Vestibular primary afferent projection to the cerebellum of the rabbit.
The vestibular primary afferent projection to the cerebellum of the rabbit was studied with retrograde and orthograde tracers. We injected individual lobules of the cerebellum with horseradish peroxidase (HRP) or wheat germ agglutinin-HRP (WGA-HRP). Following these injections the numbers of labeled and unlabeled cells in Scarpa's ganglion were counted. Approximately 64-89% of the cells in Scarpa's ganglion were labeled retrogradely following uvula-nodular injections. About 2% of the cells in the ipsilateral Scarpa's ganglion were labeled after injections of the flocculus. Virtually no cells were labeled following injections of the ventral paraflocculus. The vestibular primary afferent projection to the uvula-nodulus is so extensive that it must be part of a collateral system that also innervates the vestibular nuclei. This collateral projection pattern was confirmed by using fluorescent tracers injected into the uvula-nodulus and vestibular complex. Fluorogold was injected into the uvula-nodulus and peroxidase-rhodamine isothiocyanate was injected into the vestibular complex. More than 50% of the neurons in Scarpa's ganglion were double labeled by these subtotal injections. The dense vestibular primary afferent projection to the uvula-nodulus was confirmed by using the C fragment of tetanus toxin (TTC) injected into the labyrinth as an orthograde tracer. With the TTC technique, the vestibular primary afferent projection to the uvula-nodulus terminated exclusively in the ipsilateral granule cell layer of lobules 9d and 10. Much sparser vestibular primary afferent projections were found in the banks of major cerebellar sulci. A barely detectable projection was found to the flocculus and ventral paraflocculus.


Neural stem cell-derived exosomes and regeneration: cell-free therapeutic strategies for traumatic brain injury.
Regenerative repair of the brain after traumatic brain injury (TBI) remains an extensive clinical challenge, inspiring intensified interest in therapeutic approaches to explore superior repair strategies. Exosome therapy is another research hotspot following stem cell alternative therapy. Prior research verified that exosomes produced by neural stem cells can participate in the physiological and pathological changes associated with TBI and have potential neuroregulatory and repair functions. In comparison with their parental stem cells, exosomes have superior stability and immune tolerance and lower tumorigenic risk. In addition, they can readily penetrate the blood‒brain barrier, which makes their treatment efficiency superior to that of transplanted stem cells. Exosomes secreted by neural stem cells present a promising strategy for the development of novel regenerative therapies. Their tissue regeneration and immunomodulatory potential have made them encouraging candidates for TBI repair. The present review addresses the challenges, applications and potential mechanisms of neural stem cell exosomes in regenerating damaged brains.


Attention to single letters activates left extrastriate cortex.
Brain imaging studies examining the component processes of reading using words, non-words, and letter strings frequently report task-related activity in the left extrastriate cortex. Processing of these linguistic materials involves varying degrees of semantic, phonological, and orthographic analysis that are sensitive to individual differences in reading skill and history. In contrast, single letter processing becomes automatized early in life and is not modulated by later linguistic experience to the same degree as are words. In this study, skilled readers attended to different aspects (single letters, symbols, and colors) of an identical stimulus set during separate sessions of functional magnetic resonance imaging (fMRI). Whereas activation in some portions of ventral extrastriate cortex was shared by attention to both alphabetic and non-alphabetic features, a letter-specific area was identified in a portion of left extrastriate cortex (Brodmann's Area 37), lateral to the visual word form area. Our results demonstrate that while minimizing activity related to word-level lexical properties, cortical responses to letter recognition can be isolated from figural and color characteristics of simple stimuli. The practical utility of this finding is discussed in terms of early identification of reading disability.


Early DAS response after DMARD-start increases probability of achieving sustained DMARD-free remission in rheumatoid arthritis.
Sustained DMARD-free remission (SDFR) is increasingly achievable. The pathogenesis underlying SDFR development is unknown and patient characteristics at diagnosis poorly explain whether SDFR will be achieved. To increase the understanding, we studied the course of disease activity scores (DAS) over time in relation to SDFR development. Subsequently, we explored whether DAS course could be helpful identifying RA patients likely to achieve SDFR. 772 consecutive RA patients, promptly treated with csDMARDs (mostly methotrexate and treat-to-target treatment adjustments), were studied for SDFR development (absence of synovitis, persisting minimally 12 months after DMARD stop). The course of disease activity scores (DAS) was compared between RA patients with and without SDFR development within 7 years, using linear mixed models, stratified for ACPA. The relation between 4-month DAS and the probability of SDFR development was studied with logistic regression. Cumulative incidence of SDFR within DAS categories (< 1.6, 1.6-2.4, 2.4-3.6, ≥ 3.6) at 4 months was visualized using Kaplan-Meier curves. In ACPA-negative RA patients, those achieving SDFR showed a remarkably stronger DAS decline within the first 4 months, compared to RA patients without SDFR; - 1.73 units (95%CI, 1.28-2.18) versus - 1.07 units (95%CI, 0.90-1.23) (p < 0.001). In APCA-positive RA patients, such an effect was not observed, yet SDFR prevalence in this group was low. In ACPA-negative RA, DAS decline in the first 4 months and absolute DAS levels at 4 months (DAS4 months) were equally predictive for SDFR development. Incidence of SDFR in ACPA-negative RA patients was high (70.2%) when DAS4 months was < 1.6, whilst SDFR was rare (7.1%) when DAS4 months was ≥ 3.6. In ACPA-negative RA, an early response to treatment, i.e., a strong DAS decline within the first 4 months, is associated with a higher probability of SDFR development. DAS values at 4 months could be useful for later decisions to stop DMARDs.


Organogenesis and functional genomics of the endocrine pancreas.
Functional genomics, the analysis of the wealth of data produced by genome-wide analyses of gene expression, protein-protein, and protein-DNA interactions, has revolutionized biomedical research. Our ability to determine global gene expression profiles, transcription factor-binding sites, and histone modification maps using microarray-based technologies and next-generation sequencing applications has greatly enhanced our understanding of gene regulatory networks and the molecular wiring diagrams of cells and tissues. The organogenesis of the endocrine pancreas involves numerous signaling events within the endoderm-derived pancreatic epithelium and the surrounding mesenchyme, as well as complex transcription factor networks. Detailed understanding of the differentiation process from foregut endoderm to mature endocrine cells has enabled the rational design of in vitro differentiation protocols that coax embryonic stem cells into β-like cells that might enable cell replacement therapy for diabetes in the future. In this review, we summarize the research studies that have utilized genomic tools to elucidate endocrine pancreatic organogenesis.


Substrate Diversity of L-Threonic Acid Dehydrogenase Homologs.
Despite physiological importance of aldonic sugar acids for living organisms, little is known about metabolic pathways of these compounds. Here, we investigated the functional diversity of homologs of L-threonic acid dehydrogenase (ThrDH; UniProt ID: Q0KBC7), an enzyme composed of two NAD-binding domains (PF14833 and PF03446). Ten ThrDH homologs with different genomic context were studied; seven new enzymatic activities were identified, such as (R)-pantoate dehydrogenase, L-altronic acid dehydrogenase, 6-deoxy-L-talonate dehydrogenase, L-idonic acid dehydrogenase, D-xylonic acid dehydrogenase, D-gluconic acid dehydrogenase, and 2-hydroxy-3-oxopantoate reductase activities. Two associated metabolic pathways were identified: L-idonic acid dehydrogenase was found to be involved in the degradation of L-idonic acid through oxidation/decarboxylation in Agrobacterium radiobacter K84, while 2-hydroxy-3-oxopantoate reductase was found to participate in D-glucarate catabolism through dehydration/cleavage in Ralstonia metallidurans CH34.


Intrinsic Mechanism for Anisotropic Magnetoresistance and Experimental Confirmation in Co_{x}Fe_{1-x} Single-Crystal Films.
Using first-principles transport calculations, we predict that the anisotropic magnetoresistance (AMR) of single-crystal Co_{x}Fe_{1-x} alloys is strongly dependent on the current orientation and alloy concentration. An intrinsic mechanism for AMR is found to arise from the band crossing due to magnetization-dependent symmetry protection. These special k points can be shifted towards or away from the Fermi energy by varying the alloy composition and hence the exchange splitting, thus allowing AMR tunability. The prediction is confirmed by delicate transport measurements, which further reveal a reciprocal relationship of the longitudinal and transverse resistivities along different crystal axes.


Foreign protein degradation and instability in plants and plant tissue cultures.
Low production cost is a key factor driving the development of plants and plant tissue cultures for the synthesis of therapeutic and other foreign proteins. Because product yield and concentration exert a major influence on process economics, improving foreign protein accumulation is crucial for enhancing the commercial success of plant-based production systems. Strategies aimed at increasing transgene expression have been effective; however, a critical but poorly understood factor contributing to low foreign protein yield is post-synthesis and/or post-secretion instability and degradation. Loss of foreign protein as result of biological and physical processes such as proteolytic destruction and irreversible surface adsorption can occur in plants and plant culture systems. This review highlights the need to consider such mechanisms and outlines a range of remedial strategies aimed at minimizing foreign protein degradation and loss.


Measuring treatment response to advance precision medicine for multiple sclerosis.
To assess the independent contributions of clinical measures (relapses, Expanded Disability Status Scale [EDSS] scores, and neuroperformance measures) and nonclinical measures (new brain magnetic resonance imaging [MRI] activity and serum neurofilament light chain [sNfL] levels) for distinguishing natalizumab-treated from placebo-treated patients. We conducted post hoc analyses using data from the AFFIRM trial of natalizumab for multiple sclerosis. We used multivariable regression analyses with predictors (EDSS progression, no relapse, new or enlarging MRI activity, brain atrophy, sNfL levels, and neuroperformance worsening) to identify measures that independently discriminated between treatment groups. The multivariable model that best distinguished natalizumab from placebo was no new or enlarging T2 or gadolinium-enhancing activity on MRI (odds ratio; 95% confidence interval: 7.2; 4.7-10.9), year 2 sNfL levels <97.5th percentile (4.1; 2.6-6.2), and no relapses in years 0-2 (2.1; 1.5-3.0). The next best-fitting model was a two-component model that included no MRI activity and sNfL levels <97.5th percentile at year 2. There was little difference between the three- and two-component models. Nonclinical measures (new MRI activity and sNfL levels) discriminate between treatment and placebo groups similarly to or better than clinical outcomes composites and have implications for patient monitoring.


