributing to increased crop productivity by minimizing weed growth, but their low degradability presents a threat to the environment and human health. Allelochemicals, such as DIBOA (2,4-dihydroxy-(2H)-1,4-benzoxazin-3(4 H)-one), are secondary metabolites released by certain plants that affect the survival or growth of other organisms. Although these metabolites have an attractive potential for use as herbicides, their low natural production is a critical hurdle. Previously, the synthesis of the biologically active analog D-DIBOA (4-hydroxy-(2H)-1,4-benzoxazin-3(4H)-one) was achieved, using an engineered E. coli strain as a whole-cell biocatalyst, capable of transforming a precursor compound into D-DIBOA and exporting it into the culture medium, although it cannot be directly applied to crops. Here a chromatographic method to purify D-DIBOA from this cell culture medium without producing organic solvent wastes is described. The purification of D-DIBOA from a filtered culture medium to the pure compound could also be automated. Biological tests with the purified compound on weed models showed that it has virtually the same activity than the chemically synthesized D-DIBOA.


Aberrations in circulating ceramide levels are associated with poor clinical outcomes across localised and metastatic prostate cancer.
Dysregulated lipid metabolism is associated with more aggressive pathology and poorer prognosis in prostate cancer (PC). The primary aim of the study is to assess the relationship between the plasma lipidome and clinical outcomes in localised and metastatic PC. The secondary aim is to validate a prognostic circulating 3-lipid signature specific to metastatic castration-resistant PC (mCRPC). Comprehensive lipidomic analysis was performed on pre-treatment plasma samples from men with localised PC (N = 389), metastatic hormone-sensitive PC (mHSPC)(N = 44), or mCRPC (validation cohort, N = 137). Clinical outcomes from our previously published mCRPC cohort (N = 159) that was used to derive the prognostic circulating 3-lipid signature, were updated. Associations between circulating lipids and clinical outcomes were examined by Cox regression and latent class analysis. Circulating lipid profiles featuring elevated levels of ceramide species were associated with metastatic relapse in localised PC (HR 5.80, 95% CI 3.04-11.1, P = 1 × 10-6), earlier testosterone suppression failure in mHSPC (HR 3.70, 95% CI 1.37-10.0, P = 0.01), and shorter overall survival in mCRPC (HR 2.54, 95% CI 1.73-3.72, P = 1 × 10-6). The prognostic significance of circulating lipid profiles in localised PC was independent of standard clinicopathological and metabolic factors (P < 0.0002). The 3-lipid signature was verified in the mCRPC validation cohort (HR 2.39, 95% CI 1.63-3.51, P = 1 × 10-5). Elevated circulating ceramide species are associated with poorer clinical outcomes across the natural history of PC. These clinically actionable lipid profiles could be therapeutically targeted in prospective clinical trials to potentially improve PC outcomes.


What pollinators see does not match what they smell: Absence of color-fragrance association in the deceptive orchid Ionopsis utricularioides.
Many deceptive orchids present variation in floral color and fragrance. This might be advantageous for the plant, as it can disturb the associative avoidance learning of pollinators, promoting more visits to the flowers. Some studies have shown that color and fragrance can be correlated in polymorphic deceptive orchids, but these studies employed color traits based on the human visual system and not the visual perception of pollinators. Thus, we investigated the composition of the floral fragrance of Ionopsis utricularioides (Sw.) Lindl., a polymorphic deceptive orchid, and analyzed possible correlations with the floral color as seen by bees, Apis mellifera L. and Melipona quadrifasciata Lepeletier, using the color hexagon model. We found high color and fragrance intraspecific variation, as expected for deceptive species. However, we found no color-fragrance association in individuals, either by comparing fragrance profiles with the color variable saturation or by comparing them with the placement of individuals in the color hexagon for both bee species. This lack of correlation contradicts the biochemical pathway hypothesis, which proposes that associations between floral color and scent in polymorphic flowers arise from shared biochemical pathways. However, a complete absence of correlation between floral signals is consistent with selection arising through pollinator cognitive ecology. Lack of correlation would increase the floral variability perceived by bees, given their multimodal learning, and this variability could disrupt avoidance learning of deceptive flowers, thus enhancing the efficacy of the plant's deceptive pollination mechanism.


