Noise-induced transitions of the Atlantic Meridional Overturning Circulation in CMIP5 models.
By studying transition probabilities of the Atlantic Meridional Overturning Circulation (AMOC) in an ensemble of CMIP5 climate models, we revisit one of the stability indicators of the AMOC, i.e. the freshwater transport carried by the AMOC at the southern boundary of the Atlantic basin. A correction to this indicator, based on the transition probabilities, is suggested to measure whether an AMOC state is in a multiple equilibrium regime or not. As a consequence, the AMOC of all CMIP5 models considered is in a multiple equilibrium regime and hence, in principle, a collapsed AMOC state should exist in each of these models. The results further demonstrate the dependence of the Atlantic surface freshwater flux on the AMOC and the impact of extreme events in the AMOC on temperatures in the North Atlantic region.


The genetic toxicity of 1,2-dibromo-3-chloropropane, 1,2-dibromo-3-chloro-2-methylpropane, and 1,2,3-tribromo-2-methylpropane.
1,2-Dibromo-3-chloro-2-methylpropane (DBCMP) and 1,2,3-tribromo-2-methylpropane (TBMP) are contaminants formed during the manufacture of bromobutyl rubber. These chemicals are structurally similar to 1,2-dibromo-3-chloropropane (DBCP), a known genotoxin and rodent carcinogen. The present study compared the genotoxic properties of DBCMP and TBMP to those of DBCP. In the Salmonella assay, DBCP was positive in strains TA-98, TA-100 and TA-1535 in the presence of exogenous activation; DBCP was weakly active in TA-1535 in the absence of activation. Neither DBCMP nor TBMP produced reproducible evidence of mutagenic activity in the Salmonella assay despite the use of several different variations of this test. In the mouse lymphoma gene mutation assay, DBCP and TBMP were positive in the presence and absence of activation, while DBCMP was positive only in the absence of activation. All three test compounds were active in the Syrian hamster embryo morphologic transformation assay. The results indicated that both DBCMP and TBMP exhibited some genotoxic activity as did DBCP. The presence of the methyl group on the 2-carbon position essentially eliminated the mutagenicity of DBCMP and TBMP in the Salmonella assay.


An automated sedimentation balance.
A method of size grading powders using an automated sedimentation balance is described. The results are recorded as percentages of the total powder present in 1 or 5 mum (intervals) of particle size, after they have been multiplied by a simple correction factor. Analyses of calcium carbonate powder using this balance and the Gallenkamp balance have been compared.


Systematic quantification of histologic ventricular fibrosis in isolated mitral valve prolapse and sudden cardiac death.
Cardiac fibrosis in mitral valve prolapse (MVP) is implicated in the development of sudden cardiac death (SCD); however, the pattern remains poorly characterized. The purpose of this study was to systematically quantify left and right ventricular fibrosis in individuals with isolated MVP and SCD (iMVP-SCD), whereby other potential causes of death are excluded, compared to a control cohort. Individuals with iMVP-SCD were identified from the Victorian Institute of Forensic Medicine, Australia, and matched for age, sex, and body mass index to control cases with noncardiac death. Cardiac tissue sections were analyzed to determine collagen deposition in the left ventricular free wall (anterior, lateral, and posterior portions), interventricular septum, and right ventricle. Within the iMVP-SCD cases, the endocardial-to-epicardial distribution of fibrosis within the left ventricle was specifically characterized. Seventeen cases with iMVP-SCD were matched 1:1 with 17 controls, yielding 149 samples and 1788 histologic regions. The iMVP-SCD group had increased left ventricular (anterior, lateral, and posterior; all P <.001) and interventricular septum fibrosis (P <.001), but similar amounts of right ventricular fibrosis (P = .62) compared to controls. In iMVP-SCD, left ventricular fibrosis was significantly higher in the lateral and posterior walls compared to the anterior wall and interventricular septum (all P <.001). Within the lateral and posterior walls, iMVP-SCD cases had a significant endocardial-to-epicardial gradient of cardiac fibrosis (P <.01) similar to other known conditions that cause cardiac remodeling. Our study indicates that nonuniform left ventricular remodeling with both localized and generalized left ventricular fibrosis is important in the pathogenesis of SCD in individuals with MVP.


Fine mapping of a stripe rust resistance gene YrZM175 in bread wheat.
A stripe rust resistance gene YrZM175 in Chinese wheat cultivar Zhongmai 175 was mapped to a genomic interval of 636.4 kb on chromosome arm 2AL, and a candidate gene was predicted. Stripe rust, caused by Puccinia striiformis f. sp. tritici (PST), is a worldwide wheat disease that causes large losses in production. Fine mapping and cloning of resistance genes are important for accurate marker-assisted breeding. Here, we report the fine mapping and candidate gene analysis of stripe rust resistance gene YrZM175 in a Chinese wheat cultivar Zhongmai 175. Fifteen F1, 7,325 F2 plants and 117 F2:3 lines derived from cross Avocet S/Zhongmai 175 were inoculated with PST race CYR32 at the seedling stage in a greenhouse, and F2:3 lines were also evaluated for stripe rust reaction in the field using mixed PST races. Bulked segregant RNA-seq (BSR-seq) analyses revealed 13 SNPs in the region 762.50-768.52 Mb on chromosome arm 2AL. By genome mining, we identified SNPs and InDels between the parents and contrasting bulks and mapped YrZM175 to a 0.72-cM, 636.4-kb interval spanned by YrZM175-InD1 and YrZM175-InD2 (763,452,916-764,089,317 bp) including two putative disease resistance genes based on IWGSC RefSeq v1.0. Collinearity analysis indicated similar target genomic intervals in Chinese Spring, Aegilops tauschii (2D: 647.7-650.5 Mb), Triticum urartu (2A: 750.7-752.3 Mb), Triticum dicoccoides (2A: 771.0-774.5 Mb), Triticum turgidum (2B: 784.7-788.2 Mb), and Triticum aestivum cv. Aikang 58 (2A: 776.3-778.9 Mb) and Jagger (2A: 789.3-791.7 Mb). Through collinearity analysis, sequence alignments of resistant and susceptible parents and gene expression level analysis, we predicted TRITD2Bv1G264480 from Triticum turgidum to be a candidate gene for map-based cloning of YrZM175. A gene-specific marker for TRITD2Bv1G264480 co-segregated with the resistance gene. Molecular marker analysis and stripe rust response data revealed that YrZM175 was different from genes Yr1, Yr17, Yr32, and YrJ22 located on chromosome 2A. Fine mapping of YrZM175 lays a solid foundation for functional gene analysis and marker-assisted selection for improved stripe rust resistance in wheat.


A role for MAPK/ERK in sympathetic neuron survival: protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside.
The antimitotic nucleoside cytosine arabinoside (araC) causes apoptosis in postmitotic neurons for which two mechanisms have been suggested: (1) araC directly inhibits a trophic factor-maintained signaling pathway required for survival, effectively mimicking trophic factor withdrawal; and (2) araC induces apoptosis by a p53-dependent mechanism distinct from trophic factor withdrawal. In rat sympathetic neurons, we found that araC treatment for 12 hr induced approximately 25% apoptosis without affecting NGF-maintained signaling; there was neither reduction in the activity of mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) or protein kinase B/Akt, a kinase implicated in NGF-mediated survival, nor was there c-Jun N-terminal kinase (JNK) activation or c-Jun N-terminal phosphorylation, events implicated in apoptosis induced by NGF withdrawal. However, araC treatment, but not NGF-withdrawal, elevated expression of p53 protein before and during apoptosis. Additionally, araC-induced apoptosis was suppressed in sympathetic neurons from p53 null mice. Although MAPK/ERK activity is not necessary for NGF-induced survival, it protected against toxicity by araC, because inhibition of the MAPK pathway by PD98059 resulted in a significant increase in the rate of apoptosis induced by araC in the presence of NGF. Consistent with this finding, ciliary neurotrophic factor, which does not cause sustained activation of MAPK/ERK, did not protect against araC toxicity. Our data show that, in contrast to NGF deprivation, araC induces apoptosis via a p53-dependent, JNK-independent mechanism, against which MAPK/ERK plays a substantial protective role. Thus, NGF can suppress apoptotic mechanisms in addition to those caused by its own deprivation.


Alopecia associated with the use of selective serotonin reuptake inhibitors: Systematic review.
We aimed to systematically review published cases of alopecia (hair loss) associated with selective serotonin reuptake inhibitors (SSRIs). Four electronic databases were searched up to November 16, 2021. Thirty-eight publications describing 71 patients with a total of 81 episodes of alopecia met inclusion criteria. Patients' age ranged from 7 to 85 years and 80.3% were female. Alopecia most commonly affected scalp (98.6%). Reported time to onset ranged from 3 days to 5 years (median: 8.6 weeks). Discontinuation of the suspected SSRI led to recovery in 63.0% of episodes. Clinicians should be aware of this possible adverse effect of SSRIs.


[Pathogenetic mechanism for a female patient with hemophilia A].
To explore the pathogenetic mechanism for a female patient affected with hemophilia A (HA). Potential genetic defect was detected with inverse shifting-polymerase chain reaction (IS-PCR). The pattern of X chromosome inactivation was determined with a human androgen receptor assay (HUMARA assay). G-banded karyotyping was carried out to exclude potential chromosome aberrations. IS-PCR showed that the defect of FVIII gene was the distal type of intron 22 inversion. The HUMARA assay showed that the X chromosome inactivation was non-random, and that the mother's X chromosome activity was lower than that of the father's X chromosome which has carried the inverted FVIII gene. No abnormalities were found with G-banded chromosomes. The prevalence of female HA patient may be caused by non-random inactivation of X chromosomes.


Production of massoia lactone by Aureobasidium pullulans YTP6-14 isolated from the Gulf of Thailand and its fragrant biosurfactant properties.
In order to add to the existing knowledge about structural diversity of biosurfactants, marine environment was chosen to discover a new type of biosurfactant-producing fungus. A number of fungi were collected from the Gulf of Thailand and examined for biosurfactant productivities. A dimorphic fungus, Aureobasidium pullulans YTP6-14, produced several different biosurfactants in both heavy oil and aqueous layers of the culture. Surface tension of the aqueous layer was decreased to 31·4 mN m-1 and oil displacement area reached 53 cm2 /10 μl after 7 days of cultivation. Critical micelle concentration and minimum surface tension values of the crude biosurfactants prepared from the aqueous layer were 39 mg l-1 and 31·6 mN m-1 respectively. Surface tension values remained unchanged over a wide range of pH and NaCl concentrations, suggesting their nonionic feature. LC/MS and NMR analyses revealed that one of the main active compounds in the aqueous layer was 5-hydroxy-2-decenoic acid delta-lactone, known as massoia lactone. Massoia lactone indeed showed significant surface tension reduction capacity of 43·3 mN m-1 at 1 mg ml-1 . This is the first report for the production of a fragrant biosurfactant, massoia lactone by a fungus A. pullulans. Massoia lactone has been industrially prepared from aromatic bark of an endangered tree species, Cryptocarya massoy, growing in rainforests. This report expands the diversity of biosurfactants produced by A. pullulans and also points to its possibility in contributing to the green sustainable chemistry, and ultimately rainforest conservation.