Multitarget CFTR Modulators Endowed with Multiple Beneficial Side Effects for Cystic Fibrosis Patients: Toward a Simplified Therapeutic Approach †.
Cystic fibrosis (CF) is a multiorgan disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses and bacteria trigger acute pulmonary exacerbations, accelerating disease progression and mortality rate. Treatment complexity increases with patients' age, and simplifying the therapeutic regimen represents one of the key priorities in CF. We have recently reported the discovery of multitarget compounds able to "kill two birds with one stone" by targeting F508del-CFTR and PI4KIIIβ and thus acting simultaneously as CFTR correctors and broad-spectrum enterovirus (EV) inhibitors. Starting from these preliminary results, we report herein a hit-to-lead optimization and multidimensional structure-activity relationship (SAR) study that led to compound 23a. This compound showed good antiviral and F508del-CFTR correction potency, additivity/synergy with lumacaftor, and a promising in vitro absorption, distribution, metabolism, and excretion (ADME) profile. It was well tolerated in vivo with no sign of acute toxicity and histological alterations in key biodistribution organs.


Trustworthiness judgments and Borderline Personality Disorder: an experimental study on the interplay of happiness and trustworthiness appraisals and the effects of wearing face masks during the Covid-19 pandemic in Germany.
Judging positive emotional states or the trustworthiness of others is important for forming and maintaining social affiliations. Past studies have described alterations in these appraisal processes in Borderline Personality Disorder (BPD), which might have been exacerbated during the Covid-19 pandemic by the requirement to wear face masks. In the present study, we investigated in an online-survey a) whether social judgments are particularly strongly affected in individuals with BPD when they have to judge happiness and trustworthiness in facial stimuli covered by a mask, b) whether appraising a positive emotional state affects trustworthiness appraisals differentially in BPD and healthy individuals and c) whether social judgments are related to how individuals with BPD experience wearing masks during the pandemic. Participants (67 HC, 75 BPD) judged happiness and trustworthiness of faces with calm expression with and without masks. Additionally, data on participants' confidence in their judgments, the experience of the burden induced by wearing masks, the protective benefits of masks, and compliance to wearing masks were collected. Happiness and trustworthiness were evaluated less confidently and less intense in the BPD group compared to HC. Masks reduced happiness and trustworthiness ratings in both groups. Lower happiness appraisals contributed to lower trustworthiness appraisals except for those with BPD and low levels of symptom severity. Lower trustworthiness ratings were associated with a higher burden, attributing a lower benefit to masks and lower compliance with wearing masks in BPD. Masks do not exacerbate deficits in social judgments. However, lower trustworthiness appraisals in general were linked with more negative evaluations of wearing masks in the BPD group. The aims and hypotheses were preregistered together with the design and planned analyses ( https://aspredicted.org/f5du7.pdf ). For findings of an additionally preregistered research question on the impact of adverse childhood experiences see supplementary material.


[Monoclonal anti-prostatic acid phosphatase antibodies (production and characterization)].
5 monoclonal antibodies have been produced by Köhler and Milstein. The production and the characteristics of the monoclonal antibodies are presented. They are all IgG1 and have high specificity against prostatic cells producing prostatic acid phosphatase. These monoclonal antibodies can be used to perform immunoscintigraphies and immunolymphoscintigraphies to titrate prostatic acid phosphatase serum levels and to identify the prostatic origin of a tumor.


External cephalic version at term: a cohort study of 18 years' experience.
To analyse the outcome of referrals for external cephalic version (ECV). Retrospective cohort study of prospectively collected data. Major university hospital, UK. Women with non-cephalic presentation at term and no prior caesarean, referred to a specialist clinic. Details of referrals, ECV attempts, and perinatal outcomes were prospectively collected and analysed. Multivariate binary logistic regression models were created to determine independent predictors of ECV success, reversion, and spontaneous version. External cephalic version success rates, predictors of success and cephalic presentation at birth, and perinatal outcomes. Three thousand eight had confirmed breech presentation; 2614 women underwent ECV. Ineligibility for ECV occurred in 117 breech presentations (3.9%), and 297 eligible women (10.2%) declined it. ECV was successful in 1280 (49.0%, 95% CI 47.0-50.9%) (40% in nulliparous women; 64% in others); 1234 (97.3%) were cephalic at birth. Spontaneous version after failure occurred in 4.3% and was more common in multiparas (aOR 2.47, 95% CI 1.43-4.26) and those with a posterior fetal back (aOR 6.09, 95% CI 1.90-19.53). Reversion after successful ECV occurred in 2.2%. In women with a successful ECV whose fetus remained cephalic at birth, 85.7% delivered vaginally. The corrected perinatal mortality of the ECV cohort was 0.12%. External cephalic version has a low complication rate and is effective for most breech presentations, enabling vaginal birth and avoiding caesarean section. External cephalic version can safely be performed with most breech presentations.


Mechanisms determining phenotypic heterogeneity of hepatocytes.
This review summarizes results of biochemical and immunohistochemical studies indicating the existence of functional heterogeneity of hepatocytes depending on their localization in the hepatic acinus; this determines characteristic features of metabolism of carbohydrates, lipids, and xenobiotics. The physiological significance of hepatocyte heterogeneity is discussed. According to the proposed model of intercellular communication, the metabolic specialization of hepatocytes is determined by secretory activity of hepatic resident macrophages (Kupffer cells) localized mainly in the periportal zone of the liver acinus. Macrophages participate in secretion of a wide spectrum of intercellular mediators (cytokines, prostaglandins, growth factors) and also in metabolism of numerous blood metabolites and biologically active substances (hormones, lipoproteins, etc.). In the sinusoid and in the space of Disse (also known as perisinusoidal space) they form a concentration gradient of regulatory factors and metabolites inducing the phenotypic differences between hepatocytes.


Initial experience of real-time intraoperative C-arm computed-tomography-guided navigation surgery for pituitary tumors.
We report our initial experience of real-time intraoperative C-arm computed tomography (C-arm CT: DynaCT)-guided navigation surgery for pituitary tumors. Recent advancement in flat panel technology makes it possible to obtain CT-like images by using rotation of the C-arm of a digital subtraction angiography (DSA) system. A specially designed new suite, which has C-arm CT-imaging-capable DSA in combination with a navigation system (VectorVision Sky, BrainLAB AG, Munich, Germany), allows neurosurgeons to perform endoscopic transsphenoidal procedures under real-time navigation support. Thirty-one pituitary tumor patients were examined. During or after tumor removal, contrast-enhanced DynaCT was conducted to rule out residual tumor in 12 cases. When enhanced tumor was confirmed, additional removal was continued without moving the patients. DynaCT and subsequent image transfer to navigation system was performed in all cases without difficulties, requiring only an additional 15 minutes of surgical time. Sellar fenestration in relation to tumors and absence of hidden hematomas was confirmed in all cases. The contrast-enhanced DynaCT was found to be contributing to a better handling of the residual tumor. In 9 of these 12 cases (75%), residual tumor was detected on DynaCT; consequently, further removal was considered. In 2 cases (16%) there was no enhanced lesion, indicating complete removal. The proposed technique of intraoperative visualization in the hybrid operating room can be easy to perform and may be a useful adjunct to conventional transsphenoidal surgery for an improved resection rate and less cavernous sinus and internal carotid artery injury.


An extraordinary rare presentation of liver hydatidosis with hydatid cyst scolices.
The extraordinary finding of scolices with the characteristic hooklets may be found during the microscopic analysis in patients with cystic echinococcosis.


Biomineralization-inspired synthesis of chitosan/hydroxyapatite biocomposites based on a novel bilayer rate-controlling model.
In order to prepare sophisticated biomaterials using a biomimetic approach, a deeper understanding of biomineralization is needed. Of particular importance is the control and regulation of the mineralization process. In this study, a novel bilayer rate-controlling model was designed to investigate the factors potentially influencing mineralization. In the absence of a rate-controlling layer, nano-scale hydroxyapatite (HA) crystallites exhibited a spherical morphology, whereas, in the presence of a rate-controlling layer, HA crystallites were homogeneously dispersed and spindle-like in structure. The mineralization rate had a significant effect on controlling the morphology of crystals. Furthermore, in vitro tests demonstrated that the reaction layer containing spindle-like HA crystallites possessed superior biological properties. These results suggest that a slow mineralization rate is required for controlling the morphology of inorganic crystallites, and consumption by the rate-controlling layer ensured that the ammonia concentration remained low. This study demonstrates that a biomimetic approach can be used to prepare novel biomaterials containing HA crystallites that have different morphologies and biological properties.


The occurrence of C3 and C4 grasses in fynbos and allied shrublands in the South Eastern Cape, South Africa.
There are roughly equal numbers of C3 and C4 grass species in fynbos and allied shrublands of the warm temperate coastal regions of the south eastern Cape. Subtropical-tropical C4 species have the highest relative cover in all shrubland types, particularly in renosterveld communities on moderately fertile soils. Physiological characteristics of C3 and C4 grasses predict that C3 species will be most abundant in cool, shaded sites. This prediction, and the hypothesis that relative C3 grass cover would be highest on infertile soils, were tested by correlation and regression analyses. Results show that C3 grass cover is significantly correlated with increased post-disturbance vegetation age, low intensity grazing, high litter cover and cool, steep, poleward slopes. All these factors contribute to lower growing season temperatures, favouring the competitive growth of C3 species. Amongst the soil variables, high sand content and low levels of total nitrogen emerged as predictors of high relative C3 grass cover.


Frequency of eating alone is associated with adolescent dietary intake, perceived food-related parenting practices and weight status: cross-sectional Family Life, Activity, Sun, Health, and Eating (FLASHE) Study results.
To examine relationships between frequency of adolescents eating alone (dependent variable) and diet, weight status and perceived food-related parenting practices (independent variables). Analyses of publicly available, cross-sectional, web-based survey data from adolescents. Online consumer opinion panel. A US nationwide sample of adolescents (12-17 years) completed Family Life, Activity, Sun, Health, and Eating (FLASHE) Study surveys to report demographic and family meal characteristics, weight, dietary intake, home food availability and perceptions of parenting practices. Parents provided information about demographic characteristics. Logistic regression analyses were used to test for associations between variables. About 20 % of adolescents reported often eating alone (n 343) v. not often eating alone (n 1309). Adjusted odds of adolescents often eating alone were significantly higher for non-Hispanic Black compared with non-Hispanic White adolescents (OR=1·7) and for overweight or obese compared with normal- or underweight adolescents (OR=1·6). Adjusted odds of adolescents eating alone were significantly lower for those who reported that fruits and vegetables were often/always available in the home (OR=0·65), for those who perceived that parents had expectations about fruit and vegetable intake (OR=0·71) and for those who agreed with parental authority to make rules about intake of junk food/sugary drinks (OR=0·71). Junk food and sugary drink daily intake frequency was positively associated with often eating alone. Often eating alone was related to being overweight/obese, having less healthy dietary intake and perceptions of less supportive food-related parenting practices.