Sequential liver biopsies during long-term methotrexate treatment for psoriasis: a reappraisal.
One hundred and eighty-two liver biopsies were performed over a 10-year period on patients receiving long-term, low-dose, once weekly oral methotrexate (MTX) for severe psoriasis. Forty-nine patients had two or more biopsies during continued treatment and formed the study population for our analysis. The first and last biopsies were compared to determine progression of any histological abnormalities. Liver biopsies were assessed without knowledge of the MTX dose and allocated to one of five groups according to the severity of the histological abnormalities. These were defined as: (1) normal; (2) steatosis alone; (3) inflammation without fibrosis; (4) fibrosis; and (5) cirrhosis. The mean cumulative dose of MTX at the time of the first biopsy was 2743 mg (range 315-10,024), given over 275 weeks (range 26-738). In the interval between the first and last biopsies, patients received, on average, a further 2362 mg (range 390-7155) over 225 weeks (range 60-460). There was improvement in the histological assessment in 12 patients, no change in 28 patients, and deterioration in nine patients. None developed cirrhosis. Liver biopsy findings prompted discontinuation of MTX in four of the 49 patients on long-term treatment. This has to be weighed against the cost and morbidity of the 124 biopsies performed in these patients. Our results suggest that, with careful follow-up, the risk of development or progression of liver disease in patients receiving long-term, low-dose, once weekly oral MTX for psoriasis is modest, and that the requirement for performing routine liver biopsies in these patients needs to be reconsidered.


New Synthesized Galloyl-RGD Inhibits Melanogenesis by Regulating the CREB and ERK Signaling Pathway in B16F10 Melanoma Cells.
Gallic acid (3, 4, 5-trihydroxybenzoic acid) is a phytochemical derived from diverse herbs. It has been reported to have effective antifungal, antiviral and antioxidant activity. However, gallic acid exhibits low solubility and instability at high temperatures. In a previous study, in order to overcome these limitations, we synthesized galloyl-RGD by combining gallic acid with arginine, glycine and asparaginic acid (RGD peptide). This compound showed better thermal stability than gallic acid. In this study, we investigated the antimelanogenic effect of galloyl-RGD and the underlying mechanism for this effect. Galloyl-RGD markedly inhibited melanin content and tyrosinase activity in a concentration-dependent manner. We also found that galloyl-RGD decreased the levels of melanogenesis-related gene and protein. In addition, galloyl-RGD reduces intracellular cyclic adenosine monophosphate (cAMP) levels that leads to inhibition of cAMP-responsive element binding protein (CREB) phosphorylation and activates extracellular signal-regulated kinase (ERK) expression. These results indicate that CREB and ERK regulation by galloyl-RGD contributes to reduced melanin synthesis via degradation of microphthalmia-associated transcription factor. Therefore, galloyl-RGD can be potential candidate for application in cosmetic or pharmaceutical industry.


Pathfinder: a gamified measure to integrate general cognitive ability into the biological, medical, and behavioural sciences.
Genome-wide association (GWA) studies have uncovered DNA variants associated with individual differences in general cognitive ability (g), but these are far from capturing heritability estimates obtained from twin studies. A major barrier to finding more of this 'missing heritability' is assessment--the use of diverse measures across GWA studies as well as time and the cost of assessment. In a series of four studies, we created a 15-min (40-item), online, gamified measure of g that is highly reliable (alpha = 0.78; two-week test-retest reliability = 0.88), psychometrically valid and scalable; we called this new measure Pathfinder. In a fifth study, we administered this measure to 4,751 young adults from the Twins Early Development Study. This novel g measure, which also yields reliable verbal and nonverbal scores, correlated substantially with standard measures of g collected at previous ages (r ranging from 0.42 at age 7 to 0.57 at age 16). Pathfinder showed substantial twin heritability (0.57, 95% CIs = 0.43, 0.68) and SNP heritability (0.37, 95% CIs = 0.04, 0.70). A polygenic score computed from GWA studies of five cognitive and educational traits accounted for 12% of the variation in g, the strongest DNA-based prediction of g to date. Widespread use of this engaging new measure will advance research not only in genomics but throughout the biological, medical, and behavioural sciences.