Reduced skeletal muscle independently predicts 1-year aggravated joint destruction in patients with rheumatoid arthritis.
Numerous cross-sectional studies have reported the associations between rheumatoid arthritis (RA) and reduced skeletal muscle. We firstly explored the dynamic change of skeletal muscle and its effect on RA clinical outcomes in a real-world prospective cohort. Consecutive RA patients were treated according to the treat-to-target strategy and completed at least 1-year follow up. Clinical data and muscle index (assessed by bioelectric impedance analysis) were collected at baseline and visits at 3, 6, 9 and 12 months. Myopenia was defined by appendicular skeletal muscle mass index ⩽7.0 kg/m2 in men and ⩽5.7 kg/m2 in women. A 1-year radiographic progression as primary outcome was defined by a change in the total Sharp/van der Heijde modified score ⩾0.5 units. Among 348 recruited patients, 315 RA patients (mean age 47.9 years, 84.4% female) completed 1-year follow up. There were 143 (45.4%) RA patients showing myopenia at baseline. Compared with those without baseline myopenia, RA patients with baseline myopenia had higher rate of 1-year radiographic progression (43.4% versus 21.5%, all p < 0.05). Baseline myopenia was an independent risk factor for 1-year radiographic progression with adjusted odds ratio (AOR) of 2.5-fold, especially among RA patients in remission at baseline both defined by Disease Activity Score in 28 joints (DAS28) including C-reactive protein (DAS28-CRP) or erythrocyte sedimentation rate (DAS28-ESR) with AOR of 18.5~42.9-fold. Further analysis of six subtypes of dynamic skeletal muscle change showed that newly acquired myopenia at endpoint was associated with radiographic progression (AOR of 5.4-fold). Reduced skeletal muscle is an independent predicting factor for 1-year aggravated joint destruction, especially in remission RA. The importance of dynamic monitoring of skeletal muscle and muscle improvement therapy are worth exploration.


Influence of cigarillo packaging characteristics on young adults' perceptions and intentions: findings from three online experiments.
Packaging is an important component of tobacco marketing that influences product perceptions and use intentions. However, little research exists on cigar packaging. We leveraged variability in existing Swisher Sweets cigarillo packaging to extend the evidence base. Between 2017 and 2019, we conducted three online experiments with 774 young adult past-year cigar smokers recruited via Amazon Mechanical Turk. After viewing Swisher package images that differed by flavour descriptor and/or colour, participants rated them on perceptions and purchase intentions. In study 1, participants viewed one of four cigarillos ('Wild Rush Encore', 'Wild Rush Limited', 'Twisted Berry' and 'Strawberry'). In study 2, participants viewed two different watermelon rum-flavoured cigarillos ('Boozy Watermelon' and 'Island Madness'). In study 3, participants viewed two of three 'Wild Rush' cigarillo versions ('Encore' with or without an explicit flavour descriptor or 'Limited'). In study 1, more participants perceived 'Twisted Berry' and 'Wild Rush Limited' as tasting good and less harsh tasting compared with 'Wild Rush Encore'. In study 2, compared with 'Island Madness', more participants perceived 'Boozy Watermelon' as tasting good, less harsh tasting and used by younger users but less by masculine users; female participants were more likely to purchase 'Boozy Watermelon'. In study 3, participants perceived 'Wild Rush Encore' with the explicit flavour descriptor as tasting better than packages without and being used by younger users but less by masculine users. Variations in cigarillo packaging, even among cigarillos with the same flavour, may have differential consumer appeal, suggesting packaging features should be considered in cigar product regulation.


Is female sex a risk factor for red blood cell alloimmunization after transfusion? A systematic review.
Large scale red blood cell (RBC) antigen genotyping of donors is currently well developed. There is scarce information, however, to select patients who might benefit from preemptive extended RBC antigen-matched transfusions. Female sex has been proposed as a risk factor for RBC alloimmunization after transfusion. To asses whether females respond differently to RBC alloantigens compared with males, we conducted a literature review on RBC alloimmunization. Clinical studies on RBC alloimmunization incidence were searched for in databases from 1950 through 2011. Studies were included when data were available to calculate the female-to-male risk ratio for alloimmunization. Based on the reported age, adult patients (>18 years) were distinguished from pediatric patients (≤18 years), and articles were analyzed according to disease categories. Thirty articles fulfilled the inclusion criteria. The Mantel-Haenszel risk ratio estimate of combined adult studies showed that women with sickle cell disease had an increased relative risk (27%) on RBC alloantibodies compared with men. Other groups showed equal alloimmunization risk in women and men. Women slightly more often than men possess RBC antibodies. This is likely explained by more exposure to immunizing events through pregnancy and/or transfusions in females with sickle cell disease. The results support the current policy implemented in many countries for Rhesus/Kell matching in patients with a hemoglobinopathy irrespective of sex. Thus, based solely on sex difference, the results do not justify recommending additional matching for women, besides preemptive K and c antigen matching for women during the (pre-) fertile age, as already applied in many European countries for the prevention of fetal morbidity.


Effect of sodium butyrate in combination with X-irradiation, chemotherapeutic and cyclic AMP stimulating agents on neuroblastoma cells in culture.
Sodium butyrate, X-irradiation, chemotherapeutic agents and cyclic AMP-stimulating agents cuased reduction in the cell number (due to cell death and reduction in cell division) when added individually to mouse neuroblastoma cells in culture. However, the combination of sodium butyrate with X-irradiation, chemotherapeutic and cyclic AMP-stimulating agents produced a greater reduction in the cell number than that produced by the individual agents.


In vivo function of the proteasome in the ubiquitin pathway.
A major eukaryotic proteolytic system is known to require the covalent attachment of ubiquitin to substrates prior to their degradation, yet the proteinase involved remains poorly defined. The proteasome, a large conserved multi-subunit protein complex of the cytosol and the nucleus, has been implicated in a variety of cellular functions. It is shown here that a yeast mutant with a defective proteasome fails to degrade proteins which are subject to ubiquitin-dependent proteolysis in wild-type cells. Thus, the proteasome is part of the ubiquitin system and mediates the degradation of ubiquitin-protein conjugates in vivo.


Does the time from biopsy to surgery affect biochemical recurrence after radical prostatectomy?
To evaluate whether the time from biopsy to radical prostatectomy (RP) predicts the biochemical recurrence (BCR) after RP, as men diagnosed with clinically localized prostate cancer have several available treatment options and investigating these alternatives may delay the initiation of definitive therapy. We identified 3969 consecutive patients who had RP for clinically localized prostate cancer from 1987 to 2002; those eligible for the study had RP within a year of diagnosis. The interval between biopsy and RP was analysed both as a continuous and as a dichotomous variable (divided at 3 months). Multivariate analysis was used to evaluate the impact of time to RP on BCR. Subsets were also analysed for the effect of time to RP in patients considered to be at high risk of recurrence, with group 1 having a prostate specific antigen (PSA) level of > or = 20 ng/mL, a biopsy Gleason score of > or = 8, or clinical stage > or = T2c; and group 2 assessed as having a >40% probability of BCR using a preoperative nomogram. In all, 3149 patients met the inclusion criteria and had a mean (interquartile range) follow-up after RP of 5.4 (2.2-7.9) years. Multivariate analysis showed that the year of biopsy, PSA level before biopsy, clinical stage and biopsy Gleason score (all P < 0.001) were significantly associated with BCR after RP. The time to RP, treated either as a continuous variable (P = 0.252) or when categorized at 3 months (P = 0.939), failed to predict BCR. Further, the time to RP was not an independent predictor of BCR for patients at high risk of recurrence in group 1 (P = 0.147) or group 2 (P = 0.548). The time from biopsy to RP did not influence the probability of BCR for men who had RP within a year of diagnosis, even for those considered to be at high risk of BCR. Instead, the clinical and pathological features of the cancer provided the best estimate of the risk of BCR.


A Trigger and Response System for Preventing Cardiac Arrest in the ICU.
Although patients in the ICU are closely monitored, some ICU cardiac arrest events may be preventable. In this study, we sought to reduce the rate of cardiac arrests occurring in the ICU through a quality improvement initiative. Prospective, observational study. ICUs of a single tertiary care center. Patients hospitalized in the ICUs between August 2017 and November 2019. A comprehensive trigger and response tool. Forty-three patients experienced an ICU cardiac arrest in the preintervention epoch (6.79 arrests per 1,000 discharges), and 59 patients experienced an ICU cardiac arrest in the intervention epoch (7.91 arrests per 1,000 discharges). In the intervention epoch, the clinical trigger and response tool was activated 106 times over a 1-year period, most commonly due to unexpected new/worsening hypotension. There was no step change in arrest rate (2.24 arrests/1,000 patients; 95% CI, -1.82 to 6.28; p = 0.28) or slope change (-0.02 slope of arrest rate; 95% CI, -0.14 to 0.11; p = 0.79) comparing the preintervention and intervention time epochs. Cardiac arrests in the preintervention epoch were more likely to be "potentially preventable" than that in the intervention epoch (25.6% vs 12.3%, respectively; odds ratio, 0.58; 95% CI, 0.20-0.88; p < 0.01). A novel trigger-and-response tool did not reduce the frequency of ICU cardiac arrest. Additional investigation is needed into the optimal approach for ICU cardiac arrest prevention.


Identification of a potent and selective 5-HT1B receptor antagonist.
An SAR study around the mixed 5-HT1ABD receptor antagonist SB-272183 found that introduction of cis-2,6-dimethyl substitution onto the piperazine ring was a key structural change, which imparted a combination of both excellent selectivity over the 5-HT1A and 5-HT1D receptors and low intrinsic activity. This led to the identification of the selective 5-HT1B receptor antagonist SB-616234.