Enzymes of oxidant defence system of leucocytes and erythrocytes in bovine anaplasmosis.
The glutathione oxidant defence system in leucocytes and erythrocytes of six Anaplasma marginale-infected calves was examined by assaying glutathione peroxidase (GSH-px), glutathione reductase (GSSG-R), reduced glutathione (GSH) and superoxide dismutase (SOD). In addition, GSH-S-transferase and arginase levels were measured in leucocytes. There was a significant decline in the activities of leucocyte GSH-px, GSSG-R and SOD in the post-patent period; whereas arginase activity rose significantly following the patent period of anaplasmosis. The activity of erythrocyte SOD declined in the post-patent stage. The infection also caused a decline in red cell GSH (P less than 0.05). The results suggest that the glutathione oxidant defence system of peripheral blood cells is significantly influenced by the Anaplasma infection.


Phlegmonous gastritis: Evolving from surgical to medical disease.
We present a case of phlegmonous gastritis, which is a rare, life-threatening infection involving transmural inflammation of the stomach of multiple possible etiologies. Historically this disease has required surgical management, including gastrectomy, which is quite morbid. Evolving literature suggests that antimicrobial therapy alone may be adequate treatment for this infection. The diagnosis of phlegmonous gastritis was suggested by radiology but confirmed by endoscopic pathology. This particular case is unique given the patient's age, lack of co-morbidities and being the first description of Helicobacter pylori with phlegmonous gastritis. We report on a specific successful antimicrobial regimen and duration of therapy, which has not been well documented elsewhere in the literature, which may be helpful to clinicians.


[Preparation and in vitro study of suppositories containing No-Spa. II. Determination of release of the active principle by membrane diffusion methods].
The authors have made proposal of pharmaceutical technology of a well storable, excellent drug release No-Spa./suppository besides No-Spa./tablets and injection have been in circulation in this country. Without Estaram 299 of small hydroxyl value or combined with 10% ESTASAN oil it suits to therapeutical expectations in every respect. Physical parameters of suppositories and chemical stability of drotaverinium chloride have been excellent on the basis of one year storing. On the ground of in vitro investigations the suppository has been proposed to be introduced to human therapy as antispasmodic preparation.


Optical Coherence Tomography Can Reduce Colposcopic Referral Rates in Patients With High-Risk Human Papillomavirus.
This study aimed to evaluate the feasibility of combined human papillomavirus (HPV) and optical coherence tomography (OCT) cervical cancer screening strategies. The OCT and cytology results were compared with the pathological results to calculate the sensitivity, specificity, positive predictive value, negative predictive value, and immediate cervical intraepithelial neoplasia grade 3 or worse (CIN3+) risk. The authors compared the efficiency of colposcopy by using different triage strategies. They discussed differentiation in OCT screening in different age groups. Eight hundred thirteen participants with high-risk HPV-positive and cervical cytology results underwent OCT before colposcopy between March 1 and October 1, 2021. The HPV16/18 genotyping with OCT triage has a specificity of CIN3+ lesions (61.1%; 95% CI = 57.6%-64.6%), intraepithelial neoplasia grade 2 or worse (CIN2+) (66.0%; 95% CI = 62.4%-69.6%). The HPV16/18 genotyping with cytology triage has a specificity of CIN3+ (44.0%; 95% CI = 40.4%-47.6%), CIN2+ (47.0%; 95% CI = 43.2%-50.8%). The OCT triage has a higher positive predictive value compared with the cytology, with a significant difference in CIN2+ lesions (45.0%; 95% CI = 38.8%-51.3% vs 29.2%; 95% CI = 24.7%-33.7%). The combination of OCT and high-risk HPV triage (both genotyping and nongenotyping) had a similar immediate CIN3+ risk stratification and reduced the number of colposcopies compared with the cytological triage strategy.


The potential connections of adverse outcome pathways with the hazard identifications of typical organophosphate esters based on toxicity mechanisms.
Following the world-wide ban of brominated flame retardants (BFRs), organophosphate esters (OPEs), which could potentially affect human health and ecosystem safety, have been frequently detected in various environmental media. However, the knowledge regarding the underlying toxicity effects of OPEs remains limited. In order to address these issues, this study reviewed the related reports which have been published in recent years. This analysis process included 12 OPEs, 10 model organisms, and 15 cell lines, which were used to systematically examine the mechanisms of endocrine disruption, neurotoxicity, hepatotoxicity, and cardiotoxicity, as well as reproductive and developmental toxicity. Subsequently, an adverse outcome pathway (AOP) framework of the toxicological effects of OPEs was built. The results demonstrated that multiple different pathways may lead to a single same adverse outcome (AO), and there was a certain degree of correlation among the different AOs. It was found that among all the 12 OPEs, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) may potentially be the most toxic. In addition, rather than the parent chemicals, the metabolites of OPEs may also have different degrees of toxicity effects on aquatic organisms and humans. Overall, the results of the present study also suggested that an AOP framework should be built via fully utilizing the existing toxicity data of OPEs based on in vivo-in vitro-in silico to completely and deeply understand the toxic mechanisms of OPEs. This improved knowledge could then provide a theoretical basis for ecological risk assessments and water quality criteria research in the near future.


The key sulfometuron-methyl degrading bacteria isolation based on soil bacterial phylogenetic molecular ecological networks and application for bioremediation of contaminated soil by immobilization.
The analysis of soil bacterial community has guiding significance for fully utilization of soil microbial resources. The results of high-throughput sequencing (HTS) showed that the bacteria in the three sulfometuron-methyl contaminated soil samples were mainly composed of 677 genera, including Phenylobacterium, Bacillus, belonging to 28 phyla, including Proteobacteria, Firmicutes. The diversity and richness of bacterial community decreased with the increase in sulfometuron-methyl concentration. In addition, sulfometuron-methyl could also affect the soil bacterial function based on PICRUSt functional predictive analysis. Combined with the results of HTS and phylogenetic molecular ecological networks (pMENs), 12 genera, including Ralstonia (Pi=0.64), were identified as the key soil microflora (intra-module connectivity Zi ≥ 2.5 or inter-module connectivity Pi ≥ 0.62), and the abundance of Ralstonia significantly increased with the concentration of sulfometuron-methyl, indicating that the strains of this genus might be the potential degrading bacteria and could form a stable relationship with indigenous microorganisms. Among the isolated bacteria of genus Ralstonia, one strain, named Ralstonia sp. JM-1, was verified to possess higher sulfometuron-methyl degradation efficiency, which completely degraded 20 mg L-1 of sulfometuron-methyl within 96 h. Furthermore, the immobilized strains generated by the mixture of 2.0 g bamboo charcoal and 3.0 mL bacterial suspension for 24 h had the highest sulfometuron-methyl degradation rate than that under other conditions, and the dynamic process degrading 10-30 mg L-1 of sulfometuron-methyl conforms to the zero-order kinetic equation. The bioremediation of contaminated soil showed the immobilized strains could completely degrade sulfometuron-methyl (1.39 mg kg-1) in contaminated soil within 9 d, which is higher than that application of strains in the free state (74.8%). This study could provide ideas for the isolation of functional strains and a theoretical basis for the bioremediation of STM and other contaminated soils.


Land-use change in Indian tropical agro-ecosystems: eco-energy estimation for socio-ecological sustainability.
This study was carried out to understand the ecological and economic sustainability of floriculture and other main crops in Indian agro-ecosystems. The cultivation practices of four major flower crops, namely Jasminum multiflorum, Crossandra infundibuliformis, Chrysanthemum and Tagetes erecta, were studied in detail. The production cost of flowers in terms of energy was calculated to be 99,622-135,996 compared to 27,681-69,133 MJ ha-1 for the main crops, namely Oryza sativa, Eleusine coracana, Zea mays and Sorghum bicolor. The highest-energy input amongst the crops was recorded for Z. mays (69,133 MJ ha-1) as this is a resource-demanding crop. However, flower cultivation requires approximately twice the energy required for the cultivation of Z. mays. In terms of both energy and monetary inputs, flower cultivation needs two to three times the requirements of the main crops cultivated in the region. The monetary inputs for main crop cultivation were calculated to be ₹ 27,349 to ₹ 46,930 as compared to flower crops (₹ 62,540 to ₹ 144,355). Floriculture was found to be more efficient in monetary terms when compared to the main crops cultivated in the region. However, the energy efficiency of flower crops is lower than that of the main crops, and the energy output from flower cultivation was found to be declining in tropical agro-ecosystems in India. Amongst the various inputs, farmyard manure accounts for the highest proportion, and for its preparation, most of the raw material comes from the surrounding ecosystems. Thus, flower cultivation has a direct impact on the ecosystem resource flow. Therefore, keeping the economic and environmental sustainability in view, this study indicates that a more field-based research is required to frame appropriate policies for flower cultivation to achieve sustainable socio-ecological development.


The inhibition of trypsin, plasmin, and thrombin by benzyl 4-guanidinobenzoate and 4'-nitrobenzyl 4-guanidinobenzoate.
The inhibition of the enzymes trypsin, plasmin, and thrombin by benzyl 4-guanidinobenzoate and 4'-nitrobenzyl 4-guanidinobenzoate is caused by acylation of the active site. Second order rate constants were determined.


Cardiac function during halothane anf fluroxene anesthesia expressed by systolic time intervals.
A non-invasive method of measuring the systolic time intervals (STI) during anesthesia is described. Using the ratio between the pre-ejection period and the left ventricular ejection time (PEP/LVET-ratio) as an expression of cardiac function, it is shown in 39 patients that thiopentone exerted a marked depression on the heart (increase in PEP/LVET-ratio). This depression was further aggravated by halothane, while fluroxene caused an improvement of PEP/LVET-ratio. In the immediate post-anesthetic period PEP/LVET-ratio almost reached control value after discontinuation of fluroxene in contrast to halothane, where an increased PEP/LVET-ratio (25%) still persisted. The changes were mainly due to a prolongation of PEP without any specific change in LVET. During the study, PEP/LVET-ratio showed a close correlation to the reciprocal value of the square of the pre-ejection period (1/PEP-2). STI form 27 volunteers were measured and compared to the values from the patients before anesthesia was induced. PEP and PEP/LVET-ratio were significantly shorter in the patient group.