Matcha and Sencha green tea extracts with regard to their phenolics pattern and antioxidant and antidiabetic activity during in vitro digestion.
The purpose of this study was to compare the polyphenol, antioxidant and antidiabetic potential of powdered Matcha and bagged Sencha tea during in vitro digestion. Total phenols (TP), flavonoids (TF), flavanols (TFLA), antioxidant and antidiabetic (α-glucosidase inhibition) activity were higher in Matcha tea before and in most in vitro digestion phases. Upon gastric digestion, in Matcha tea TP, TF, TFLA were 2.6, 1.4 and 1.2 times significantly higher (p ≤ 0.05), respectively; gallic acid, gallocatechin, epigallocatechin, quercetin and kaempferol 1.5, 1.6, 1.8, 1.7, 1.2 times, respectively; whereas antioxidant activity was significantly (p ≤ 0.05) higher 3.2 and 1.1 times with ABTS and FRAP and α-glucosidase inhibition 1.8 times. After the intestinal phase, TP and TFLA were 3.4 and 1.7 times significantly (p ≤ 0.05) higher, respectively, antioxidant activity was significantly (p ≤ 0.05) higher 2.4 and 2.0 times with ABTS and FRAP, respectively, while inhibition of α-glucosidase was 1.7 time significantly (p ≤ 0.05) higher in Matcha tea, but the differences in TF, TP and identified phenolics (with the exception of gallic acid) between Matcha and Sencha tea were neutralized. Our results are the first to demonstrate that, during digestion of Matcha powder together with its water extract, Matcha polyphenols are more bioavailable and possess higher antioxidant and antidiabetic activity compared to Sencha. The online version contains supplementary material available at 10.1007/s13197-021-05086-5.


Neuroglobin expression and function in the temporal cortex of bilirubin encephalopathy rats.
Bilirubin encephalopathy (BE) is a neurological syndrome in newborns, mainly caused by neuronal injury due to excessive oxidative stress produced by unconjugated bilirubin (UCB). Neuroglobin (NGB) can protect the brain by removing oxidative stress species, but its expression and significance in BE are not clear. To address this question, the neonatal BE model was established by injecting UCB into the cerebellomedullary cistern of 7-day-old SD rats. Rats were divided into a sham and BE 6 hr group, BE 12 hr group, BE 24 hr group, and BE 7 d group according to UCB action times. Hematoxylin/eosin and Nissl staining, and electron microscopy were employed to observe the pathological and ultrastructural changes of nerve cells in each group. Immunofluorescence staining was used to detect NGB expression sites and cell types. Western blotting and quantitative PCR served to detect NGB expression and test the mitochondrial apoptosis signal pathway. The results confirm that UCB can lead to pathological damage and ultrastructural changes in rats' temporal cortex, increasing the expression of apoptosis-related proteins Bax, Bcl-2, Cyt c, Caspase-3, and neuronal NGB. UCB promotes NGB expression with an increase in action time and reach a peak at 12 hr. In summary, brain damage induced by UCB will cause an increase in NGB expression, the increasing NGB can inhibit neuron apoptosis in early BE phases. Therefore, promoting the expression of endogenous NGB, to act as a neuroprotective agent may be a potential treatment strategy for BE.