The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice.
Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscular disorder and cognitive dysfunction caused by mutations in the dystrophin gene. It is characterized by excess inflammatory responses in the muscle and repeated degeneration and regeneration cycles. Neutral sphingomyelinase 2/sphingomyelin phosphodiesterase 3 (nSMase2/Smpd3) hydrolyzes sphingomyelin in lipid rafts. This protein thus modulates inflammatory responses, cell survival or apoptosis pathways, and the secretion of extracellular vesicles in a Ca2+-dependent manner. However, its roles in dystrophic pathology have not yet been clarified. To investigate the effects of the loss of nSMase2/Smpd3 on dystrophic muscles and its role in the abnormal behavior observed in DMD patients, we generated mdx mice lacking the nSMase2/Smpd3 gene (mdx:Smpd3 double knockout [DKO] mice). Young mdx:Smpd3 DKO mice exhibited reduced muscular degeneration and decreased inflammation responses, but later on they showed exacerbated muscular necrosis. In addition, the abnormal stress response displayed by mdx mice was improved in the mdx:Smpd3 DKO mice, with the recovery of brain-derived neurotrophic factor (Bdnf) expression in the hippocampus. nSMase2/Smpd3-modulated lipid raft integrity is a potential therapeutic target for DMD.


Antibiotics Effects on the Fecal Metabolome in Preterm Infants.
Within a randomized prospective pilot study of preterm infants born at less than 33 weeks' gestation, weekly fecal samples from 19 infants were collected and metabolomic analysis was performed. The objective was to evaluate for differences in fecal metabolites in infants exposed to antibiotics vs. not exposed to antibiotics in the first 48 h after birth. Metabolomics analysis was performed on 123 stool samples. Significant differences were seen in the antibiotics vs. no antibiotics groups, including pathways related to vitamin biosynthesis, bile acids, amino acid metabolism, and neurotransmitters. Early antibiotic exposure in preterm infants may alter metabolites in the intestinal tract of preterm infants. Broader multi-omic studies that address mechanisms will guide more prudent antibiotic use in this population.


Novel copper-based therapeutic agent for anti-inflammatory: synthesis, characterization, and biochemical activities of copper(II) complexes of hydroxyflavone Schiff bases.
Four hydroxyflavone derivatives have been synthesized with the aim of obtaining a good model of superoxide dismutase. Better to mimic the natural metalloenzyme, copper complexes have been designed. The Cu(II) complexes of general formulae, [CuL] where L = 5-hydroxyflavone-o-phenylenediamine (L¹H₂)/m-phenylenediamine (L²H₂) and 3-hydroxyflavone-o-phenylenediamine (L³H₂)/m-phenylenediamine (L⁴H₂) have been synthesized. The structural features have been determined from their analytical and spectral data. All the Cu(II) complexes exhibit square planar geometry. Redox behavior of copper complexes was studied and the present ligand systems stabilize the unusual oxidation state of the copper ion during electrolysis. The in vitro antimicrobial activities of the investigated compounds were tested against the bacterial species Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, and Pseudomonas aeruginosa and fungal species Aspergillus niger, Rhizopus stolonifer, Aspergillus flavus, Rhizoctonia bataicola, and Candida albicans. Superoxide dismutase and anti-inflammatory activities of the copper complexes have also been measured and discussed.


Oncologic Outcomes after Localized Prostate Cancer Treatment: Associations with Pretreatment Prostate Magnetic Resonance Imaging Findings.
We investigated whether T2-weighted magnetic resonance imaging findings could improve upon established prognostic indicators of metastatic disease and prostate cancer specific survival. For a cohort of 3,406 consecutive men who underwent prostate magnetic resonance imaging before prostatectomy (2,160) or radiotherapy (1,246) between 2001 and 2006, T2-weighted magnetic resonance imaging exams were retrospectively interpreted and categorized as I) no focal suspicious lesion, II) organ confined focal lesion, III) focal lesion with extraprostatic extension or IV) focal lesion with seminal vesicle invasion. Clinical risk was recorded based on European Association of Urology (EAU) guidelines and the Cancer of the Prostate Risk Assessment (CAPRA) scoring system. Survival probabilities and c-indices were estimated using Cox models and inverse probability censoring weights, respectively. The median followup was 10.8 years (IQR 8.6-13.0). Higher magnetic resonance imaging categories were associated with a higher likelihood of developing metastases (HR 3.5-18.1, p <0.001 for all magnetic resonance imaging categories) and prostate cancer death (HR 3.1-29.7, p <0.001-0.025); these associations were statistically independent of EAU risk categories, CAPRA scores and treatment type (surgery vs radiation). Combining EAU risk or CAPRA scores with magnetic resonance imaging categories significantly improved prognostication of metastases (c-indices: EAU: 0.798, EAU + magnetic resonance imaging: 0.872; CAPRA: 0.808, CAPRA + magnetic resonance imaging: 0.877) and prostate cancer death (c-indices: EAU 0.813, EAU + magnetic resonance imaging: 0.889; CAPRA: 0.814, CAPRA + magnetic resonance imaging: 0.892; p <0.001 for all). Magnetic resonance imaging findings of localized prostate cancer are associated with clinically relevant long-term oncologic outcomes. Combining magnetic resonance imaging and clinicopathological data results in more accurate prognostication, which could facilitate individualized patient management.


Pulmonary function in children and adolescents with untreated idiopathic scoliosis: a systematic review with meta-regression analysis.
One of the controversies in untreated idiopathic scoliosis is the influence of curve size on respiratory function. Whereas scoliosis patients with curves over 90 to 100 degrees are agreed to be at risk for cardiorespiratory failure in later life, the impairment of curves below 90 degrees is generally considered mild. Although various studies showed that pulmonary function is affected in patients with scoliosis, quantification of the relation between curve size and pulmonary function is lacking. This systematic review with meta-regression analysis aims to characterize the relation between pulmonary function tests and scoliosis severity in children and adolescents with idiopathic scoliosis. Systematic review with meta-regression analysis. Pubmed, Embase, Cochrane, and CINAHL were systematically searched until November 3, 2020, for original articles that reported (1) severity of scoliosis quantified in Cobb angle, and (2) pulmonary function tests in children and adolescents with untreated idiopathic scoliosis. Exclusion criteria were other types of scoliosis, non-original data, post-treatment data, and case reports. All study designs were included, and relevant study details and patient characteristics were extracted. The primary outcome was the effect of Cobb angle on pulmonary function as expressed by the slope coefficient of a linear meta-regression analysis. A total of 126 studies, including 8,723 patients, were retrieved. Meta-regression analysis revealed a statistically significant inverse relation between thoracic Cobb angle and absolute and predicted forced vital capacity in 1 second, forced vital capacity, vital capacity, and total lung capacity. For these outcomes, the slope coefficients showed a decrease of 1% of the predicted pulmonary function per 2.6 to 4.5 degrees of scoliosis. A multivariable meta-regression analysis of potential confounders (age, year of publication, and kyphosis) hardly affected the majority of the outcomes. This meta-regression analysis of summary data (means) from 126 studies showed an inverse relationship between the thoracic Cobb angle and pulmonary function. In contrast to previous conclusions, the decline in pulmonary function appears to be gradual over the full range of Cobb angles between <20 and >120 degrees. These findings strengthen the relevance of minimizing curve progression in children with idiopathic scoliosis.


Resonance Rayleigh scattering study on the interaction of gold nanoparticles with berberine hydrochloride and its analytical application.
The interaction of gold nanoparticles with berberine hydrochloride has been studied by using resonance Rayleigh scattering (RRS) spectra. In pH 3.8-5.5 aqueous solution, citrate acid ([H2L2-]) self-assembled on the surface of positively charged gold nanoparticles (average diameter is about 12.0 nm) to form a supermolecular complex with negative charges. By virtue of electrostatic attraction, hydrophobic force and charge transfer, the complex bound with berberine to form complex, which had bigger diameter (35 nm) than gold nanoparticles. The formation of the binding production not only resulted in the red shift of absorption of gold nanoparticles from 518 to 672 nm, but also led to the greatly enhancement of RRS intensity. At the same time, the intensities of second-order scattering (SOS) and frequency-doubling scattering (FDS) were also increased. Under definite condition, the increment of the RRS (DeltaI) were proportional to the concentration of berberine. A sensitive and simple method for the determination of berberine based on the RRS technique has been developed. The detection limit (3sigma) for berberine was 0.40 ng mL(-1) and the quantitative determination range was 1.33-240 ng mL(-1). In this work, the optimum conditions of reaction, the effect of foreign substances and the analytical application had been investigated.


The origin and evolution of cell-intrinsic antibacterial defenses in eukaryotes.
To survive in a world dominated by bacteria, eukaryotes have evolved numerous self-defense strategies. While some defenses are recent evolutionary innovations, others are ancient, with roots early in eukaryotic history. With a focus on antibacterial immunity, we highlight the evolution of pattern recognition receptors that detect bacteria, where diverse functional classes have been formed from the repeated use and reuse of a small set of protein domains. Next, we discuss core microbicidal strategies shared across eukaryotes, and how these systems may have been co-opted from ancient cellular mechanisms. We propose that studying antibacterial responses across diverse eukaryotes can reveal novel modes of defense, while highlighting the critical innovations that occurred early in the evolution of our own immune systems.


T wave alternans as a predictor of recurrent ventricular tachyarrhythmias in ICD recipients: prospective comparison with conventional risk markers.
The current standard for arrhythmic risk stratification is electrophysiologic (EP) testing, which, due to its invasive nature, is limited to patients already known to be at high risk. A number of noninvasive tests, such as determination of left ventricular ejection fraction (LVEF) or heart rate variability, have been evaluated as additional risk stratifiers. Microvolt T wave alternans (TWA) is a promising new risk marker. Prospective evaluation of noninvasive risk markers in low- or moderate-risk populations requires studies involving very large numbers of patients, and in such studies, documentation of the occurrence of ventricular tachyarrhythmias is difficult. In the present study, we identified a high-risk population, recipients of an implantable cardioverter defibrillator (ICD), and prospectively compared microvolt TWA with invasive EP testing and other risk markers with respect to their ability to predict recurrence of ventricular tachyarrhythmias as documented by ICD electrograms. Ninety-five patients with a history of ventricular tachyarrhythmias undergoing implantation of an ICD underwent EP testing, assessment of TWA, as well as determination of LVEF, baroreflex sensitivity, signal-averaged ECG, analysis of 24-hour Holter monitoring, and QT dispersion from the 12-lead surface ECG. The endpoint of the study was first appropriate ICD therapy for electrogram-documented ventricular fibrillation or tachycardia during follow-up. Kaplan-Meier survival analysis revealed that TWA (P < 0.006) and LVEF (P < 0.04) were the only significant univariate risk stratifiers. EP testing was not statistically significant (P < 0.2). Multivariate Cox regression analysis revealed that TWA was the only statistically significant independent risk factor. Measurement of microvolt TWA compared favorably with both invasive EP testing and other currently used noninvasive risk assessment methods in predicting recurrence of ventricular tachyarrhythmias in ICD recipients. This study suggests that TWA might also be a powerful tool for risk stratification in low- or moderate-risk patients, and needs to be prospectively evaluated in such populations.