Design, Development and Validation of a Knee Brace to Standardize the US Imaging Evaluation of Knee Osteoarthritis.
A repeatable and reliable follow-up of knee injuries would be desirable to prevent delayed diagnosis and to monitor the efficacy of the applied treatment over time. Ultrasound (US) techniques are an attractive option to this purpose, since they are safe, low-cost and non-invasive. However, its use in the clinical practice is limited by the high dependency on the operator's experience. Hence, the objective of this study is to provide a standardization of the US image acquisition process for knee osteoarthritis (OA) allowing an extended clinical use of US technologies in this domain. Clinical specifications were provided by expert musculoskeletal radiologists thus identifying the subject poses and the US probe positions needed to evaluate the cartilage structure, signs of synovitis and joint effusion. Such considerations were used to derive the technical requirements needed for the development of a wearable brace equipped with specific openings to guide the correct placement of the probe. The feasibility of the developed wearable brace was tested on three healthy volunteers, which were asked to acquire informative US images, similar to the reference images performed by the musculoskeletal radiologist. Thanks to the knee brace, the untrained subjects were able to self-acquire informative B-mode images comparable to the corresponding images acquired by an expert clinician. The use of a knee brace intended for knee OA US diagnosis demonstrated the possibility to standardize the acquisition protocol and make its application achievable also for untrained subjects, representing a key step toward tele-ultrasonography.


The contribution of transport and chemical processes on coastal ozone and emission control strategies to reduce ozone.
The interaction between transport and chemistry is pivotal for local ozone (O3) concentration, especially for a coastal region where the upstream sources might change diurnally. In the current emission control policy, most pollutants, such as particulate matter, SO2, NOx, and CO, decrease while the annual O3 trend might increase due to the complex feedbacks of precursors. In this study, we investigate the influence of transport upon the wintertime O3 diurnal trend over ZuoYing Kaohsiung, an urban coastal site in southern Taiwan, by constructing a two-dimensional numerical model coupling both physical mechanisms and core chemical processes and provide a feasible emission control strategy. The transport process (i.e., import vs. export) for the daytime is determined using the Leighton Ratio (Φ), the ratio of O3-production over O3-loss rate, under the pseudo-steady-state condition. Φ shows a deviation of -9 to +13% from the photo-stationary state, and experiences a transition from import effect before 10:15 to weakening import or net export effect afterward associated with a net O3 production as sea breeze starts developing. The significantly higher Φ derived from observation than from simulation by a factor of 1.35 might be resulted from the over-reported NO2 due to NOy contribution on the NO2 measurement, and the influence of aerosol and cloud possibly reducing ∼30% on applied NO2 photolysis rate constant, associated with aerosol optical depth of 0.75 ± 0.15 and single scattering albedo of 0.85 ± 0.15. In this studied NOx-saturated regime, the addition of sea breeze convergence over the land enhances the maximal O3 by ∼10%, mainly due to the O3 accumulation (∼88%). Furthermore, the ozone isopleth analysis as a function of non-methane hydrocarbons and NOx emissions provides an achievable strategy to decrease both maximum daily ozone and the increment of ozone from morning to maximum by reducing hydrocarbons and NOx emissions, which can also eliminate the additional nitrate contribution on the aerosols.


Prognostic significance of skin reactivity in patients with bronchogenic carcinoma grouped according to the TNM classification.
Untreated patients with bronchogenic carcinoma of the epidermoid type showed a marked depression of cutaneous delayed hypersensitivity reactions to DNCB, PPD and Varidase. As compared to a control group of healthy individuals and to a control group of patients with non-malignant chest diseases, 46% of cases responded to the DNCB skin test, 56% to the PPD skin test and 39% to the Varidase skin test. The patients were subsequently divided according to the TNM classification in stage I, II and III groups. Correlation of the skin test positivity to the stage of the disease and to the survival of patients was followed.


Synthesis and evaluation of fluorobenzoylated di- and tripeptides as inhibitors of cyclooxygenase-2 (COX-2).
A series of fluorobenzoylated di- and tripeptides as potential leads for the development of molecular probes for imaging of COX-2 expression was prepared according to standard Fmoc-based solid-phase peptide synthesis. All peptides were assessed for their COX-2 inhibitory potency and selectivity profile in a fluorescence-based COX binding assay. Within the series of 15 peptides tested, cysteine-containing peptides numbered 7, 8, 11 and 12, respectively, were the most potent COX-2 inhibitors possessing IC(50) values ranging from 5 to 85 μM. Fluorobenzoylated tripeptides 7 and 8 displayed some COX-2 selectivity (COX-2 selectivity index 2.1 and 1.6), whereas fluorobenzoylated dipeptides 11 and 12 were shown not to be COX-2 selective. Fluorbenzoylated tripeptide FB-Phe-Cys-Ser-OH was further used in molecular modeling docking studies to determine the binding mode within the active site of the COX-2 enzyme.


Inhibiting RRM2 to enhance the anticancer activity of chemotherapy.
RRM2, the small subunit of ribonucleotide reductase, is identified as a tumor promotor and therapeutic target. It is common to see the overexpression of RRM2 in chemo-resistant cancer cells and patients. RRM2 mediates the resistance of many chemotherapeutic drugs and could become the predictor for chemosensitivity and prognosis. Therefore, inhibition of RRM2 may be an effective means to enhance the anticancer activity of chemotherapy. This review tries to discuss the mechanisms of RRM2 overexpression and the role of RRM2 in resistance to chemotherapy. Additionally, we compile the studies on small interfering RNA targets RRM2, RRM2 inhibitors, kinase inhibitors, and other ways that could overcome the resistance of chemotherapy or exert synergistic anticancer activity with chemotherapy through the expression inhibition or the enzyme inactivation of RRM2.


Increased steroid responsiveness of young children with nephrotic syndrome in Nigeria.
A previous study on the nephrotic syndrome (NS) in our unit showed that the histological patterns associated with steroid resistance were more common in children over 5 years of age. The aim of the study was to determine the incidence of steroid-responsiveness amongst nephrotic children <or=5 years. All children with NS aged <or=5 years at the onset of disease presenting to University College Hospital, Ibadan were enrolled. Prednisolone was given daily, 60 mg/m2, for 4 weeks and then 40 mg/m2 on alternate days for at least 12 weeks. Twenty children (9 boys and 11 girls) were enrolled between 1999 and 2002. The median age (range) at onset of disease was 4 (2-5) years. Remission was achieved in 12 (60%) children. There is a satisfactory response to prednisolone in two-thirds of Nigerian children aged <or=5 years with NS.


Free fatty acids sensitize hepatocytes to bile acid-induced apoptosis.
Delivery of free fatty acids to the liver in nonalcoholic fatty liver disease (NAFLD) may render hepatocytes more vulnerable to glycochenodeoxycholic acid (GCDCA)-induced apoptosis. Fat overloading was induced in HepG2-Ntcp cells and primary rat hepatocytes by incubation with palmitic or oleic acid. Apoptosis was quantified by measuring caspase 3/7 activity and transcription of interleukin (IL) 8 and IL-22 by quantitative real-time PCR. Oleic acid (500 microM) alone did not induce apoptosis, while palmitic acid (500 microM) increased apoptosis 5-fold. GCDCA did not induce significant apoptosis at low micromolar concentrations (5-30 microM) in non-steatotic cells. However, at the same concentrations, GCDCA increased apoptosis 3-fold in oleic acid-pretreated HepG2-Ntcp cells and 3.5-fold in primary rat hepatocytes. Pretreatment with oleic acid increased GCDCA-induced gene transcription of the proinflammatory cytokines IL-8 and IL-22 5-fold and 19-fold, respectively. Thus, low levels of cholestasis normally not considered harmful could advance liver injury in patients with NAFLD.


Gambierdiscus and Fukuyoa as potential indicators of ciguatera risk in the Balearic Islands.
Gambierdiscus and Fukuyoa are genera of toxic dinoflagellates which were mainly considered as endemic to marine intertropical areas, and that are well known as producers of ciguatoxins (CTXs) and maitotoxins (MTXs). Ciguatera poisoning (CP) is a human poisoning occurring after the consumption of fish or more rarely, shellfish containing CTXs. The presence of these microalgae in a coastal area is an indication of potential risk of CP. This study assesses the risk of CP in the Balearic Islands (Western Mediterranean Sea) according to the distribution of both microalgae genera, and the presence of CTX-like and MTX-like toxicity in microalgal cultures as determined by neuro-2a cell based-assay (neuro-2a CBA). Genetic identification of forty-three cultured microalgal strains isolated from 2016 to 2019 revealed that all of them belong to the species G. australes and F. paulensis. Both species were widely distributed in Formentera, Majorca and Minorca. Additionally, all strains of G. australes and two of F. paulensis exhibited signals of CTX-like toxicity ranging respectively between 1 and 380 and 8-16 fg CTX1B equivalents (equiv.) • cell-1. Four extracts of F. paulensis exhibited a novel toxicity response in neuro-2a cells consisting of the recovery of the cell viability in the presence of ouabain and veratridine. In addition, G. australes showed MTX-like toxicity while F. paulensis strains did not. Overall, the low CTX-like toxicities detected indicate that the potential risk of CP in the Balearic Islands is low, although, the presence of CTX-like and MTX-like toxicity in those strains reveal the necessity to monitor these genera in the Mediterranean Sea.


Small intestinal and hepatic amylase activity of different vertebrates and invertebrates.
Studies have been done on amylase activity of the small intestine and liver of toad, calotes, pigeon rat, guinea pig and pilaglobosa. It has been found that amylase activity was maximum in pigeon, rat, guinea pig and then in calotes and pilaglobosa and least activity was found in toad, and seem to be related to the phylogeny and the dietary habbit.


Atypical haemorrhagic colloid cyst: 2 case reports surgical management and review of literature.
Colloid cysts are benign cystic lesions located at the anterior part of the third ventricle mostly at the foramen of Monro and contain colloid material. Hemorrhage in a colloid cyst is exceedingly rare. Only 15 clinically diagnosed cases of haemorrhagic cysts were reported in the literature and 5 more cases on autopsy. Here we report two rare cases of a haemorrhagic colloid cyst describing the atypical radiological findings, the undertaken surgical procedures and histopathological results. We presented 2 cases of haemorrhagic third ventricle colloid cysts. First case is a 27-year-old male patient, presented with dizziness, nausea, vomiting and blurring of vision. He was operated by transcortical endoscopic transventricular excision of a third ventricular cyst and the insertion of external ventricular drain. The second patient is a 21-year-old male, presented with history of worsening headache for 1 month associated with blurring of vision. The patient had a transcortical microscopic, transventricular cyst excision. Many questions regarding the best way to diagnose and manage such lesions remain unanswered. Hence, we summarize the relevant diagnostic images and best surgical techniques. We concluded that, though exceedingly rare, colloid cyst can bleed and cause rapid deterioration in neurological status, thus, presence of atypical features should alert the physicians to consider atypical colloid cyst that would be valuable in surgical decision making whether endoscopic or microscopic.