Monosomy X as a recurring sole cytogenetic abnormality associated with myelodysplastic diseases.
Solitary loss of the X chromosome is associated with Turner syndrome and not hematological disorders. We describe five patients with non-constitutional loss of the X chromosome as the sole cytogenetic abnormality in their bone marrow. Three of the five patients had myelodysplastic syndrome (MDS), one case had AML M-6 with evidence suggestive of an evolving MDS, and the last patient had a dysplastic marrow. A review of the literature identified sporadic reports of an association of monosomy X and several hematologic disorders, as well as a few solid tumors. In this series of patients, monosomy X as a sole non-constitutional cytogenetic abnormality in bone marrow is associated with myelodysplastic diseases. In addition, fluorescence in situ hybridization analysis with an X centromere probe indicated that monosomy X was present in erythroid precursors, myeloblasts, promyelocytes, myelocytes, metamyelocytes, granulocytes, and monocytes, while mature lymphocytes presented with two copies of the X chromosome. The molecular cytogenetic evidence supports the diagnosis of a myelodysplastic disorder in these cases and documents the potential role of FISH in hematological disease.


Drug-related challenges following primary total hip and knee arthroplasty.
We aimed to characterize the in-hospital analgesic use among total hip or knee arthroplasty (THA or TKA) patients, and to identify possible drug-related challenges. We identified 15 263 patients operated with a THA or TKA between 1 January 2012 and 30 April 2016. The prevalence of analgesic users and patients with potential clinically relevant drug-drug interactions (DDIs), along with the prevalence of readmission among patients with vs. without a DDI, were calculated. A DDI was defined as the combination of (A) a diuretic, an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker, and an non-steroidal anti-inflammatory Drug (NSAID); (B) warfarin and an NSAID; and (C) a benzodiazepine or a benzodiazepine-related drug and an opioid. The prevalence of analgesics administered in THA and TKA patients was 99.3% and 99.1% for paracetamol and 93.8% and 98.8% for opioids, respectively. The prevalence of patients who received interaction A, B or C was 8.4%, 2.5% and 40.7%, respectively. Patients with vs. without a DDI had a higher prevalence of 30-day readmission. In conclusion, most THA and TKA patients were administered paracetamol or opioids. The prevalence of 30-day readmission was higher in patients with than in patients without a potential clinically relevant DDI.


Distinct Associations of Deprivation and Threat With Alterations in Brain Structure in Early Childhood.
The dimensional model of adversity and psychopathology hypothesizes deprivation and threat impact distinct neurobiological pathways, such as brain structure. This hypothesis has not been examined longitudinally or in young children. This study tested longitudinal associations between threat and deprivation measured in preschool and brain structure in childhood. It was hypothesized that threat would be associated with amygdala and hippocampal subcortical volume and deprivation would be associated with cortical thickness in association cortex. The study included T1-weighted scans from 72 children (5-10 years old, 54.2% female participants). Threat was measured by the presence of domestic violence, sexual abuse, physical abuse, or neighborhood violence. Deprivation was measured by the presence of neglect. Associations of deprivation or threat with brain structure were examined controlling for other dimension (deprivation or threat) and nuisance covariates using whole-brain vertex-wise analyses. Subcortical volume was extracted, and the same associations were examined using multiple regression. Threat was associated with widespread decreases in cortical surface area across the prefrontal cortex and other regions. Threat was not associated with amygdala or hippocampal volume. Deprivation was associated with increased thickness in occipital cortex, insula, and cingulate. Results suggest distinct associations of deprivation and threat on brain structure in early childhood. Threat is associated with widespread differences in surface area, and deprivation is associated with differences in cortical thickness. These observations are consistent with work in adolescence and adulthood and reflect how dimensions of adversity differentially impact neural structure.


Central action of an inhibitor of brain dopa-decarboxylase, NSD-1015, on cyanamide-induced alcohol drinking in rats.
A cannula for repeated intracerebroventricular (ICV) infusion was implanted stereotaxically in 16 male Sprague-Dawley rats. Subsequently, an alcohol preference test was given to each animal to establish its preferred concentration in the presence of water. After the alcohol solution was removed, 15 mg/kg cyanamide was injected subcutaneously for 4 days to maximize volitional intake of the single preferred solution of alcohol, which ranged from 7-15% in these animals. The L-aromatic amino acid decarboxylase inhibitor, NSD-1015 (3-hydroxybenzylhydrazine dihydrochloride) was then given ICV twice daily in a volume of 5.0 microliters in the following doses: 0.005, 0.01, 0.1 and 1.0 micrograms. NSD-1015 in all doses attenuated the g/kg alcohol intake of the rats; however, this decline was significant only at the lowest dose, which was pharmacologically specific, since neither food nor water intakes were altered by the treatment. Following the ICV infusions of NSD-1015, alcohol drinking returned essentially to postcyanamide levels. Further, during the interval of administration of NSD-1015, the cyanamide-induced decline in food consumption was reversed. These observations are in agreement with previous findings obtained under similar experimental conditions with the L-aromatic amino acid decarboxylase inhibitor, benserazide (Ro4-4602). They suggest that central decarboxylation or other effects of this drug on limbic system structures involved in the intake of alcohol could comprise a part of the mechanism underlying the induction of drinking. Further support is also provided for the involvement of brain dopamine and/or serotonin in the specific pattern of alcohol consumption in the rat.