Isolation of the ryanodine receptor from cardiac sarcoplasmic reticulum and identity with the feet structures.
Ryanodine, a highly toxic alkaloid, reacts specifically with the Ca2+ release channels which are localized in the terminal cisternae of sarcoplasmic reticulum (SR). In this study, the ryanodine receptor from cardiac SR has been purified, characterized, and compared with that of skeletal muscle SR. The ryanodine receptor was solubilized with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) in the presence of phospholipids. Purification was performed by sequential affinity chromatography followed by gel permeation chromatography in the presence of CHAPS and phospholipids. The enrichment of the receptor from cardiac microsomes was about 110-fold. The purified receptor contained a major polypeptide band of Mr 340,000 with a minor band of Mr 300,000 (absorbance ratio 100/8) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Electron microscopy of the purified receptor from heart showed square structures of 222 +/- 21 A/side, which is the unique characteristic of feet structures of junctional face membrane of terminal cisternae of SR. Recently, we isolated the ryanodine receptor from skeletal muscle (Inui, M., Saito, A., and Fleischer, S. (1987) J. Biol. Chem. 262, 1740-1747). The ryanodine receptors from heart and skeletal muscle have similar characteristics in terms of protein composition, morphology, chromatographic behavior, and Ca2+, salt, and phospholipid dependence of ryanodine binding. However, there are distinct differences: 1) the Mr of the receptor is slightly larger for skeletal muscle (Mr approximately 360,000); 2) the purified receptor from heart contains two different affinities for ryanodine binding with Kd values in the nanomolar and micromolar ranges, contrasting with that of skeletal muscle SR which shows only the high affinity binding; 3) the affinity of the purified cardiac receptor for ryanodine was 4-5-fold higher than that of skeletal muscle, measured under identical conditions. The greater sensitivity in ryanodine in intact heart can be directly explained by the tighter binding of the ryanodine receptor from heart. The present study suggests that basically similar machinery (the ryanodine receptor and foot structure) is involved in triggering Ca2+ release from cardiac and skeletal muscle SR, albeit there are distinct differences in the sensitivity to ryanodine and other ligands in heart versus skeletal muscle.


Long-term effects of early maternal deprivation on goat social behaviour.
Early maternal deprivation has been shown to disrupt goat kids' social behaviour and stress-coping strategy, and has long-term effects in other species like cattle. We studied the long-term effects of early maternal deprivation on 18-month-old goats. Seventeen goats were raised together with their dams (DR kids) and other lactating goats and kids, while 18 goats were separated from their dams three days after birth and artificially reared together (AR kids). Kids of both treatments were weaned around two to three months of age, grouped and raised together until this study 15 months later. Affiliative, playful, and agonistic behaviour was recorded by focal sampling in the home pen, when the focal goat had rejoined the herd after being physically isolated for 3 minutes, and after the focal goat was restrained and manipulated for 3 minutes. Behavioural observations were also conducted after the goats were introduced in groups of four in a herd of 77 unknown, lactating multiparous goats. Avoidance distance tests were performed in the home pen to assess the human-animal relationship. Salivary cortisol was measured before and after physical isolation, and faecal glucocorticoid metabolites were measured before and 24 hours after introduction in the lactating herd. In the home pen, AR goats were involved in less head nudging than DR goats, but other social behaviours or their behavioural and physiological response to the various stressful situations were not affected by their rearing treatment. Upon introduction in a DR lactating herd, most of the agonistic interactions observed were initiated by multiparous goats towards the introduced AR and DR goats alike. AR goats received more threats from the multiparous goats than DR goats, but were involved in less clashing than DR goats. AR goats showed less avoidance of familiar and unfamiliar humans than DR goats. Overall, previously AR and DR goats showed only a few differences in affiliative and agonistic behaviours in their home pen or after being exposed to different stressors 15 months later. Nonetheless, after being introduced into a multiparous goat herd, AR goats were still threatened more often than DR goats, and DR goats clashed more than AR goats, suggesting some persistent differences in their social abilities observed at an early age before and after weaning. As predicted, AR goats remained less fearful of humans than DR goats.


Dose-Intense Cisplatin-Based Neoadjuvant Chemotherapy Increases Survival in Advanced Cervical Cancer: An Up-to-Date Meta-Analysis.
We set out to demonstrate the benefit of using dose-intense cisplatin-based neoadjuvant chemotherapy in terms of overall survival and progression-free survival. We searched through MEDLINE and Cochrane Library databases up to May 2021 to identify randomized clinical trials comparing the benefit of using cisplatin-based neoadjuvant chemotherapy followed by local treatment with local treatment alone for the treatment of locally advanced cervical cancer. The PRISMA statement was applied. Twenty-two randomized clinical trials were retrieved between 1991 and 2019, corresponding to 3632 women with FIGO stages IB2-IVA cervical cancer. More than 50% of the randomized clinical trials were assessed as having a low risk of bias. There was no benefit of neoadjuvant chemotherapy on overall survival, but there was significant heterogeneity across studies (I2 = 45%, p = 0.01). In contrast, dose-intense cisplatin at over 72.5 mg/m2/3 weeks was significantly associated with increased overall survival (RR = 0.87, p < 0.05) with no heterogeneity across the pooled studies (I2 = 36%, p = 0.11). The survival benefit was even greater when cisplatin was administered at a dose over 105 mg/m2/3 weeks (RR = 0.79, p < 0.05). Even though radiotherapy combined with weekly cisplatin-based chemotherapy remains standard of care for the treatment of locally advanced cervical cancer, our meta-analysis makes it possible to consider the use of dose-intense cisplatin-based neoadjuvant chemotherapy when local treatment is suboptimal and opens perspectives for designing new clinical trials in this setting. Neoadjuvant chemotherapy could be proposed when surgery is local treatment instead of standard chemoradiotherapy for the treatment of locally advanced cervical cancer.


Chelating diamide based rate enhancement of intramolecular alkene hydroaminations catalyzed by a neutral Sc(III) complex.
[reaction: see text] Neutral scandium amido complexes are viable catalysts for intramolecular alkene hydroamination. Catalytic activity is strongly coupled to the electronic character of the Sc(III) ligand environment with chelating diamide coordination providing a precatalyst possessing substantially improved activity and superb distereoselectivity in the synthesis of trans-2,5-disubstituted pyrrolidines.


Observations of a free-ranging adult female dingo (Canis dingo) and littermates' responses to the death of a pup.
In contrast to several species of cetaceans and primates, behavioural responses to dead conspecifics have rarely been reported in wild canids. Here we provide details of the responses of an adult female and littermates to a dying and subsequently dead pup, including what appeared to be four instances of transport of the deceased pup by the mother over a two-day period, one of which was directly observed and filmed. We tentatively propose that, in the absence of any evidence of consumption of the pup, its transport by the mother could be interpreted as care-giving behaviour emanating from an enduring mother-infant bond, in a similar vein to what has been suggested for several other species exhibiting such behaviour.


VCP binding influences intracellular distribution of the slow Wallerian degeneration protein, Wld(S).
Wallerian degeneration slow (Wld(S)) mice express a chimeric protein that delays axonal degeneration. The N-terminal domain (N70), which is essential for axonal protection in vivo, binds valosin-containing protein (VCP) and targets both Wld(S) and VCP to discrete nuclear foci. We characterized the formation, composition and localization of these potentially important foci. Missense mutations show that the N-terminal sixteen residues (N16) of Wld(S) are essential for both VCP binding and targeting Wld(S) to nuclear foci. Removing N16 abolishes foci, and VCP binding sequences from ataxin-3 or HrdI restore them. In vitro, these puncta co-localize with proteasome subunits. In vivo, Wld(S) assumes a range of nuclear distribution patterns, including puncta, and its neuronal expression and intranuclear distribution is region-specific and varies between spontaneous and transgenic Wld(S) models. We conclude that VCP influences Wld(S) intracellular distribution, and thus potentially its function, by binding within the N70 domain required for axon protection.


Is the prognosis of heart failure improving?
BACKGROUND AND METHODS": Heart failure is common and effective therapy exists but as yet there is little evidence that the overall prognosis is improving in clinical practice. We sought to determine if mortality, re-admission with heart failure and re-admission for any cause, had changed between cohorts of first-time admissions for heart failure identified in 1984, 1988 and 1992 using linked hospital discharge and mortality data from Scotland (population approximately 5 million). The number of first-time admissions for heart failure increased by 30% between 1984 and 1992, from 9716 to 12640. Their mean age was 74 years and 54% were women. Over the same period 3-year mortality declined in patients < 65 years from 53 to 41% (reduction in risk 12% (95% confidence interval 9-15%. Log-rank 70.0; P<0.001) and for patients > or =65 years from 71% to 66% (reduction in risk 5% (95% confidence interval 3-6%. Log-rank 74.5; P<0.0001). Time to death or first re-admission with heart failure also improved but not time to death or first re-admission for any cause. The total number of re-admissions increased between 1984 and 1992 but bed-days occupancy for heart failure and for any cause, adjusted for days alive, declined due to a reduction in length of stay. These data suggest that the prognosis of patients with a first admission for heart failure is improving. The timing of improvement coincides with the gradual increase in the use of angiotensin converting enzyme inhibitors for heart failure although a causal link cannot be proved from these data.


Immuno-suppressive effects of aqueous extract of soapnut Sapindus emarginatus on the larvae and pupae of vector mosquito, Aedes aegypti.
We recently reported the presence of potent anti-mosquito activity in aqueous kernel extract of the soapnut, Sapindus emarginatus, and demonstrated its impact on marker enzymes in larvae and pupae of the vector mosquito, Aedes aegypti. As a sequel to these findings, the present study elucidates immunotoxicity of this extract with respect to hemocyte-mediated cellular immune responses in fourth instar larvae and pupae as well as cuticular melanization reaction in the larvae of A. aegypti. The exposure of these two developmental stages of the mosquito to the soapnut extract at a lethal threshold concentration neither affected hemocyte viability tested up to 3h in vitro nor did it influence the hemocyte count. By contrast, exposure of the mosquito larvae and pupae to this extract significantly reduced the ability of their hemocytes to bind yeast cells, an important early event in the process of non-self recognition by immune cells. Consequently, the phagocytic activity of these hemocytes against yeast cells was also found to be adversely affected upon exposure of larvae and pupae to the extract. Besides, a perceptible initial delay in melanization reaction at the injured site of the cuticle in the extract-exposed larvae was observed. All these findings demonstrate, for the first time, the immuno-suppressive potential of a botanical biocide in the vector mosquito.


A double outlet to relieve left ventricular hypertension.
The patient with aortic stenosis may have reduced left ventricular outflow with a relatively normal valvular architecture and little or no myocardial hypertrophy. For such a patient, surgery directly on the outflow structures may involve serious problems and "trade-offs". Construction of a supplementary conduit from the ventricular apex to the abdominal aorta can provide a valid alternative to more conventional approaches.