Modeling spatio-temporal assessment of land use land cover of Lahore and its impact on land surface temperature using multi-spectral remote sensing data.
Urban sprawl, also widely known as urbanization, is one of the significant problems in the world. This research aims to assess and predict the urban growth and impact on land surface temperature (LST) of Lahore as well as land use and land cover (LULC) with a cellular automata Markov chain (CA-Markov chain). LULC and LST distributions were mapped using Landsat (5, 7, and 8) data from 1990, 2004, and 2018. Long-term changes to the landscape were simulated using a CA-Markov model at 14-year intervals from 2018 to 2046. Results indicate that the built-up area was increased from 342.54 (18.41%) to 720.31 (38.71%) km2. Meanwhile, barren land, water, and vegetation area was decreased from 728.63 (39.16%) to 544.83 (29.28%) km2, from 64.85 (3.49%) to 34.78 (1.87%) km2, and from 724.53 (38.94%) to 560.63 (30.13%) km2, respectively. In addition, urban index, a non-vegetation index, accurately predicted LST, showing the maximum correlation R2 = 0.87 with respect to retrieved LST. According to CA-Markov chain analysis, we can predict the growth of built-up area from 830.22 to 955.53 km2 between 2032 and 2046, based on the development from 1990 to 2018. As urban index as the predictor anticipated that the LST 20-23 °C and 24-27 °C, regions would all decline in coverage from 5.30 to 4.79% and 15.79 to 13.77% in 2032 and 2046, while the temperature 36-39 °C regions would all grow in coverage from 15.60 to 17.21% of the city. Our results indicate severe conditions, and the authorities should consider some strategies to mitigate this problem. These findings are significant for the planning and development division to ensure the long-term usage of land resources for urbanization expansion projects in the future.


Ultrasensitive Electrochemical DNA Biosensor Based on a Label-Free Assembling Strategy Using a Triblock polyA DNA Probe.
Multiblock DNA probe attracted a large amount of scientific attention, for the development of multitarget biosensor and improved specificity/sensitivity. However, the development of multiblock DNA probes highly relied on the chemical synthesis of organic linkers or nanomaterials, which limited their practicability and biological compatibility. In this work, we developed a label-free assembling strategy using a triblock DNA capture probe, which connects two DNA probes with its intrinsic polyA fragment (probe-PolyA-probe, PAP). The middle polyA segment has a high affinity to the gold electrode surface, leading to excellent reproducibility, stability, and regeneration of our biosensor. Two flanking capture probes were tandemly co-assembled on the electrode surface with consistent spatial relationship and exactly the same amount. When combined with the target DNA, the hybridization stability was improved, because of the strong base stacking effect of two capture probes. The sensitivity of our biosensor was proved to be 10 fM, with a wide analysis range between 10 fM to 1 nM. Our PAP-based biosensor showed excellent specificity when facing mismatched DNA sequences. Even single nucleotide polymorphisms can be distinguished by each probe. The excellent practicability of our biosensor was demonstrated by analyzing genomic DNA both with and without PCR amplification.


Pyrantel in small animal medicine: 30 years on.
Pyrantel, a tetrahydropyrimidine nicotinic agonist anthelmintic, has been used in companion animal medicine since the 1970s to control two important nematode groups, the hookworms and the roundworms. Given the zoonotic potential of these parasites, pyrantel has served a dual role in helping to protect the health of both companion animals and the public for more than 30 years. This review describes the history and mechanism of action of this drug, and collates evidence that resistance to pyrantel has developed in at least one canine nematode, the hookworm Ancylostoma caninum. The role of in vitro diagnosis tests in managing anthelmintic resistance in companion animal parasites is discussed, as are management practices that may reduce the rate at which resistance develops.


A putative alpha-helical porin from Corynebacterium glutamicum.
The cell wall of Corynebacterium glutamicum contains a mycolic acid layer, which is a protective nonpolar barrier similar to the outer membrane of Gram-negative bacteria. The exchange of material across this barrier requires porins. Porin B (PorB) is one of them. Recombinant PorB has been produced in Escherichia coli, purified, crystallized and analyzed by X-ray diffraction, yielding 16 independent molecular structures in four different crystal forms at resolutions up to 1.8 A. All 16 molecules have the same globular core, which consists of 70 residues forming four alpha-helices tied together by a disulfide bridge. The 16 structures vary greatly with respect to the 29 residues in the N- and C-terminal extensions. Since corynebacteria belong to the group of mycolata that includes some prominent human pathogens, the observed structure may be of medical relevance. Due to the clearly established solid structure of the core, the native porin has to be oligomeric, and the reported structure is one of the subunits. An alpha-helical porin in a bacterial outer envelope is surprising because all presently known structures of such porins consist of beta-barrels. Since none of the four crystal packing arrangements was compatible with an oligomeric membrane channel, we constructed a model of such an oligomer that was consistent with all available data of native PorB. The proposed model is based on the required polar interior and nonpolar exterior of the porin, on a recurring crystal packing contact around a 2-fold axis, on the assumption of a simple C(n) symmetry (a symmetric arrangement around an n-fold axis), on the experimentally established electric conductivity and anion selectivity and on the generally observed shape of porin channels.


Arthroscopic scapholunate dorsal capsulodesis: A 30-patient case series comparing postoperative splint immobilization versus immobilization and connected K-wiring.
The aim of this retrospective study was to compare the results of arthroscopic dorsal capsulodesis performed with or without temporary K-wiring to treat patients who had sustained scapholunate ligament injuries. Our case series included 30 patients with an average age of 37 years (range: 19-55) of whom 12 were female. Dorsal scapholunate capsulodesis was carried out in all patients. In 15 patients, splint immobilization only was used (group I). For the remaining 15 patients, supplementary scapholunate and scaphocapitate K-wiring was performed (group II). The outcomes, whether K-wiring was used or not, were not as good as the outcomes of other published studies. In our study, the reported QuickDASH score was on average higher than 20/100, pain score was higher than 2/10, grip strength was less than 70% of the contralateral side. There was one postoperative complication in the first group and three complications in the second group; five cases of DISI were reported in the first group and three in the second group. There were no significant differences between the two groups. Based on our findings, supplementary K-wiring is not necessary when a dorsal scapholunate capsulodesis is performed. The outcomes of our study were not as good as those of other published series, potentially due to a shorter follow-up and the more severe ligament injuries in our case series.


Exome sequence analysis of rare frequency variants in Late-Onset Alzheimer Disease.
Alzheimer disease (AD) is a leading cause of dementia in elderly patients who continue to live between 3 and 11 years of diagnosis. A steep rise in AD incidents is observed in the elderly population in East-Asian countries. The disease progresses through several changes, including memory loss, behavioural issues, and cognitive impairment. The etiology of AD is hard to determine because of its complex nature. The whole exome sequences of late-onset AD (LOAD) patients of Korean origin are investigated to identify rare genetic variants that may influence the complex disorder. Computational annotation was performed to assess the function of candidate variants in LOAD. The in silico pathogenicity prediction tools such as SIFT, Polyphen-2, Mutation Taster, CADD, LRT, PROVEAN, DANN, VEST3, fathmm-MKL, GERP + + , SiPhy, phastCons, and phyloP identified around 17 genes harbouring deleterious variants. The variants in the ALDH3A2 and RAD54B genes were pathogenic, while in 15 other genes were predicted to be variants of unknown significance. These variants can be potential risk candidates contributing to AD. In silico computational techniques such as molecular docking, molecular dynamic simulation and steered molecular dynamics were carried out to understand the structural insights of RAD54B with ATP. The simulation of mutant (T459N) RAD54B with ATP revealed reduced binding strength of ATP at its binding site. In addition, lower binding free energy was observed when compared to the wild-type RAD54B. Our study shows that the identified uncommon variants are linked to AD and could be probable predisposing genetic factors of LOAD.


Septicemia with Agrobacterium species from a permanent vena cephalica catheter. A case report.
A case of Agrobacterium septicemia is reported in a 47-year-old woman with disseminated adenomcarcinoma mammae and a permanent vena cephalica catheter.


HIV and Islam: is HIV prevalence lower among Muslims?
Religious constraints on sexuality may have consequences for the transmission of sexually transmitted diseases. Recognising that several Islamic tenets may have the effect, if followed, of reducing the sexual transmission of HIV, this paper tests the hypothesis that Muslims have lower HIV prevalence than non-Muslims. Among 38 sub-Saharan African countries, the percentage of Muslims within countries negatively predicted HIV prevalence. A survey of published journal articles containing data on HIV prevalence and religious affiliation showed that six of seven such studies indicated a negative relationship between HIV prevalence and being Muslim. Additional studies on the relationship of risk factors to HIV prevalence gave mixed evidence with respect to following Islamic sexual codes (e.g., vs. extramarital affairs) and other factors, but that benefits arising from circumcision may help account for lower HIV prevalence among Muslims.


Dehydrogenation of 3-phenoxybenzyl alcohol in isolated perfused rabbit skin, skin homogenate and purified dehydrogenases.
The formation of 3-phenoxybenzoic acid from 3-phenoxybenzyl alcohol was determined in (a) rabbit ears, single-pass perfused with a protein-free buffer, pH 7.4; (b) the microsomal fraction and its supernatant from homogenized rabbit skin; and (c) purified alcohol dehydrogenase from horse liver and baker's yeast. The inhibition of product formation in (a) was about 60% by various 4-methylpyrazole concentrations, but metyrapone had no effect. Following ultracentrifugation, only the supernatant of homogenized skin showed product formation (apparent Vmay: 32 pmol/min per cm2 skin; apparent Km: 64 microM). 3-Phenoxybenzyl alcohol and ethanol dehydrogenation was similar by alcohol dehydrogenase from horse liver (apparent Km: 0.7 vs. 0.4 mM; apparent Vmax: 0.3 vs. 0.2 U/ microg protein). In baker's yeast, the apparent Km of 3-phenoxybenzoic acid formation was several times larger than that for ethanol dehydrogenation. The KI of 4-methylpyrazole for alcohol dehydrogenase from horse liver was 0.6 (3-phenoxybenzyl alcohol) vs. 0.04 microM (ethanol). The KI for ethanol in baker's yeast was 470 microM. In conclusion dehydrogenation is an important metabolic pathway in the skin for xenobiotics with an aliphatic alcohol at a side chain.