The roles of the alternative NADH dehydrogenases during oxidative stress in cultures of the filamentous fungus Aspergillus niger.
Despite the importance of filamentous fungi in the biotechnology industry, little is known about their metabolism under the stressful conditions experienced in typical production fermenters. In the present study, oxygen enrichment was used to recreate an industrial batch process, and the effects of the increasing dissolved oxygen tension were studied as regards the cellular metabolism. It was found that elevated dissolved oxygen tension led to an oxidatively stressful environment, as detailed by rapid initial increases in reactive oxygen species (ROS) concentrations and antioxidant enzyme activities. Intracellular protein concentrations also decreased in oxygenated cultures; this appeared to be concomitant with a decrease in the adenosine-5'-triphosphate (ATP) pool in these cultures. Oxygenated cultures showed early senescence and death compared to aerated control cultures. Despite earlier studies proposing various mechanisms for such findings in fungal cultures subjected to oxidative stress, these findings can best be explained by the fact that in such cultures the activity of alternative NADH dehydrogenases was significantly increased, which served to maintain lower ROS concentrations throughout the duration of the process but in doing so also reduced the ability of the organism to create a proton motive force by which to drive ATP synthesis. The findings of the present study help further our understanding of the central roles of these highly conserved enzymes within fungal metabolism under oxidative stress.


Potential role of α-lipoic acid and Ginkgo biloba against silver nanoparticles-induced neuronal apoptosis and blood-brain barrier impairments in rats.
This study explored whether silver nanoparticles (AgNPs) can disrupt tight-junctions integrity resulted in blood-brain barrier dysfunction along with oxidative stress, pro-inflammation, and apoptosis induction. Additionally, neuroprotective activities of α-lipoic acid (LA) and Ginkgo biloba (GB) were investigated. Forty adults rats were enrolled into; Control, AgNPs (50 mg/kg), LA (100 mg/kg) + AgNPs, and GB (120 mg/kg) + AgNPs. After 30 days, neuronal changes were assessed biochemically and histopathologically. Brain tissues oxidative indices, mRNA expression of proinflammatory cytokines and tight-junction proteins and pro-apoptotic biomarker, caspase-3 were investigated. AgNPs exposure enhanced lipid peroxidation (+195%) along with declines in glutathione (-43%), glutathione peroxidase (-34%), glutathione S-transferase (-31%), catalase (-43%), and superoxide dismutase (-38%) activities in brain tissues. The apparent brain oxidative damage was associated with obvious neuronal dysfunction that was ascertained by neuropathological lesions. AgNPs lowered serum acetylcholine esterase, iron and copper levels, and increased creatine phosphokinase and creatine phosphokinase-brain type activities. Following AgNPs exposure, brain silver and iron contents were increased, but the copper level was decreased. AgNPs up-regulated TNF-α (6.5-fold) and IL-1β (8.9-fold) transcript levels, and simultaneously over-expressed the caspase-3 protein in cerebrum and cerebellum inducing cell apoptosis. Moreover, AgNPs down-regulated the transcript levels of tight-junction proteins; JP-1 (0.65-fold) and JAM-3(0.81-fold). LA and relatively GB improved the serious effects of AgNPs on the blood-brain barrier function and tight-junction proteins through their antioxidants, anti-inflammatory, and anti-apoptotic efficacies. Co-treatment with LA or GB may be favorable in ameliorating the neurotoxic side effects of AgNPs.