Quality of life of COVID-19 recovered patients: a 1-year follow-up study from Bangladesh.
The COVID-19 pandemic posed a danger to global public health because of the unprecedented physical, mental, social, and environmental impact affecting quality of life (QoL). The study aimed to find the changes in QoL among COVID-19 recovered individuals and explore the determinants of change more than 1 year after recovery in low-resource settings. COVID-19 patients from all eight divisions of Bangladesh who were confirmed positive by reverse transcription-polymerase chain reaction from June 2020 to November 2020 and who subsequently recovered were followed up twice, once immediately after recovery and again 1 year after the first follow-up. The follow-up study was conducted from November 2021 to January 2022 among 2438 individuals using the World Health Organization Quality of Life Brief Version (WHOQOL-BREF). After excluding 48 deaths, 95 were rejected to participate, 618 were inaccessible, and there were 45 cases of incomplete data. Descriptive statistics, paired-sample analyses, generalized estimating equation (GEE) analysis, and multivariable logistic regression analyses were performed to test the mean difference in participants' QoL scores between the two interviews. Most participants (n = 1710, 70.1%) were male, and one-fourth (24.4%) were older than 46. The average physical domain score decreased significantly from baseline to follow-up, and the average scores in psychological, social, and environmental domains increased significantly at follow-up (P < 0.05). By the GEE equation approach, after adjusting for other factors, we found that older age groups (P < 0.001), being female (P < 0.001), having hospital admission during COVID-19 illness (P < 0.001), and having three or more chronic diseases (P < 0.001), were significantly associated with lower physical and psychological QoL scores. Higher age and female sex [adjusted odd ratio (aOR) = 1.3, 95% confidence interval (CI) 1.0-1.6] were associated with reduced social domain scores on multivariable logistic regression analysis. Urban or semi-urban people were 49% less likely (aOR = 0.5, 95% CI 0.4-0.7) and 32% less likely (aOR = 0.7, 95% CI 0.5-0.9) to have a reduced QoL score in the psychological domain and the social domain respectively, than rural people. Higher-income people were more likely to experience a decrease in QoL scores in physical, psychological, social, and environmental domains. Married people were 1.8 times more likely (aOR = 1.8, 95% CI 1.3-2.4) to have a decreased social QoL score. In the second interview, people admitted to hospitals during their COVID-19 infection showed a 1.3 times higher chance (aOR = 1.3, 95% CI 1.1-1.6) of a decreased environmental QoL score. Almost 13% of participants developed one or more chronic diseases between the first and second interviews. Moreover, 7.9% suffered from reinfection by COVID-19 during this 1-year time. The present study found that the QoL of COVID-19 recovered people improved 1 year after recovery, particularly in psychological, social, and environmental domains. However, age, sex, the severity of COVID-19, smoking habits, and comorbidities were significantly negatively associated with QoL. Events of reinfection and the emergence of chronic disease were independent determinants of the decline in QoL scores in psychological, social, and physical domains, respectively. Strong policies to prevent and minimize smoking must be implemented in Bangladesh, and we must monitor and manage chronic diseases in people who have recovered from COVID-19.


Rapid Surface Reconstruction of Amorphous Co(OH)2 /WOx with Rich Oxygen Vacancies to Promote Oxygen Evolution.
Herein, a transition metal dissolution-oxygen vacancy strategy, based on dissolution of highly oxidized transition metal species in alkaline electrolyte, was suggested to construct a high-performance amorphous Co(OH)2 /WOx (a-CoW) catalyst for the oxygen evolution reaction (OER). The surface reconstruction of a-CoW and its evolution were described by regulating oxygen vacancies. With continuous dissolution of W species, oxygen vacancies on the surface were generated rapidly, the surface reconstruction was promoted, and the OER performance was improved significantly. During the surface reconstruction, W species also played a role in electronic modulation for Co. Due to its rapid surface reconstruction, a-CoW exhibited excellent OER performance in alkaline electrolyte with an overpotential of 208 mV at 10 mA cm-2 and had long-term stability for at least 120 h. This work shows that the transition metal dissolution-oxygen vacancy strategy is effective for preparation of high-performance catalysts.


Role of superoxide dismutase in ischemic brain injury: a study using SOD-1 transgenic mice.
1. Nitric oxide radicals (NO) play an important role in the pathophysiology of focal cerebral ischemia. 2. Vascular NO can reduce ischemic brain injury by increasing CBF, whereas neuronal NO may mediate neurotoxicity following brain ischemia, mainly by its reaction with superoxide to generate peroxynitrite. 3. These findings could contribute to a strategy for the treatment of cerebral ischemia.


Involvement of Parkin-mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease-related sarcopenia.
Sarcopenia is characterized by the loss of skeletal muscle mass and strength and is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) exposure, a major cause for COPD, induces mitochondrial damage, which has been implicated in sarcopenia pathogenesis. The current study sought to examine the involvement of insufficient Parkin-mediated mitophagy, a mitochondrion-selective autophagy, in the mechanisms by which dysfunctional mitochondria accumulate with excessive reactive oxygen species (ROS) production in the development of COPD-related sarcopenia. The involvement of Parkin-mediated mitophagy was examined using in vitro models of myotube formation, in vivo CS-exposure model using Parkin-/- mice, and human muscle samples from patients with COPD-related sarcopenia. Cigarette smoke extract (CSE) induced myotube atrophy with concomitant 30% reduction in Parkin expression levels (P < 0.05). Parkin-mediated mitophagy regulated myotube atrophy by modulating mitochondrial damage and mitochondrial ROS production. Increased mitochondrial ROS was responsible for myotube atrophy by activating Muscle Ring Finger 1 (MuRF-1)-mediated myosin heavy chain (MHC) degradation. Parkin-/- mice with prolonged CS exposure showed enhanced limb muscle atrophy with a 31.7% reduction in limb muscle weights (P < 0.01) and 2.3 times greater MuRF-1 expression (P < 0.01) compared with wild-type mice with concomitant accumulation of damaged mitochondria and oxidative modifications in 4HNE expression. Patients with COPD-related sarcopenia exhibited significantly reduced Parkin but increased MuRF-1 protein levels (35% lower and 2.5 times greater protein levels compared with control patients, P < 0.01 and P < 0.05, respectively) and damaged mitochondria accumulation demonstrated in muscles. Electric pulse stimulation-induced muscle contraction prevented CSE-induced MHC reduction by maintaining Parkin levels in myotubes. Taken together, COPD-related sarcopenia can be attributed to insufficient Parkin-mediated mitophagy and increased mitochondrial ROS causing enhanced muscle atrophy through MuRF-1 activation, which may be at least partly preventable through optimal physical exercise.


Evaluating gene by sex and age interactions on cardiovascular risk factors in Brazilian families.
In family studies, it is important to evaluate the impact of genes and environmental factors on traits of interest. In particular, the relative influences of both genes and the environment may vary in different strata of the population of interest, such as young and old individuals, or males and females. In this paper, extensions of the variance components model are used to evaluate heterogeneity in the genetic and environmental variance components due to the effects of sex and age (the cutoff between young and old was 43 yrs). The data analyzed were from 81 Brazilian families (1,675 individuals) of the Baependi Family Heart Study. The models allowing for heterogeneity of variance components by sex suggest that genetic and environmental variances are not different in males and females for diastolic blood pressure, LDL-cholesterol, and HDL-cholesterol, independent of the covariates included in the models. However, for systolic blood pressure, fasting glucose and triglycerides, the evidence for heterogeneity was dependent on the covariates in the model. For instance, in the presence of sex and age covariates, heterogeneity in the genetic variance component was suggested for fasting glucose. But, for systolic blood pressure, there was no evidence of heterogeneity in any of the two variance components. Except for the LDL-cholesterol, models allowing for heterogeneity by age provide evidence of heterogeneity in genetic variance for triglycerides and systolic and diastolic blood pressure. There was evidence of heterogeneity in environmental variance in fasting glucose and HDL-cholesterol. Our results suggest that heterogeneity in trait variances should not be ignored in the design and analyses of gene-finding studies involving these traits, as it may generate additional information about gene effects, and allow the investigation of more sophisticated models such as the model including sex-specific oligogenic variance components.


High-fat taste challenge reveals altered striatal response in women recovered from bulimia nervosa: A pilot study.
Individuals with anorexia nervosa (AN) and bulimia nervosa (BN) tend to have disordered thinking and eating behaviours in regards to fat containing foods. This is the first study to investigate neuronal pathways that may contribute to altered fat consumption in eating disordered patients. We used functional magnetic resonance imaging (fMRI) to compare responses to a high-fat cream stimulus, water, and a non-caloric viscous stimulus (CMC) to control for response to viscosity in individuals recovered from AN (N = 15), BN (N = 14) and a healthy control sample (CW, N = 18). An interaction analysis (ANOVAR) comparing the three groups (AN, BN, CW) and the three conditions (cream, CMC, water) revealed significant differences in the left anterior ventral striatum (AVS). A post hoc analysis displayed a higher magnitude of response for the contrast cream/water in BN compared to AN or CW and for the contrast CMC/water in BN compared to AN. BN showed an exaggerated AVS response for the cream/water contrast in comparison to AN or CW. Moreover, BN showed an exaggerated AVS response for the CMC/water contrast in comparison to AN. These findings support the possibility that BN have an altered hedonic and/or motivational drive to consume fats.


Family structure, marital discord and offspring's psychopathology in early adulthood: a prospective study.
With marital breakdown and discord relatively common, we examined whether family structure and the quality of marital relationship have a long-term impact on offspring's psychopathology in early adulthood. This study aimed to examine the association of family structure and marital discord in the family with a wide range of offspring's mental health and problem behaviours at 21 years. Data were from the Mater-University of Queensland Study of Pregnancy, a population based birth cohort study, which commenced in Brisbane, Australia in 1981. Mothers and children were followed up at birth, 6 months and 5, 14 and 21 years after the initial interview. Marital status and marital quality were assessed at the 14 year follow-up. Young Adult Self-Report sub-scales of mental health and problem behaviours were measured at the 21-year follow-up. Type of family structure and the quality of marital relationship (at the 14-year follow-up) predicted offspring's psychopathology at 21 years. When a selected group of confounding factors were included in the multivariate analyses, children who lived with a step-father, un-partnered mother, or in families where parents had conflict in marital relationship reported higher symptoms of psychopathology at 21 years. The association between marital problems and young adult psychopathology does not appear to be confounded by a wide range of confounding variables. Further research is needed to explore the mechanism of these associations to develop preventive programmes.