The permeability of artificial dentine carious lesions.
This study aimed to verify whether two demineralisation solutions, with different fluoride concentrations, would produce subsurface lesions in dentine, as assessed by microradiography, with different mineral loss profiles and, subsequently, to determine the dentine permeability of the two altered tissues. Forty-five human coronal portions were prepared and randomly divided into two test groups (20 specimens each) with the remaining five as a control group. Each test group was exposed to a demineralisation solution containing either 1 or 5 ppm fluoride for five days. There were highly significant differences between the two test groups for all microradiographic parameters, except for lesion depth. The increase in dentine permeability from baseline to day 5 was statistically significant within each of the two test groups, but not for the control group. The differences in the mineral content profile of the two lesions did not influence the magnitude of change in their permeability.


A Chicken Tapasin ortholog can chaperone empty HLA-B∗37:01 molecules independent of other peptide-loading components.
Human Tapasin (hTapasin) is the main chaperone of MHC-I molecules, enabling peptide loading and antigen repertoire optimization across HLA allotypes. However, it is restricted to the endoplasmic reticulum (ER) lumen as part of the protein loading complex (PLC), and therefore is highly unstable when expressed in recombinant form. Additional stabilizing co-factors such as ERp57 are required to catalyze peptide exchange in vitro, limiting uses for the generation of pMHC-I molecules of desired antigen specificities. Here, we show that the chicken Tapasin (chTapasin) ortholog can be expressed recombinantly at high yields in a stable form, independent of co-chaperones. chTapasin can bind the human HLA-B∗37:01 with low micromolar-range affinity to form a stable tertiary complex. Biophysical characterization by methyl-based NMR methods reveals that chTapasin recognizes a conserved β2m epitope on HLA-B∗37:01, consistent with previously solved X-ray structures of hTapasin. Finally, we provide evidence that the B∗37:01/chTapasin complex is peptide-receptive and can be dissociated upon binding of high-affinity peptides. Our results highlight the use of chTapasin as a stable scaffold for protein engineering applications aiming to expand the ligand exchange function on human MHC-I and MHC-like molecules.


Prevalence of myocardial perfusion abnormalities in end-stage liver disease.
The prevalence of coronary artery disease (CAD) in end-stage liver disease (ESLD) being evaluated for orthotopic liver transplantation (OLT) is unclear based on variable definition used for CAD. The aim of this study to investigate the prevalence of abnormal stress myocardial perfusion single-photon emission computed tomography (MPS) imaging, as a marker for CAD, among patients with ESLD who were referred for stress MPS imaging as a routine work up before OLT. This was a single-center, retrospective study. We reviewed data on 167 patients who were referred for MPS as a routine work up before OLT over the last 2 years. All patients underwent evaluation for CAD risk factors [age, hypercholesterolemia, diabetes mellitus (DM), hypertension (HTN), and smoking], and stress MPS as per standard protocol. The total number of patients referred for stress MPS was 167. Seven patients (4% of total study population) were excluded from the study due to poor and/or nondiagnostic studies. 147 patients (92%) had normal, but only 13 patients (8%) had abnormal MPS scans. DM and male gender were the most independent risk factors for abnormal MPS with P value of 0.046, and 0.26, respectively. There was no significant association between the abnormal MPS result and HTN, hypercholesterolemia, smoking, age or etiology of the liver disease. Based on our data, the prevalence of abnormal MPS and left ventricular ejection fraction in patients with ESLD was found to be 8%. DM and male gender were the most independent predictor factors for abnormal MPS. True prevalence of CAD and usefulness of MPS in patients with ESLD can only be studied using a very large and randomized prospective study.


Correcting power and p-value calculations for bias in diffusion tensor imaging.
Diffusion tensor imaging (DTI) provides quantitative parametric maps sensitive to tissue microarchitecture (e.g., fractional anisotropy, FA). These maps are estimated through computational processes and subject to random distortions including variance and bias. Traditional statistical procedures commonly used for study planning (including power analyses and p-value/alpha-rate thresholds) specifically model variability, but neglect potential impacts of bias. Herein, we quantitatively investigate the impacts of bias in DTI on hypothesis test properties (power and alpha-rate) using a two-sided hypothesis testing framework. We present theoretical evaluation of bias on hypothesis test properties, evaluate the bias estimation technique SIMEX for DTI hypothesis testing using simulated data, and evaluate the impacts of bias on spatially varying power and alpha rates in an empirical study of 21 subjects. Bias is shown to inflame alpha rates, distort the power curve, and cause significant power loss even in empirical settings where the expected difference in bias between groups is zero. These adverse effects can be attenuated by properly accounting for bias in the calculation of power and p-values.


Effect of veratrum alkaloids on right and left atrial receptors in the cat.
1. The effects of veriloid and veratridine on right and left atrial receptors have been studied in cats. 2. Threshold doses of these drugs for right atrial receptors were found to be almost twice those for left atrial receptors. Beyond threshold doses, however, the dose-response curves were similar. 3. The sensitivity of left atrial receptors to veratridine was not altered by an increase in PCO2 and/or decrease in PO2 of left atrial blood. Therefore, the difference in the behaviour of left and right atrial receptors to these drugs is not due to the differences in PO2 and PCO2 of blood in the two atria. They are more likely to be a feature of the regenerative regions of the receptors.


Dynamic postural control in injured collegiate cross-country runners is not associated with running-related injury.
Biomechanical factors have been associated with running-related injury, but associations are unclear. Dynamic postural stability may be a factor related to injury that has not been studied extensively. Does dynamic postural control differ in those with a history of running-related injury or those who go on to sustain a running-related injury? Sixty-five (45 injured; 20 uninjured) and fifty-eight (13 injured; 45 uninjured) collegiate cross-country runners were available for our retrospective and prospective analyses. Time to stabilization and dynamic postural stability index were collected during two separate jump landing tasks (forward and lateral direction) for each leg. Retrospective injury was tabulated by a running history survey. Prospective injuries were recorded by a licensed athletic trainer during the competitive season. Differences in postural stability were compared between injured and uninjured groups and between limbs using two-way ANOVA's. An overall group by leg comparison was completed for each task. The non-dominant limb demonstrated better postural stability indices regardless of injury history. An interaction was observed between limbs and history of injury for the anterior-posterior time to stabilization for the lateral task. The non-dominant limb demonstrated better medio-lateral postural stability indices and time to stabilization during the lateral task, regardless of prospective injury. Dynamic postural stability was reduced in the dominant limb, but no clear differences were seen between injured and uninjured runners. This suggests dynamic postural stability may be altered in individuals with a history of a running-related injury, but no relationship to subsequent injury was substantiated. Further work is needed to understand how dynamic postural stability may be related to running-related injury.


Method repeatability for measuring Enterococcus in southern California beach sands.
A recent study that evaluated 22 methods for enumerating faecal indicator bacteria in sand recommended standardization to a preferred method, but all researchers involved in that study had extensive experience in processing sand samples. The purpose of this study was to evaluate how well the recommended method can be transferred to laboratories without such experience. Eight southern California laboratories that rarely measure bacteria in sand processed six sand and three water samples in replicates to assess repeatability. Among-laboratory variability was found to be less than within-laboratory variability, with no significant differences in results among any of the laboratories. Moreover, within-laboratory variability was comparable between the sand and water samples, indicating that the elution procedure added little additional method error even when performed by laboratories without prior experience. The simple extraction method for enumerating Enterococcus in beach sands was easily transferable to and repeatable among laboratories with little or no prior experience. The demonstrated success of technology transfer will further demonstrate the success of method standardization and adoption, aiding in understanding of how sands affect surface water quality.


The Key Role of Initiation Timing on Stroke Rehabilitation by Remote Ischemic Conditioning with Exercise (RICE).
Physical therapy is an integral part of post-stroke rehabilitation. Remote ischemic conditioning (RIC) induces neuroprotection within 24 hours after stroke, during which exercise is unsafe and ineffective. We combined RIC with exercise to establish a novel rehabilitation strategy, RICE (RIC+Exercise). The aim of this study was to optimize the RICE protocol in neurorehabilitation. Thirty-two adult male Sprague-Dawley rats were placed in one of four groups: stroke with no rehabilitation or stroke with various RICE protocols. To further understand the mechanisms underlying neurorehabilitation, sixteen adult male Sprague-Dawley were added, each placed in one of two groups: stroke with exerciseor RIC . Long-term functional outcomes were determined by beam balance, rota-rod, grid walk, forelimb placing, and Morris water maze tests up to 28 days after stroke (p < 0.05). Changes in neuroplasticity including synaptogenesis (assessed by measuring synaptophysin, post-synaptic density protein-95, and brain-derived neutrophic factor), angiogenesis (via vascular endothelial growth factor, Angiopoietin-1, and Angiopoietin-2), and regulatory molecules (including hypoxia inducible factor-1α, phospholipase D2 and the mechanistic target of rapamycin pathway), were all measured at both mRNA and protein levels (p < 0.05). All rehabilitation groups showed significant improvement in functional outcomes and levels of synaptogenesis and angiogenesis. 5 day RICE groups, in which RIC was started five days prior to exercise, demonstrated the greatest improvement among these parameters. The results also suggested that the HIF-1α/PLD2/mTOR signaling pathway may be implicated in post-stroke neuroplasticity. RICE, particularly RIC initiation at hour 6 post-reperfusion followed by exercise on day 5, enhanced post-stroke rehabilitation in rats.


Ultraviolet-Light-emitting-diode activated monochloramine for the degradation of carbamazepine: Kinetics, mechanisms, by-product formation, and toxicity.
Monochloramine (NH2Cl) oxidant combined with a Ultraviolet (UV)-Light-emitting-diode (LED) light source forms a new advanced oxidation process (AOP), which can achieve high-efficiency degradation of carbamazepine (CBZ). The degradation of CBZ displayed pseudo-first-order reaction kinetics (R2 > 0.98, kCBZ = 0.0043 cm2 mJ-1 at pH 7). The degradation of CBZ was dependent on UV-LED wavelength, with maximum degradation efficiency observed at 265 nm since it was the lowest wavelength studied among UV-LEDs. Variation in pH across the range, which might be expected under normal environmental conditions (pH 6-8), and the presence of Cl- had no significant effect on the degradation efficiency of CBZ, while the presence of HCO3- and natural organic matter (NOM) inhibited degradation. Electron paramagnetic resonance (EPR) experiments detected OH in the system. Probe compounds were used to distinguish the contribution of reactive chlorine species (RCS). It was proved that OH and Cl played major roles and OH was responsible for around 50% of the observed degradation of CBZ. Eight transformative products (TPs) in the degradation process of CBZ were identified, with a generally decreasing toxicity. The concentration of disinfection by-products (DBPs) formed during CBZ degradation was all within limits of WHO and China standard for drinking water. Although the concentration of nitrogen-containing DBPs (N-DBPs) was the lowest, N-DBPs were the main contributors to toxicity, and these would require more attention in practical applications. UV-LED/NH2Cl AOP was identified as an effective way to degrade pharmaceutically active compounds.