Inactivation and removal of human immunodeficiency virus in monoclonal purified antihemophilic factor (human) (Hemofil M).
Cold supernatant which was prepared from factor VIII:C containing cryoprecipitate was seeded with HIV-1, then treated with a mixture of tri (n-butyl) phosphate (TNBP) and triton X-100. A greater than 10(11)-fold reduction of HIV-1 infectivity was observed. In a separate experiment, cold supernatant which had been seeded with HIV-1 was chromatographed on an immunoaffinity column, resulting in a 10(4)-fold reduction of infectivity. None of the 17 patients treated with the purified product and followed for at least three months has shown serologic evidence of HIV-1 or other viral infections.


Organics removal from landfill leachate and activated sludge production in SBR reactors.
This study is aimed at estimating organic compounds removal and sludge production in SBR during treatment of landfill leachate. Four series were performed. At each series, experiments were carried out at the hydraulic retention time (HRT) of 12, 6, 3 and 2d. The series varied in SBR filling strategies, duration of the mixing and aeration phases, and the sludge age. In series 1 and 2 (a short filling period, mixing and aeration phases in the operating cycle), the relationship between organics concentration (COD) in the leachate treated and HRT was pseudo-first-order kinetics. In series 3 (with mixing and aeration phases) and series 4 (only aeration phase) with leachate supplied by means of a peristaltic pump for 4h of the cycle (filling during reaction period) - this relationship was zero-order kinetics. Activated sludge production expressed as the observed coefficient of biomass production (Y(obs)) decreased correspondingly with increasing HRT. The smallest differences between reactors were observed in series 3 in which Y(obs) was almost stable (0.55-0.6 mg VSS/mg COD). The elimination of the mixing phase in the cycle (series 4) caused the Y(obs) to decrease significantly from 0.32 mg VSS/mg COD at HRT 2d to 0.04 mg VSS/mg COD at HRT 12d. The theoretical yield coefficient Y accounted for 0.534 mg VSS/mg COD (series 1) and 0.583 mg VSS/mg COD (series 2). In series 3 and 4, it was almost stable (0.628 mg VSS/mg COD and 0.616 mg VSS/mg COD, respectively). After the elimination of the mixing phase in the operating cycle, the specific biomass decay rate increased from 0.006 d(-1) (series 3) to 0.032 d(-1) (series 4). The operating conditions employing mixing/aeration or only aeration phases enable regulation of the sludge production. The SBRs operated under aerobic conditions are more favourable at a short hydraulic retention time. At long hydraulic retention time, it can lead to a decrease in biomass concentration in the SBR as a result of cell decay. On the contrary, in the activated sludge at long HRT, a short filling period and operating cycle of the reactor with the mixing and aeration phases seem the most favourable.


The assessment of regional abnormalities of the left ventricle by angiography.
A method of regional wall motion analysis of left ventricular cineangiograms which does not make assumptions about ventricular geometry is described. The technique measures the movement of the ventricular perimeter in relation to the geometric center of gravity of the endsystolic frame expressing movement as a change in radical length. 10 control patinets each with 3 left ventricular cineangiograms, comprise the group for definition of normal values of movement and permit estimations of reproducibility within and across patient groups. Isolated examples of abnormal wall motion are shown.