Terrestrial runoff influences the transport and contamination levels of Toxoplasma gondii in marine organisms.
There is a growing concern regarding the potential adverse impact of Toxoplasma gondii contamination of the marine environment on marine wildlife and public health. Terrestrial runoff is a significant route for dissemination of T. gondii oocysts from land to sea. Yet, the influence of terrestrial runoff on T. gondii prevalence in marine animals in China is largely unknown. To address this concern, we examined the presence of T. gondii in marine oysters Crassostrea spp., rockfish Sebastes schlegelii (S. schlegelii), fat greenling fish Hexagrammos otakii (H. otakii), and Asian paddle crab Charybdis japonica (C. japonica) using a PCR assay targeting T. gondii B1 gene. A total of 1920 samples were randomly collected, in Jan-Dec 2020, from terrestrial runoff areas (TRA, TRB, and TRC) and non-terrestrial runoff area (Grape bay) in Weihai, China. T. gondii prevalence in TRB and TRC was 6.04 % and 5.83 %, respectively, which was higher than 2.29 % detected in the non-terrestrial runoff area. The highest prevalence was detected in Crassostrea spp., and a correlation was observed between T. gondii prevalence and weight of Crassostrea spp. The temperature, but not precipitation, significantly correlated with T. gondii prevalence. Understanding the fate of T. gondii delivered to oceans by terrestrial runoff is critical for predicting future disease risks for marine wildlife and humans.


Colonic perforation by amyloidosis. Report of a case.
One patient with a colonic perforation associated with secondary amyloidosis and ankylosing rheumatoid spondylitis was treated successfully. To our knowledge, this is the first case described of colonic perforation in amyloidosis.


Mississippi mud in the 1990s: risks and outcomes of vancomycin-associated toxicity in general oncology practice.
Discrepancies between the severity of toxicities reported in early clinical trials and recent clinical experience with vancomycin have led to confusion regarding the need for routine serum vancomycin level monitoring and discontinuation of vancomycin when toxicities occur. Therefore, the authors examined the incidence, outcomes, and predictive factors of vancomycin-associated toxicities in general oncology practice with the goal of developing clinically relevant prediction rules and guidelines. All 742 consecutive cancer patients who received vancomycin at a comprehensive cancer center during a 3-month period were followed prospectively for the development and outcome of phlebitis, rash, ototoxicity, and nephrotoxicity. Logistic regression was used to derive a multiple variable model of the risk of nephrotoxicity. A clinical prediction rule, the Nephrotoxicity Risk Score, was developed from the risk model and validated prospectively. Phlebitis occurred in 3% of patients (95% confidence interval [95% CI], 2-4%), predominantly those with recently inserted central venous catheters. Rashes occurred in 11% of patients (95% CI, 9-13%); however, all but 4 patients also were receiving beta-lactam antibiotics. Clinical evidence of ototoxicity developed in 6% of patients (95% CI, 4-9%) who were receiving vancomycin plus other ototoxic agents and only 3% of patients (95% CI, 2-5%) not receiving other ototoxic agents (P = 0.08). Nephrotoxicity occurred in 17% of patients (95% CI, 15-20%). Logistic regression revealed that factors associated with an increased risk of nephrotoxicity included administration of other mild to moderate (P = 0.01) or severely nephrotoxic agents (P < 0.001) or an acute physiology and chronic health evaluation (APACHE) score > 40 (P = 0.002). Elevated serum vancomycin peak levels did not reliably predict subsequent nephrotoxicity. Vancomycin-associated toxicities usually are mild and self-limiting. Some patients are at a significantly higher risk of nephrotoxicity but the authors believe these individuals can be identified reliably with the Nephrotoxicity Risk Index using information available at vancomycin initiation. Further testing of the Nephrotoxicity Risk Index is ongoing.


A Case of Acute Zonal Occult Outer Retinopathy in which Oct en Face Imaging Was Useful for Diagnosis and Follow-up.
A 23-year-old woman presented with a 1-month history of visual abnormalities in her right eye. A visual field test revealed temporal abnormalities in the right eye. Optical coherence tomography revealed an indistinct ellipsoid zone (EZ) on the B-scan image and hyporeflective areas in the EZ layer on the en face image in the right eye. We diagnosed the patient with acute zonal occult outer retinopathy. Visual field tests and B-scan images improved to almost normal at 6 months, but hyporeflective areas remained on the en face images. Thus, en face images may be more sensitive at detecting abnormalities in the outer retina than other modalities.


Pre-treatment 3H-TdR labelling of cervical biopsies: histology, staging and tumour response to radiotherapy.
Pre-treatment data from tumour biopsies labelled in vitro with tritiated thymidine are reported for 54 patients undergoing radical radiotherapy by 137Cs or Cathetron 60Co intracavitary insertions plus external irradiation for carcinoma of the uterine cervix. Labelling indices were obtained ranging from 1.8 to 27.8%. No correlation was observed between mean labelling indices and the histological type of tumour or its degree of differentiation. Comparison of data obtained in this study with previously reported data for carcinoma in situ and invasive carcinoma indicate that with increasing clinical stage of the disease, a considerable lengthening of the potential doubling time of the tumour cells, from less than 1 to 8 days, occurs. The degree of vaginal spread of the tumour was directly related to the degree of parametrial involvement. The mean time taken for the vaginal component of the tumour to resolve following radiotherapy was related to its initial spread and the pre-treatment labelling index. The greater the spread of the tumour, the lower the labelling index and the longer the time taken for resolution. Up to 1 year following radiotherapy the incidence of locally recurrent, or metastatic disease was unrelated to the pre-treatment labelling index.


Ciliogenesis and Hedgehog signalling are suppressed downstream of KRAS during acinar-ductal metaplasia in mouse.
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths worldwide, but has a 5-year survival rate of only 7% primarily due to late diagnosis and ineffective therapies. To treat or even prevent PDAC, it is vital that we understand the initiating events that lead to tumour onset. PDAC develops from preneoplastic lesions, most commonly pancreatic intraepithelial neoplasias (PanINs), driven by constitutive activation of KRAS. In patients, PanINs are associated with regions of acinar-to-ductal metaplasia (ADM) where, in response to inflammation, acini dedifferentiate to a pancreatic progenitor-like fate. In healthy tissue this process is reversible leading to regeneration of the pancreas; however, in the presence of oncogenic KRAS, regeneration is blocked and ADM can give rise to PanIN lesions. Here, we used a 3D mouse acinar culture that recapitulates ADM in vitro to explore how KRAS prevents regeneration. Regeneration is regulated by Hedgehog (Hh) signalling, which is transduced via the primary cilium. In wild-type acini, cilia assemble upon ADM and Hh target gene expression is upregulated; however, ciliogenesis and Hh signalling are suppressed during ADM in cells expressing oncogenic KRAS. We show that ciliogenesis fails due to ectopic activation of the cilium disassembly pathway, which is mediated by AurkA, a direct transcriptional target of KRAS. Inhibition of AurkA is able to rescue primary cilia and restore Hh signalling. We suggest that this could be used as a mechanism to prevent the formation of early lesions and thereby prevent progression to PDAC.


The Case for Algebraic Biology: from Research to Education.
Though it goes without saying that linear algebra is fundamental to mathematical biology, polynomial algebra is less visible. In this article, we will give a brief tour of four diverse biological problems where multivariate polynomials play a central role-a subfield that is sometimes called algebraic biology. Namely, these topics include biochemical reaction networks, Boolean models of gene regulatory networks, algebraic statistics and genomics, and place fields in neuroscience. After that, we will summarize the history of discrete and algebraic structures in mathematical biology, from their early appearances in the late 1960s to the current day. Finally, we will discuss the role of algebraic biology in the modern classroom and curriculum, including resources in the literature and relevant software. Our goal is to make this article widely accessible, reaching the mathematical biologist who knows no algebra, the algebraist who knows no biology, and especially the interested student who is curious about the synergy between these two seemingly unrelated fields.


Radiographic progression in patients with ankylosing spondylitis according to tumor necrosis factor blocker exposure: Observation Study of Korean Spondyloarthropathy Registry (OSKAR) data.
To evaluate the influence of tumor necrosis factor (TNF) blocker on the radiographic progression in ankylosing spondylitis (AS) patients. A total of 610 patients were recruited. We stratified two groups (TNF blocker naïve and exposure patients). After then, we analyzed the radiographic spinal progression. Univariable and multivariable analyses were performed to identify predictors associated with radiographic progression, which was assessed by the modified Stokes AS Spinal Score (mSASSS). As this was an observational study, the patients were not randomized to the treatment arm. Therefore, propensity score matching was also done with age, gender, and the baseline CRP. The generalized estimating equation model was performed in the post-matched samples. Potential confounders were included in the model. Agreements between the two readers were excellent. Of the 610 patients with AS, 341 patients did not have any exposure to TNF blocker. The radiographic progression (mean±SEM) was not significantly different between groups (4.73±1.01, and 6.14±2.00, P=0.54) in spite of adjusting for confounding factors (age, gender, disease duration, smoking, CRP level, NSAID intake, and baseline mSASSS). Propensity score matching was done to confirm the effect of TNF blockers on radiographic progression. Even after adjusting for the TNF blocker exposure, the result still remained not significant with an OR for progression while taking TNF blocker of 0.69 (P=0.41; 95% CI: 0.29-1.63). Our registry data showed that TNF blocker failed to affect the radiographic progression over 5 years in AS patients.


In-depth study of agave fiber structure using Fourier transform infrared spectroscopy.
FTIR spectroscopy is a powerful method to analyse materials and especially fiber structure. This technique is largely used to obtain quick information on the fiber composition and to detect possible transformations after physical and chemical treatments. Unlike other techniques, FTIR is a quick method which demands a reduced amount of fibers. Furthermore, it is a non destructive method especially for Attenuated Total Reflectance (ATR), and Near Infrared (NIR) spectroscopy which are nowadays widely used. In this work, FTIR spectrum of agave fiber has been thoroughly investigated. Because of its complexity, the spectrum was separated into two regions: CH and hydrogen bond stretching (>2500cm-1) and "fingerprint" region (<2000cm-1). A detailed study of intermolecular and intramolecular chains was made. Infrared ratios (Lateral Order Index, Total Crystallinity Index, and Hydrogen Bond Intensity) were used to study the crystallinity and the degree of regularity of agave fiber.