Histone-H1 inhibits translation by reticulocyte lysates with relative mRNA selectivity.
Histone-H1 purified from rat skeletal muscle is a relatively potent inhibitor of peptide chain initiation in a cell free system, the rabbit reticulocyte lysate (50% inhibition at approximately 0.4 microM). H1 does not inhibit formation of the ternary complex nor its attachment to 40S ribosomes; the data are compatible with H1 binding to mRNA. The inhibition shows mRNA selectivity: translation of beta-globin mRNA is more affected than that of alpha-globin mRNA and hepatic albumin mRNA more than total hepatic mRNA. Whether or not histone-H1 plays a role in translational regulation in intact cells is conjectural, it may serve as a useful model for protein-mRNA interactions.


Inter- and intra-observational variability in immunohistochemistry: a multicentre analysis of diffuse large B-cell lymphoma staining.
Although many immunohistochemical (IHC) cancer biomarkers have been identified, very few have translated into routine clinical practice, primarily because of technical and observational inconsistencies between studies. However, despite the obvious need to address such variability, very few studies have done so. Using bcl-6, CD10, MUM1, GCET1 and FOXP1 antibody staining on diffuse large B-cell lymphoma cases (n = 138) as a model, we employed Cronbach α analysis to quantify interobserver and intraobserver variability between four independent observers (two per institution), scoring two tissue microarrays (TMAs) stained at both institutions using differing staining procedures. The overall concordance between all observations irrespective of staining procedure or TMA source was high (average α = 0.951), with the highest level being reached for CD10 staining (average α = 0.967) and the lowest for bcl-6 (average α = 0.924). Interslide and interinstitutional reproducibility were similarly high (average α = 0.952 and average α = 0.934, respectively). Interobserver/intrainstitutional and interobserver/interinstitutional comparisons showed lower levels of concordance (average α = 0.870 and average α = 0.877, respectively), and intraobserver/interinstitutional comparisons showed the lowest levels of concordance (average α = 0.810), particularly for bcl-6 staining (α = 0.658). This study suggests that most variability in IHC studies between centres results from inherent limitations of the biomarkers investigated rather than procedural or observational differences.


Regulation of hydrogen peroxide in eye humors. Effect of 3-amino-1H-1,2,4-triazole on catalase and glutathione peroxidase of rabbit eye.
Activities of catalase (H2O2: H2O2 oxidoreductase, EC 188.8.131.52) and GSH peroxidase (GSH: H202 oxidoreductase, EC 18.104.22.168) have been measured in iris, ciliary body, retina, corneal epithelium, corneal endothelium, lens capsule-epithelium and decapsulated lens. 3-Amino-1H-1,2,4-triazole is a specific inhibitor of catalase and a potent cataractogenic agent. We observed marked inhibition of catalase activity in these tissues 1--6 h after the administration of a single intravenous dose of 1 g 3-aminotriazole per kg body weight in rabbit. This was associated with a 2--3-fold increase in the H2O2 concentrations of aqueous humor and vitreous humor. The increased peroxide concentrations were restored to the physiological levels as the catalase activity of eye tissues gradually returned to normal with time after injection. Under the conditions, GSH peroxidase activity of the afore-mentioned eye tissues was unaltered, GSH and protein sulfhydryl of lens were not changed, and ascorbic acid of aqueous humor and vitreous humor was not significantly altered. Based on these findings our conclusion is that catalase of eye tissues regulates the endogenous H2O2 in eye humors to the physiological level. We speculate that H2O2 may be the triggering factor in cataract induced by 3-aminotriazole.


A prognostic model combining CD4/CD8 ratio and N stage predicts the risk of distant metastasis for patients with nasopharyngeal carcinoma treated by intensity modulated radiotherapy.
This study aimed to evaluate the correlation between circulating lymphocyte subsets and clinical variables, and design an effective prognostic model for distant metastasis-free survival (DMFS) in NPC. In this study, subsets of circulating lymphocytes were determined in 719 non-metastatic NPC patients before treatment. Overall survival and DMFS was monitored. Significant prognostic factors were identified using univariate and multivariate analyses. Results showed that the percentage of CD19+ lymphocytes correlated negatively with TNM stage (r = -0.082, P = 0.028). Patients with higher CD4/CD8 ratios (≥ 1.77) showed better 5-year DMFS than patients with lower ratios (91.9% vs. 85.4%, P < 0.001). Multivariate analysis revealed that CD4/CD8 ratio (HR, 0.450; 95% confidence interval [CI], 0.266-0.760; P = 0.003) and N classification (HR, 2.294; 95% CI, 1.370-3.839; P = 0.002) were independently prognostic factors for DMFS. The prognostic N-R model was developed and divided patients into three groups: (1) low-risk (early N stage and CD4/CD8 ratio ≥ 1.77); (2) intermediate-risk (advanced N stage or CD4/CD8 ratio < 1.77) and (3) high-risk (advanced N stage and CD4/CD8 ratio < 1.77) of distant metastasis. In conclusion our prognostic model, based on clinical N stage and CD4/CD8 ratio, may predict the risk of distant metastasis, allowing individualized treatment for NPC.


County community health associations of net voting shift in the 2016 U.S. presidential election.
In the U.S. presidential election of 2016, substantial shift in voting patterns occurred relative to previous elections. Although this shift has been associated with both education and race, the extent to which this shift was related to public health status is unclear. To determine the extent to which county community health was associated with changes in voting between the presidential elections of 2016 and 2012. Ecological study with principal component analysis (PCA) using principal axis method to extract the components, then generalized linear regression. General community. All counties in the United States. Physically unhealthy days, mentally unhealthy days, percent food insecure, teen birth rate, primary care physician visit rate, age-adjusted mortality rate, violent crime rate, average health care costs, percent diabetic, and percent overweight or obese. The percentage of Donald Trump votes in 2016 minus percentage of Mitt Romney votes in 2012 ("net voting shift"). Complete public health data was available for 3,009 counties which were included in the analysis. The mean net voting shift was 5.4% (+/- 5.8%). Of these 3,009 counties, 2,641 (87.8%) had positive net voting shift (shifted towards Trump) and 368 counties (12.2%) had negative net voting shift (shifted away from Trump). The first principal component ("unhealthy score") accounted for 68% of the total variance in the data. The unhealthy score included all health variables except primary care physician rate, violent crime rate, and health care costs. The mean unhealthy score for counties was 0.39 (SD 0.16). Higher normalized unhealthy score was associated with positive net voting shift (22.1% shift per unit unhealthy, p < 0.0001). This association was stronger in states that switched Electoral College votes from 2012 to 2016 than in other states (5.9% per unit unhealthy, p <0.0001). Substantial association exists between a shift toward voting for Donald Trump in 2016 relative to Mitt Romney in 2012 and measures of poor public health. Although these results do not demonstrate causality, these results suggest a possible role for health status in political choices.


Phenotyping of peripheral blood lymphocytes in adult coeliac disease.
In coeliac disease immunological abnormalities are not confined to the small bowel and it has been suggested that changes in peripheral blood lymphocytes may predispose to autoimmune or malignant complications. Using dual-colour immunofluorescence with labelled monoclonal antibodies, multiparameter flow cytometry was used to analyse peripheral blood lymphocytes in 32 untreated coeliacs, 29 treated coeliacs and 20 healthy volunteers. When the absolute numbers were considered, a decrease of CD3+, CD4+, CD8+ and CD19+ lymphocytes was found in untreated coeliacs compared with treated coeliacs and healthy volunteers. The proportion of CD3+ was significantly higher in untreated coeliacs (P<0.05) than in healthy volunteers. No differences were observed in CD4+, CD8+ and CD19+ subsets between the three groups studied. The proportion of CD3+ CD25+ and CD3+ HLA-DR+ cells were higher in untreated coeliacs (P<0. 001 and P>0.005) and in treated coeliacs (P<0.005 and P<0.05) than in healthy volunteers. On the contrary, natural killer cells and cytotoxic cells were lower in untreated and treated coeliacs than in healthy volunteers. As regards B-cell subsets, the only difference was the increase in FcepsilonR+ B cells in untreated coeliacs. The absolute reduction of peripheral lymphocytes in coeliac disease probably reflects their compartimentalization in intestinal mucosa. The decrease of natural killer cells and cytotoxic cells may be in keeping with the increased prevalence of malignancy in this condition. Finally, the phenotypic changes found in untreated coeliacs indicate T-cell activation.


Relationship Factors and Condom Use Among Women with a History of Intimate Partner Violence.
Women who experience intimate partner violence (IPV) are at increased risk for HIV infection. To further the understanding of the dyadic factors that impact condom use among women, we investigated the impact of three relationship factors (i.e., power, fear, and dependence) on the association between HIV-related information, motivation, and behavioral skills [constructs from the information-motivation-behavioral skills (IMB) model] and condom use among abused women. Data from 133 urban, low-income women recruited from several community-based agencies (e.g., domestic violence agencies, women's health organizations, hospitals, Department of Health and Human Services, and Family Court) showed that these women experienced high levels of IPV and that relationship power, fear of abuse, and partner dependence were all associated with condom use. Multivariable models revealed that fear of abuse and partner dependence moderated the association between IMB constructs and condom use but relationship power did not. Results highlight the critical need to incorporate strategies to address relationship factors in HIV prevention programs with abused women.


MpoxRadar: a worldwide MPXV genomic surveillance dashboard.
The mpox virus (MPXV) is mutating at an exceptional rate for a DNA virus and its global spread is concerning, making genomic surveillance a necessity. With MpoxRadar, we provide an interactive dashboard to track virus variants on mutation level worldwide. MpoxRadar allows users to select among different genomes as reference for comparison. The occurrence of mutation profiles based on the selected reference is indicated on an interactive world map that shows the respective geographic sampling site in customizable time ranges to easily follow the frequency or trend of defined mutations. Furthermore, the user can filter for specific mutations, genes, countries, genome types, and sequencing protocols and download the filtered data directly from MpoxRadar. On the server, we automatically download all MPXV genomes and metadata from the National Center for Biotechnology Information (NCBI) on a daily basis, align them to the different reference genomes, generate mutation profiles, which are stored and linked to the available metainformation in a database. This makes MpoxRadar a practical tool for the genomic survaillance of MPXV, supporting users with limited computational resources. MpoxRadar is open-source and freely accessible at https://MpoxRadar.net.