Evaluation of varicella vaccine effectiveness during outbreaks in schools or nurseries by cross-sectional study.
The aim of this study was to elucidate vaccine effectiveness (VE) during varicella outbreaks in schools and nurseries in Japan. An outbreak was defined as emergence of three or more cases of varicella within 21 days at the same institute. Clinical information such as varicella vaccination status, and history of varicella was collected. If a child had varicella during the outbreak, information about absences, fever, and disease severity was collected. From September 2018 to January 2020, four outbreaks were reported around our institute from three elementary schools and one nursery. A total of 676 children were analyzed in this study. Seventy-six children (11.2%) were unvaccinated, 309 (45.7%) had received one dose of vaccine, and 291 (43.0%) had received two doses. Most children in Pre-K2 (1-2 years old) to Pre-K6 (5-6 years old), who were the targets of the national immunization schedule, received two doses. Meanwhile, most children older than third grade received single dose. Seventy-five children (11.1%) had varicella. Varicella prevalence from Pre-K5 to the third grade was greater than 10%. The adjusted VEs of single- and two-dose of varicella vaccine were 57.8% and 89.0%. The number of days absent was significantly longer in unvaccinated children than single-dose recipients (P = 0.0145). Unvaccinated children had significantly more severe skin eruptions than single-dose recipients (P = 0.0046) and two-dose recipients (P = 0.0258). Although VEs of single-dose varicella vaccination during outbreaks was not high, the VE of two-dose vaccination was similar to that in a previously reported case-control study.


Influence of operational parameters on photocatalytic degradation of a genotoxic azo dye Acid Violet 7 in aqueous ZnO suspensions.
The photocatalytic degradation of a genotoxic azo dye Acid Violet 7 (AV 7) using ZnO as a photocatalyst in aqueous solution has been investigated under UV irradiation. The degradation is higher with UV/ZnO process than with UV/TiO(2)-P25 process at pH 9. The effects of different parameters such as pH of the solution, amount of catalyst, initial dye concentration and the influence of cations, anions and oxidants on photodegradation of AV 7 were analyzed. Addition of oxidants except H(2)O(2) has no significant effect on degradation. The degradation of AV 7 follows pseudo-first order kinetics according to the Langmuir-Hinshelwood model. The degradation of AV 7 has also been confirmed by COD and CV measurements.


Total rhinoplasty or prosthesis?
This article outlines the basic anatomy of the nose as it relates to a pleasing facial appearance and discusses the problems involved in the reconstruction and rehabilitation of the patient sustaining total rhinectomy.


Structural and functional characterization of the abnormal Z alpha 1-antitrypsin isolated from human liver.
alpha 1-Antitrypsin has been isolated from liver inclusion bodies of a subject with a homozygous Z deficiency. The inhibitor was recovered in a fully active form by extraction in high salt at either pH 2.0 or pH 8.0. Carbohydrate analysis indicated a protein in the 'high mannose' form, and this was collaborated by its sensitivity to endo-beta N-glucosaminidase. These data suggest that the abnormal alpha 1-antitrypsin is blocked in the secretory pathway prior to its entrance into the Golgi, and that this blockage is not due to a gross misfolding of the polypeptide.


Usability of the head impulse test in routine clinical practice in the emergency department to differentiate vestibular neuritis from stroke.
The bedside head impulse test (bHIT) is used to differentiate vestibular neuritis (VN) from posterior circulation stroke (PCS) in patients presenting with acute vestibular syndrome (AVS). If assessed by neuro-otological experts, diagnostic accuracy is high. We report on its diagnostic accuracy when applied by nonexperts during routine clinical practice in the emergency department (ED), its impact on patient management, and the potential diagnostic yield of the video-oculography-supported head impulse test (vHIT). Medical chart review of 38 AVS patients presenting to our university medical center's ED, assessed by neurology residents. We collected bHIT results (abnormal/peripheral or normal/central) and whether patients were admitted to the stroke unit or general neurological ward. Final diagnosis (VN, n = 24; PCS, n = 14) was determined by clinical course, magnetic resonance imaging, and vHIT. The bHIT's accuracy was only 58%. Its sensitivity for VN was high (88%), but due to many false-abnormal bHITs in PCS (36%), the specificity was low (64%). The vHIT yielded excellent specificity (100%) and moderate sensitivity (67%). The decision on the patient's further care was almost arbitrary and independent from the bHIT: 58% of VN and 57% of PCS patients were admitted to the stroke unit. The bHIT, applied by nonexperts during routine practice in the ED, has low accuracy, is too often mistaken as abnormal/peripheral, and is not consistently used for patients' in-hospital triage. As false-abnormal bHITs can lead to misdiagnosis/mistreatment of stroke patients, we recommend that bHIT applied by nonexperts should be reassessed by a neuro-otological expert or preferably quantitative vHIT in the ED.