Temporal and spatial variations in the behavior of shrubsteppe birds.
We documented patterns of activity and microhabitat use by breeding male Sage Sparrows (Amphispiza belli) and Brewer's Sparrows (Spizella breweri) in the semiarid shrubsteppe of northwestern U.S.A. to determine how their behavior varies in space and time and how these variations relate to environmental features. In analyses of several sites with multiple plots that were studied for 2-4 yr, the frequencies of activities and substrate use varied significantly with year, plot, and location. The major activities, foraging and singing, varied inversely with one another. Thus, although the general structure of the activity budgets of these species was stable (i.e. foraging and singing were always the most frequent activities), there was considerable variation in the quantitative details of their behavior in space and time. Using stepwise regression, we related these variations in behavior to variations in environmental features such as the densities of the same or other species, the number of species in the community, and coverages of the different substrate types. Few patterns emerged, and those that did were generally not in accord with our expectations. In particular, patterns of substrate use were not related to variations in coverages of those substrates. Sage Sparrows, for example, increased their use of sagebrush and grass with increasing grass coverage and with increasing densities of Sage Sparrows. Responses to both variables suggested nonlinear threshold patterns.We interpret the variations in behavior as indicating a loose coupling between behavior and proximate environmental conditions for these species. In such situations, the variability of behavior complicates attempts to test ecological hypotheses (e.g. behavioral niche partitioning) with data from a limited number of locations or years.


Acute toxicity of an organophosphate insecticide sumithion to striped catfish Pangasianodon hypophthalmus.
Sumithion is widely used for crop safety and eradication of tiger bugs (Cicindela spp.) from larval rearing aquaculture ponds. To satisfy the high demand of fries and fingerlings of widely cultured species striped catfish, spawns are produced in large scale in the hatcheries through hormone induced breeding, and subsequently these spawns are reared in nursery ponds and marketed to fingerlings vendors for stocking in grow-out ponds. Considering the importance of healthy fries and fingerlings the present experiment was conducted to evaluate the toxic effects of sumithion on striped catfish fingerlings. Fish were exposed for 96 h to six concentrations of sumithion (0, 3, 4, 5, 6 and 7 mg/l) each with three replications. The 96 h LC50 value was calculated using probit analysis. After 96 h of exposure fishes were sacrificed to measure hemato-biochemical (Hemoglobin, Hb; Red blood cell, RBC; White blood cell, WBC and blood glucose) parameters. In addition, formation of micronucleus (MN) was examined in the blood erythrocytes. The 96 h LC50 value of sumithion for striped catfish was 5.886 mg/l. The values of RBCs and Hb decreased significantly in different concentrations of the toxicant compared to control, while the values of WBC and blood glucose levels showed opposite scenario. Consequently, the frequencies of formation of MN increased significantly in different concentrations of the toxicant compared to the control. The results of the current study denoted that sumithion exerts toxicity to striped catfish. It is expected that the findings of the present research will help in the development of awareness of the concerned people about the toxic effect of sumithion as well as other insecticides and pesticides in the environment.


A detailed comparative analysis on the overall codon usage patterns in West Nile virus.
West Nile virus (WNV) is a member of the family Flaviviridae and its genome consists of an 11-kb single-stranded, positive-sense RNA. WNV is maintained in an enzootic cycle between mosquitoes and birds, but can also infect and cause disease in horses and humans, which serve as incidental dead-end hosts. Understanding the extent and causes of biases in codon usage is essential to the comprehension of viral evolution. In this study, we performed a comprehensive analysis of 449 WNV strains, for which complete genome sequences are available. Effective number of codons (ENC) indicates that the overall codon usage among WNV strains is only slightly biased. Codon adaptation index (CAI) values found for WNV genes are different from the CAI values found for human genes. The relative synonymous codon usage among WNV strains isolated from birds, equines, humans and mosquitoes are roughly similar and are influenced by the relative dinucleotide frequencies. Taking together, the results of this work suggest that WNV genomic biases are the result of the evolution of genome composition, the need to escape the antiviral cell responses and a dynamic process of mutation and selection to re-adapt its codon usage to different environments.


Effectiveness of Stem Cell Therapy in the Treatment of Ovarian Disorders and Female Infertility: A Systematic Review.
Infertility is a major problem worldwide. Various strategies are being used to develop better treatments for infertility and The most trending strategy is the stem cell therapy. In this study, the literature on stem cell therapy for ovarian disorders is summarized with analysis of current developments. Different published studies on stem cell-based therapy for the treatment of various types of ovarian insufficiency and disorders such as Premature Ovarian Insufficiency (POI) in the affected female population in animal or human clinical studies are systematically reviewed. We monitored five databases, including PubMed, Cochrane, Embase, Scopus, and ProQuest. A comprehensive online search was done using the criteria targeting the application of stem cells in animal models for menopause. Two independent reviewers carefully evaluated titles and abstracts of studies. The stem cell type, source, dosage, route of administration were highlighted in various POI animals models. Non-relevant and review articles were excluded. 648 published studies were identified during the initial comprehensive search process from which 41 were selected according to designed criteria. Based on our analysis, stem cells could accelerate ovarian tissues rejuvenation, regulate systemic sex-related hormones levels and eventually increase fertility rate. The evidence suggests that stem cell-based therapies could be considered as an alternative modality to deal with women undergoing POI.


Determination of ultra-trace formaldehyde in air using ammonium sulfate as derivatization reagent and capillary electrophoresis coupled with on-line electrochemiluminescence detection.
The reaction between formaldehyde and ammonium ion to produce hexamethylenetetramine is well known. The reaction conditions are very easily controlled in situ and the experiment operation is very simple. However, such derivatization reaction for trace formaldehyde determination using capillary electrophoresis (CE) electrochemiluminescence (ECL) has not been reported before. In this study, the application of ammoniun sulfate as derivatization reagent to in-situ determination of formaldehyde in air was reported. Based on ECL enhancement of tris(2,2'-bipyridyl)ruthenium(II) with hexamethylenetetramine, a novel approach for the determination of ultra-trace formaldehyde in air using CE coupled with on-line ECL of tris(2,2'-bipyridyl)ruthenium(II) has been developed. The parameters affecting separation and detection such as detection potential, concentration and pH of phosphate buffer, and electrokinetic voltage, were investigated. Under the optimal conditions, the linear concentration range of formaldehyde in air was from 0.48 μg/m(3) to 96 mg/m(3) (linear range covering 5 orders of magnitude). The limit of detection (3σ) was 0.15 μg/m(3). The relative standard deviations of peak height and migration time for six consecutive injection of 1 ng/mL formaldehyde derivative were 0.9% and 0.8%, respectively. The recoveries of formaldehyde in air were between 99.3% and 101%.


Selective inhibitory effect of (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and 2'-nor-cyclic GMP on adenovirus replication in vitro.
The inhibitory effects of 20 selected antiviral compounds on the replication of adenoviruses (types 1 to 8) in vitro were investigated. While 18 compounds were ineffective, 2 compounds, namely (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA] and 9-[(2-hydroxy-1,3,2-dioxaphosphorinan-5-yl)oxymethyl]guanine P-oxide (2'-nor-cyclic GMP), were highly effective against all adenovirus types assayed in human embryonic fibroblast cultures. Their 50% inhibitory doses were 1.1 microgram/ml for (S)-HPMPA and 4.1 micrograms/ml for 2'-nor-cyclic GMP. They were nontoxic for the host cells at the effective antiviral doses.


An improved technique to facilitate transcervical thymectomy for myasthenia gravis.
We have used the transcervical method of thymectomy in patients with myasthenia gravis and believe that complete thymectomy is accomplished with minimum morbidity. For the past eight years we have used an improved technique for the transcervical approach, employing a specially designed sternal retractor that permits improved visualization of the anterior mediastinum. We have reviewed 65 patients operated on between 1977 and 1986. Patients were assessed using a modified Osserman classification (0 = asymptomatic; 1 = ocular signs and symptoms; 2 = mild generalized weakness; 3 = moderate generalized weakness; 4 = severe generalized weakness, respiratory dysfunction, or both). The mean grade for all patients at the time of thymectomy was 2.7. At most recent follow-up, the mean clinical grade was 0.5. In addition, 85% of patients were free of generalized weakness, 95% had improved by at least one grade, and 86% had improved by two or more grades. Comparing these results with those reported following thymectomy through a sternotomy reveals that the transcervical approach gives equivalent results.


Calf stretching and plantar fascia-specific stretching for plantar fasciitis: A systematic review and meta-analysis.
Plantar fasciitis (PF) is the most common cause of heel pain. A calf stretching (CS) and a plantar fascia-specific stretching (PFSS) are two stretching techniques commonly administered by health care providers. To evaluate the literature on the application of these two stretching techniques in the treatment of PF and investigate their effectiveness and efficacy. A search of PubMed, Web of Sciences, PEDro, CINHAL and Scopus was conducted. Studies that applied stretching as a co-intervention were excluded. The risk of bias was assessed to determine the internal validity of the included trials. The GRADE approach was adopted to determine the overall quality. Pooled analysis was performed to determine the treatment effects of CS and PFSS in terms of the mean difference in the visual analog scale pain score. Eight articles were found that represented randomized controlled trial and met the inclusion criteria. There was very low-quality evidence that the combined CS and PFSS was less effective in the short term than the other therapies. Comparison between CS and PFSS revealed moderate quality evidence for a larger effect of pain score reduction for PFSS treatment over CS, while very low-quality evidence supported that combined CS and PFSS or CS alone was superior to sham stretching. There was moderate to very low-quality evidence of the effectiveness of stretching for PF. The treatment effect of stretching was large and comparable to other therapies. Future trials of higher quality are needed to clarify findings or to confirm findings.


δ13C values of CO2 from soil respiration on sites with crops of C3 and C4 type of photosynthesis.
Based on the differential discrimination between 13CO2 and 12CO2 during photosynthetic CO2 fixation by C3 and C4 plants, the relative contribution of organic soil material of varying age can be checked by measuring the δ13C value of CO2 evolved during soil respiration.The CO2 from a soil cropped only with C3 plants for at least 7 years showed a δ13C value very close to that of C3 plant tissue. Correspondingly, a soil bearing the C4 plant maize for at least 6 years had a δ13C value for the respiratory CO2 quite near to that of a typical C4 plant. A soil cropped with maize in the year of study only showed intermediate δ13C values, with a tendency towards C4. With soil standardised for cultivation and cropping, a quantification of the part that fresh organic matter and especially the last year plant residues play in soil respiration, can be achieved.