Elastic properties of an intact and ACL-ruptured knee joint: measurement, mathematical modelling, and haptic rendering.
An analytical, dynamic model of the human knee joint has been developed to simulate the unloaded knee joint behaviour in 6 degrees of freedom. It is based on extensive robot-based measurements of the elastic properties of a human cadaver knee joint. The measured data are compared with data from the literature to ensure that a proper database for modelling is used. The analytical modelling of the passive elastic joint properties is done with Local Linear Model Trees. The deduced knee joint model incorporates passive elastic properties of the internal knee joint structures, passive elastic muscle forces, damping forces, gravitational forces, and external forces. There are two sets of parameters, one simulating the movement of the intact knee joint, and a second simulating the knee joint with ruptured anterior cruciate ligament. The dynamic model can be easily processed in real-time. It is implemented in the haptic display of the Munich Knee Joint Simulator (MKS), which enables a person to move a plastic leg driven by a robot manipulator and feel the simulated knee joint force. Orthopaedic physicians judged the performance of the dynamic knee joint model by executing physical knee joint tests at the MKS.


Molecular analysis of the β-globin gene cluster haplotypes in a Sudanese population with sickle cell anaemia.
Sudan has a multiethnic population with a high frequency of Hb S, but little is known about the β(S) haplotypes in this population. Blood samples from Sudanese Hb SS individuals were taken at two locations. Family history, age, ethnicity and clinical symptoms were recorded for each subject. Hb S was investigated using cellulose acetate electrophoresis (CAE) and cation exchange-high performance liquid chromatography. Dried blood samples from 93 individuals were used for β(S) haplotype identification based on restriction fragment length polymorphism analysis for seven restriction sites. Haplotypes could be assigned unequivocally to 143 chromosomes. Four of the five typical β(S) -globin haplotypes were identified. The most frequent was the Cameroon (35.0%), followed by the Benin (29.4%), the Senegal (18.2%) and the Bantu (2.8%). The Indian-Arab haplotype was not observed. Three atypical haplotypes were identified in 17 patients, occurring at a combined frequency of 14.6%. One of these, found at the high frequency of 11.8%, possibly represented a new Sudan haplotype. β(S) Haplotyes were demonstrated successfully from dried blood samples. A new haplotype is apparent in Sudan, in addition to the four African haplotypes.


Laparoscopic vasectomy: case report and review of the literature.
A 42-year-old man undergoing bilateral laparoscopic hernia repair requested vasectomy for family planning purposes. Bilateral vasectomy was done by a laparoscopic approach at the time of extraperitoneal hernia repair, and a separate scrotal incision was avoided. In addition to reporting a case of laparoscopic vasectomy, we review the published literature on this topic.


Novel metabolomics markers are associated with pre-clinical decline in hand grip strength in community-dwelling older adults.
Hand grip strength (HGS) has been proposed as a robust predictor for frailty and sarcopenia. Hence, identifying biomarkers for declining HGS accompanying aging could deepen our understanding of the biological underpinnings, informing pre-emptive intervention. Acylcarnitines (ACs) are metabolites generated by fatty acid metabolism in the mitochondria and are dysregulated in multiple disorders affecting the musculature. However, they have not been comprehensively profiled and examined regarding their utility in predicting variability in declining HGS, longitudinally. Thus, we aimed to: 1) validate previous findings on insignificant cross-sectional association between ACs and HGS, and 2) examine whether baseline ACs were associated with both decline and variability in HGS over 18 months, in community-dwelling older adults. We included participants who had HGS measured with dynamometer longitudinally (N = 121). We quantified ACs by targeted plasma metabolomics profiling. Multivariable linear regressions were then performed. Cross-sectionally, ACs were not significantly associated with HGS. Longitudinally, baseline short-chain dicarboxylic and hydroxylated acylcarnitines (AC-DC/-OH) levels were inversely associated with and significantly explained the variability in 18-month decline in HGS. A specific AC species, the C4-OH, accounted for most of the variance explained. We showed novel biomarkers for declining HGS, furthering molecular understanding and informing nutritional pre-emptive programs.


The costa of trichomonads: A complex macromolecular cytoskeleton structure made of uncommon proteins.
The costa is a prominent striated fibre that is found in protozoa of the Trichomonadidae family that present an undulating membrane. It is composed primarily of proteins that have not yet been explored. In this study, we used cell fractionation to obtain a highly enriched costa fraction whose structure and composition was further analysed by electron microscopy and mass spectrometry. Electron microscopy of negatively stained samples revealed that the costa, which is a periodic structure with alternating electron-dense and electron-lucent bands, displays three distinct regions, named the head, neck and body. Fourier transform analysis showed that the electron-lucent bands present sub-bands with a regular pattern. An analysis of the costa fraction via one- and two-dimensional electrophoresis and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) allowed the identification of 54 hypothetical proteins. Fourteen of those proteins were considered to be major components of the fraction. The costa of T. foetus is a complex and organised cytoskeleton structure made of a large number of proteins which is assembled into filamentous structures. Some of these proteins exhibit uncharacterised domains and no function related according to gene ontology, suggesting that the costa structure may be formed by a new class of proteins that differ from those previously described in other organisms. Seven of these proteins contain prefoldin domains displaying coiled-coil regions. This propriety is shared with proteins of the striated fibres of other protozoan as well as in intermediate filaments. Our observations suggest the presence of a new class of the cytoskeleton filaments in T. foetus. We believe that our data could auxiliate in determining the specific locations of these proteins in the distinct regions that compose the costa, as well as to define the functional roles of each component. Therefore, our study will help in the better understanding of the organisation and function of this structure in unicellular organisms.


Complexity engineering: New ideas for engineering design and engineering education.
This paper presents a theoretical approach to complexity engineering by considering the complex thinking framework proposed by Edgar Morin. The main foundations of this approach are an open system design, emergence, randomness inclusion, and Gödel incompleteness, which are contextualized using real-word instructive problems. Considering these concepts, several conjectures related to engineering activity and engineering education are presented taking several Brazilian catastrophes as counterexamples.


Differential regulation of cAMP by endogenous versus transfected formylpeptide chemoattractant receptors: implications for Gi-coupled receptor signaling.
Endogenous neutrophil formylpeptide receptors do not inhibit adenylylcyclase activation. The ability of a cloned and transfected human formylpeptide receptor to mediate the inhibition of adenylylcyclase was assessed in the human embryonic kidney 293 TSA cell line. Inclusion of 1 microM fMetLeuPhe resulted in a ca. 50% inhibition of isoproterenol-stimulated cAMP in transfected cells. Activation of adenylylcyclase by isoproterenol was inhibited ca. 30% by fMetLeuPhe in membranes prepared from transfected cells but not in membranes prepared from neutrophils. Prior treatment of transfected cells with pertussis toxin abrogated the inhibitory effect of fMetLeuPhe. These data indicate that factors in addition to the primary structure of the formylpeptide receptor govern its transductional activities.


B-type natriuretic peptide-guided chronic heart failure therapy: a meta-analysis of 11 randomised controlled trials.
The use of plasma levels of B-type natriuretic peptides (BNPs) to guide treatment of patients with chronic heart failure (HF) has been investigated in a number of randomised controlled trials (RCTs). However, the benefits have been variable. We therefore performed a meta-analysis to examine the overall effect of BNP-guided drug therapy on all-cause mortality and HF rehospitalisation in patients with chronic HF. We identified RCTs by systematic search of MEDLINE, EMBASE and the Cochrane Controlled Clinical Trials Register Database. Eligible RCTs were those that enrolled more than 40 patients and involved comparison of BNP-guided versus guideline-guided drug therapy of the patients with chronic HF in the outpatient setting. Eleven RCTs with a total of 2414 patients and with a mean duration of 12 months (range, 3-36 months) were included in the meta-analysis. Overall, there was a significantly decreased risk of all-cause mortality (relative risk [RR], 0.83; 95% confidence interval [CI], 0.69-0.99; P=0.035; I(2)=0%) and HF rehospitalisation (RR, 0.75; 95% CI, 0.62-0.91; P=0.004; I(2)=62.2%) in the BNP-guided therapy group. Age, baseline BNP are the major dominants of HF rehospitalisation when analysed using meta-regression. In the subgroup analysis, HF rehospitalisation was significantly decreased in the patients younger than 70 years (RR, 0.45; 95% CI, 0.33-0.61; P=0.000; I(2)=0.0%), or with baseline higher BNP (≥2114pg/mL) (RR, 0.53; 95% CI, 0.39-0.72; P=0.000; I(2)=21.8%). Compared with usual clinical care, B-type natriuretic peptide-guided therapy reduces all-cause mortality and HF rehospitalisation, especially in patients younger than 70 years or with higher baseline BNP.


Highly selective and sensitive fluorescent probe possessing AIEE and ICT properties for rapid detection of Pb2+ in aqueous medium and its applications in living cells.
In this paper, a novel rapid, highly selective and sensitive Pb2+ fluorescent probe (E)-N'-((2-(4'-(diphenylamino)-[1,1'-biphenyl]-4-yl)-2H-1,2,3-triazol-4-yl)methylene) (DBTBH) was synthesized. The probe DBTBH not only exhibited more excellent selectivity and sensitivity to Pb2+ detection compared with other analytes (include metal ions and anions) in H2 O:THF solution (v:v = 9:1, 10 mM Tris-HCl, 1 mM KI, pH 7.4), but also had excellent optical properties such as aggregation-induced emission enhancement (AIEE) and intramolecular charge transfer (ICT). Detection limit of the probe DBTBH towards Pb2+ was 4.49 × 10-8 M. The possible mechanism was verified by 1 H NMR titration and HR-MS. Furthermore, the successful detection of Pb2+ by DBTBH in real water samples and HeLa cells indicated that DBTBH has great potential for selective recognition of Pb2+ in the natural environment and biological systems. These findings will provide a promising new idea for designing better Pb2+ fluorescent probes in the future.


ACTH-like peptides and opiate receptors in the rat brain: structure-activity studies.
The present study aims at further identifying the interaction of ACTH-like peptides and rat brain opiate receptors in vitro. The sequence ACTH4-10 is crucial with respect to affinity since it is the shortest sequence to inhibit the binding of [3H]-dihydromorphine and [3H]-naltrexone to these receptors. A second active site seems to be localized in the N-terminal part of ACTH11-24. This structure-activity relationship is compared to that observed for these peptides on the adrenal cortex and behavior.