Rational emotive health therapy for the management of depressive symptoms among parents of children with intellectual and reading disabilities in English language.
There is little data in developing countries such as Nigeria with regard to the impact of caring for their children with intellectual and reading disability (IRD) on the quality of life of the parents and the risk of psychopathology. The main objective of the study was to assess the level of psychopathology, i.e., depression among parents of children with intellectual and reading disabilities. This was pretest/posttest control group design with 198 parents (99 fathers/99 mothers) of 100 children with the diagnosis of IRD. The measures used in this study for data collection was Beck Depression Inventory (BDI). Repeated measures analysis of variance (ANOVA) was employed for data analysis. Result obtained showed a significant high proportion of depressive symptoms among parents of children with intellectual and reading disabilities at initial assessment. Furthermore, the REHT intervention resulted in a significant reduction in depression of parents in treatment group as compared to those in the control group. The presence of a child with intellectual and reading disabilities does not cause parents to become depressed but irrational beliefs about their children's mental and reading deficiencies may contribute to unhealthy thinking and feelings about the future of their children. REHT is very effective in assisting depressed parents of children with intellectual and reading disabilities to think rationally about their children and work towards overcoming disability-related as well as behavior-related irrational beliefs. The mental health providers, therapists and counselors should apply the REHT in managing people with psychological distress especially parents of children with intellectual and reading disabilities who may have psychological diagnosis of depression.


Cytodifferentiation and immunocharacteristics of adenohypophysial cells in the toad, Bufo melanostictus.
Employing the unlabelled antibody enzyme technique cytodifferentiation, immunocharacteristics and topographical distribution of melanotropic (MSH), adrenocorticotropic (ACTH), thyrotropic (TSH), prolactin (PRL), gonadotropic (GTH) and growth hormone (GH) secreting cells in the embryonic/larval as well as adult pituitary gland of the common Indian toad, Bufo melanostictus, have been studied by using antisera raised in rabbit against mammalian hypophysial hormones. Immunoreactive MSH and ACTH cells appear first in the dorsocaudal and rostral regions of the pituitary anlage (PA) at stage 21 (Gosner's classification) of the embryonic development. This is followed by the differentiation of TSH and PRL cells at stage 22 in the midventral and central regions of the PA respectively. Finally, at stage 23 the GTH cells appear in the rostral and the GH cells in the caudal regions of the PA. With the progress of the development, cells showing immunoreactivity to various antisera gradually increase in number, size, granular content and finally occupy the characteristic adult disposition. The MSH cells comprise the pars intermedia. In the pars distalis (PD) the ACTH cells are localized in the rostroventral region, TSH cells in the central region and the GH cells in the dorsocaudal region. However, GTH and PRL cells are distributed throughout the PD.


An enzymatic platform for the asymmetric amination of primary, secondary and tertiary C(sp3)-H bonds.
The ability to selectively functionalize ubiquitous C-H bonds streamlines the construction of complex molecular architectures from easily available precursors. Here we report enzyme catalysts derived from a cytochrome P450 that use a nitrene transfer mechanism for the enantioselective amination of primary, secondary and tertiary C(sp3)-H bonds. These fully genetically encoded enzymes are produced and function in bacteria, where they can be optimized by directed evolution for a broad spectrum of enantioselective C(sp3)-H amination reactions. These catalysts can aminate a variety of benzylic, allylic and aliphatic C-H bonds in excellent enantioselectivity with access to either antipode of product. Enantioselective amination of primary C(sp3)-H bonds in substrates that bear geminal dimethyl substituents furnished chiral amines that feature a quaternary stereocentre. Moreover, these enzymes enabled the enantioconvergent transformation of racemic substrates that possess a tertiary C(sp3)-H bond to afford products that bear a tetrasubstituted stereocentre, a process that has eluded small-molecule catalysts. Further engineering allowed for the enantioselective construction of methyl-ethyl stereocentres, which is notoriously challenging in asymmetric catalysis.