Identification and characterization of sera from HIV-infected individuals with broad cross-neutralizing activity against group M (env clade A-H) and group O primary HIV-1 isolates.
A previous study on cross-clade neutralization activity, identified three key isolates, MNlab (envB/gagB; X4 coreceptor), VI525 (envG/gagH, envA/gagA; R5X4) and CA9 (Group O; R5), that allowed discrimination of sera, likely or unlikely to neutralize primary HIV-1 isolates belonging to Group M (env clades A-H) and Group O. The prognostic ability of these three isolates was verified by means of an external validation on a different and larger set of sera. A total of 79 different sera (66 HIV-1, 10 HIV-2, 1 HIV-1+2 and 2 SIV(cpz)) were examined first for their capacity to neutralize the three key isolates, next sera were challenged against 12 other primary HIV-1 isolates of Group M (env A-H) and 2 isolates of Group O. Sera that neutralized all three isolates with an ID(50) titer of > or =1/40, also neutralized the 14 other primary isolates belonging to different genetic groups and clades. Sera that did not neutralize all three isolates did not exert broad cross-neutralizing activity. The neutralizing activity was antibody-mediated because it was absorbed and eluted from a Prot-G column. Competition-neutralization experiments using recombinant gp120 (HIV-1 MNlab) reduced the neutralizing capacity, suggesting that the neutralizing antibodies were directed against the Env protein. Remarkably, the broad cross-neutralization activity was found primarily in African female patients. In conclusion, this study confirms that three isolates are sufficient to allow identification of broad cross-neutralizing sera.


Deoxyribonuclease II purified from Euglena gracilis SM-ZK, a chloroplast-lacking mutant: comparison with porcine spleen deoxyribonuclease II.
An acid deoxyribonuclease was extracted from Euglena gracilis SM-ZK, a chloroplast-lacking strain, by homogenizing the cells in 50 mM sodium acetate (pH 4.6). The enzyme was then purified by heat treatment and a series of chromatographic separations. The molecular mass of the Euglena acid DNase was estimated to be 45 kDa by sensitive activity staining in an SDS-polyacrylamide gel using SYBR Green. Treatment of the Euglena enzyme with a reducing agent prior to electrophoresis destroyed its DNase activity in the gel, indicating that disulfide bridging is essential for its enzyme activity. Nucleolytic properties of this enzyme are essentially the same as to those of porcine DNase II. The Euglena enzyme acts on both double-stranded (ds) and single-stranded DNA, but acts preferentially on dsDNA with an optimum pH at approximately 5.3. EDTA did not inhibit its enzyme activity. Euglena DNase makes double-strand breaks in circular DNA substrate and generates a terminus with 3'-phosphate and 5'-OH. These results indicate that the Euglena acid DNase is in fact a member of the DNase II family.


Validation of the JapanSCORE versus the logistic EuroSCORE for predicting operative mortality of cardiovascular surgery in Yamaguchi University Hospital.
Recent studies have shown that the European System for Cardiac Operative Risk Evaluation (Euro-SCORE) is a reliable risk model in cardiac surgery. In Japan, the JapanSCORE has been devised as the Japanese original risk model for cardiovascular surgery. We evaluated the validity of the JapanSCORE, especially in comparison with the logistic EuroSCORE METHODS: We calculated the predicted mortality according to two risk models for 523 consecutive patients who underwent cardiovascular surgery within a 6-year period (July 2003 to June 2009) at Yamaguchi University Hospital. We assessed the scores' validity by calculating the area under the receiver operating characteristics curve (C-index) and by the chi-squared test or Fisher's exact test. The C-indexes were 0.688 with the logistic EuroSCORE and 0.770 with the JapanSCORE (P = 0.053). Although the difference was not significant, the JapanSCORE tended to be more accurate. The C-indexes limited to isolated coronary artery bypass grafting (CABG) were 0.564 with the logistic EuroSCORE and 0.790 with the JapanSCORE (P = 0.001). The Japan-SCORE was significantly more valid than the logistic EuroSCORE for isolated CABG. The actual mortality was 4.0%; the mean predictive mortality was 5.6% with the JapanSCORE and 15.1% with the logistic Euro-SCORE. The mortality predicted by the JapanSCORE was closer to the observed mortality. There was a significant difference between the observed mortality and the logistic EuroSCORE (P < 0.0001). The JapanSCORE seems to be a more reliable risk model than the logistic EuroSCORE for patients undergoing cardiac or thoracic aortic surgery at Yamaguchi University Hospital.


Comparative study on the composition of four different varieties of garlic.
Garlic is used as a medicinal seasoning worldwide. The aim of this work was to compare four varieties of garlic: 'Taicangbaipi', 'Ershuizao', 'Hongqixing', and 'Single-clove'; among them, 'Ershuizao' and 'Hongqixing' are unique to the Sichuan Province of China. Firstly, soluble sugar, starch, and the protein content of the garlic were analysed. There was more soluble sugar in 'Single-clove', total starch in 'Hongqixing', and protein content in 'Ershuizao' relative to the other three varieties, respectively. Gas chromatography-mass spectrometry analysis showed that 'Ershuizao' and 'Hongqixing' contained high levels of 5-hydroxymethylfurfural, which has antitumor, antioxidant, and cytoprotective effects. Indeed, the extracts from these two types of garlic were more effective at inhibiting tumour growth than that from the others. Moreover, the sulphide content and antimicrobial effects of 'Ershuizao' and 'Hongqixing' garlic were also higher than those of the other two types of garlic. In addition, changes observed in the membrane permeability and protein leakage suggest that the antimicrobial activity of the 'Ershuizao' and 'Hongqixing' extracts may be due to the destruction of the structural integrity of the cell membranes, leading to cell death.


Thermoregulatory response to an organophosphate and carbamate insecticide mixture: testing the assumption of dose-additivity.
Most toxicity data are based on studies using single compounds. This study assessed if there is an interaction between mixtures of the anticholinesterase insecticides chlorpyrifos (CHP) and carbaryl (CAR) using hypothermia and cholinesterase (ChE) inhibition as toxicological endpoints. Core temperature (T(c)) was continuously monitored by radiotelemetry in adult Long-Evans rats administered CHP at doses ranging from 0 to 50mg/kg and CAR doses of 0-150 mg/kg. The temperature index (TI), an integration of the change in T(c) over a 12h period, was quantified. Effects of mixtures of CHP and CAR in 2:1 and 1:1 ratios on the TI were examined and the data analyzed using a statistical model designed to assess significant departures from additivity for chemical mixtures. CHP and CAR elicited a marked hypothermia and dose-related decrease in the TI. The TI response to a 2:1 ratio of CHP:CAR was significantly less than that predicted by additivity. The TI response to a 1:1 ratio of CHP and CAR was not significantly different from the predicted additivity. Plasma and brain ChE activity were measured 4h after dosing with CHP, CAR, and mixtures in separate groups of rats. There was a dose-additive interaction for the inhibition of brain ChE for the 2:1 ratio, but an antagonistic effect for the 1:1 ratio. The 2:1 and 1:1 mixtures had an antagonistic interaction on plasma ChE. Overall, the departures from additivity for the physiological (i.e., temperature) and biochemical (i.e., ChE inhibition) endpoints for the 2:1 and 1:1 mixtures studies did not coincide as expected. An interaction between CHP and CAR appears to depend on the ratio of compounds in the mixture as well as the biological endpoint.


Island flaps with an exclusively venous pedicle. A report of eleven cases and a preliminary haemodynamic study.
Eleven cases are reported of island flaps containing only venous pedicles. All but two survived completely without arterial input and all the successful cases were on the extremities. The possible reasons for this are discussed.


Accumulation of exogenous activated TGF-β in the superficial zone of articular cartilage.
It was recently demonstrated that mechanical shearing of synovial fluid (SF), induced during joint motion, rapidly activates latent transforming growth factor β (TGF-β). This discovery raised the possibility of a physiological process consisting of latent TGF-β supply to SF, activation via shearing, and transport of TGF-β into the cartilage matrix. Therefore, the two primary objectives of this investigation were to characterize the secretion rate of latent TGF-β into SF, and the transport of active TGF-β across the articular surface and into the cartilage layer. Experiments on tissue explants demonstrate that high levels of latent TGF-β1 are secreted from both the synovium and all three articular cartilage zones (superficial, middle, and deep), suggesting that these tissues are capable of continuously replenishing latent TGF-β to SF. Furthermore, upon exposure of cartilage to active TGF-β1, the peptide accumulates in the superficial zone (SZ) due to the presence of an overwhelming concentration of nonspecific TGF-β binding sites in the extracellular matrix. Although this response leads to high levels of active TGF-β in the SZ, the active peptide is unable to penetrate deeper into the middle and deep zones of cartilage. These results provide strong evidence for a sequential physiologic mechanism through which SZ chondrocytes gain access to active TGF-β: the synovium and articular cartilage secrete latent TGF-β into the SF and, upon activation, TGF-β transports back into the cartilage layer, binding exclusively to the SZ.


Staying in Healthy Contact: How Peroxisomes Interact with Other Cell Organelles.
Peroxisomes share extensive metabolic connections with other cell organelles. Membrane contact sites (MCSs) establish and maintain such interactions, and they are vital for organelle positioning and motility. In the past few years peroxisome interactions and MCSs with other cellular organelles have been explored extensively, resulting in the identification of new MCSs, the tethering molecules involved, and their functional characterization. Defective tethering and compartmental communication can lead to pathological conditions that can be termed 'organelle interaction diseases'. We review peroxisome-organelle interactions in mammals and summarize the most recent knowledge of mammalian peroxisomal organelle contacts in health and disease.


Positive effects of "El Niño" on macrozoobenthos inhabiting hypoxic areas of the Peruvian upwelling system.
Soft-bottom macrozoobenthos was sampled at monthly intervals between September 1981 and September 1984 at a normally hypoxic site (34 m depth) in Ancón Bay (Peru). Temperature, salinity, and dissolved oxygen were measured and related to changes in community structure. Large increases in the number of species, density, biomass, and diversity of macrozoobenthos were observed during the 1982-1983 El Niño (EN) thermal anomaly and for 1 year afterwards. These favourable changes were mainly associated with increased oxygen concentrations found in water masses near the bottom. Results are consistent with the hypothesis that the processes of post-catastrophic recovery of macrozoobenthos on marine soft bottoms are largely predictable, although certain particular mechanisms seem to exist for post-hypoxic recovery during El Niño in areas of the Peruvian coastal upwelling.


Construction and characterization of a CTLA-4-targeted scFv-melittin fusion protein as a potential immunosuppressive agent for organ transplant.
Immunotoxins with selective cytotoxicity are frequently used as therapeutic immunosuppressive agents in solid-organ transplantation because of their efficiency and high specificity. In this study, we present a new recombinant immunotoxin termed anti-CTLA-4-scFv-melittin prepared from Escherichia coli aimed at clearing activated T cells at the same time avoiding all-round decline in systematic immunity. This fusion protein is composed of anti-CTLA-4-scFv unit and melittin analog unit with properties of low immunogenicity and selective cytotoxicity to CTLA-4-positive T cells. In preliminary biological activity assays, our results confirmed the feasibility of activated T cell clearance strategy and there were significant differences in cell survival rates between CTLA-4-positive group and control group at all experimental concentrations of the immunotoxin. The selective cytotoxicity, low immunogenicity, and low production cost make it an attractive alternate to traditional immunosuppressants.