The role of sigma 1 receptor in organization of endoplasmic reticulum signaling microdomains.
Sigma 1 receptor (S1R) is a 223-amino-acid-long transmembrane endoplasmic reticulum (ER) protein. S1R modulates activity of multiple effector proteins and is a well-established drug target. However, signaling functions of S1R in cells are poorly understood. Here, we test the hypothesis that biological activity of S1R in cells can be explained by its ability to interact with cholesterol and to form cholesterol-enriched microdomains in the ER membrane. By performing experiments in reduced reconstitution systems, we demonstrate direct effects of cholesterol on S1R clustering. We identify a novel cholesterol-binding motif in the transmembrane region of human S1R. Mutations of this motif impair association of recombinant S1R with cholesterol beads, affect S1R clustering in vitro and disrupt S1R subcellular localization. We demonstrate that S1R-induced membrane microdomains have increased local membrane thickness and that increased local cholesterol concentration and/or membrane thickness in these microdomains can modulate signaling of inositol-requiring enzyme 1α in the ER. Further, S1R agonists cause disruption of S1R clusters, suggesting that biological activity of S1R agonists is linked to remodeling of ER membrane microdomains. Our results provide novel insights into S1R-mediated signaling mechanisms in cells.


Angiotensin-converting enzyme 2 and renal disease.
The renin-angiotensin system (RAS) is a pivotal player in the physiology and pathophysiology of cardiovascular and renal systems. Discovery of angiotensin-converting enzyme 2 (ACE2), capable of cleaving RAS effector peptide angiotensin (Ang) II into biologically active Ang-(1-7), has increased the complexity of our knowledge of the RAS. ACE2 expression is abundant in the kidney and is thought to provide protection against injury. This review emphasizes current experimental and clinical findings that examine ACE2 in the context of kidney injury and its potential therapeutic impact for treatment of kidney disease. Clinical studies have reported upregulation of ACE2 in urine from diabetic patients, which may be reflective of pathological shedding of renal ACE2 as suggested by mechanistic experiments. Studies in experimental models have investigated the feasibility of pharmacological induction of ACE2 for improvement of renal function, inflammation, and fibrosis. Emerging concepts about the RAS indicate that ACE2 is a critical regulator of angiotensin peptide metabolism and the pathogenesis of renal disease. Human recombinant ACE2 is available and may be a practical clinical approach to enzyme replacement. Elucidating precise roles of ACE2 throughout disease progression will enrich our view of the RAS and help identify novel targets and appropriate strategies for intervention.


Neuropsychological findings in pediatric maltreatment: relationship of PTSD, dissociative symptoms, and abuse/neglect indices to neurocognitive outcomes.
Maltreated (n = 38), maltreated + posttraumatic stress disorder (PTSD; n = 60), and control youth (n = 104) underwent comprehensive neuropsychological testing. The two maltreated groups performed significantly lower on IQ, academic achievement, and nearly all of the neurocognitive domains than controls. Maltreated + PTSD performed significantly worse than maltreated youth without PTSD on a task in the visuospatial domain that assessed higher order visuoconstructive abilities. No group differences were evident on the fine motor domain. PTSD diagnosis duration negatively correlated with the visuospatial, and dissociation negatively correlated with the attention domain. Cumulative lifetime maltreatment types experienced negatively correlated with academic achievement. Sexual abuse negatively correlated with language and memory functions after controlling for other maltreatment types. These data support the adverse effects of maltreatment on neuropsychological functions in youth and suggest that all child protective services identified youth should be comprehensively examined for the integrity of their neuropsychological functioning and academic skills, regardless of the presence or absence of mental health symptoms.


Popliteal pterygium syndrome with special consideration of the cleft malformation: case report.
This report describes a new case of popliteal pterygium syndrome (PPS) and also a treatment protocol. The patient presented with the complete complex of PPS and additional abnormalities that have not been described in the literature: a sinus of the upper lip, an extreme hypopoplastic prolabium with aplasia of the vestibule in this area, and a velar pterygium.


Scalable synthesis of cortistatin A and related structures.
Full details are provided for an improved synthesis of cortistatin A and related structures as well as the underlying logic and evolution of strategy. The highly functionalized cortistatin A-ring embedded with a key heteroadamantane was synthesized by a simple and scalable five-step sequence. A chemoselective, tandem geminal dihalogenation of an unactivated methyl group, a reductive fragmentation/trapping/elimination of a bromocyclopropane, and a facile chemoselective etherification reaction afforded the cortistatin A core, dubbed "cortistatinone". A selective Δ(16)-alkene reduction with Raney Ni provided cortistatin A. With this scalable and practical route, copious quantities of cortistatinone, Δ(16)-cortistatin A (the equipotent direct precursor to cortistatin A), and its related analogues were prepared for further biological studies.


Replication of the genome of alphaviruses.
The genome of Semliki Forest virus (SFV) is 11,442 nucleotides with a 5' cap-structure and a 3' poly(A) tail of about 100 residues. The genome of the closely relate Sindbis virus (SIN) is slightly longer (11,703 nucleotides). The parental RNA is first translated from the 5' two thirds to yield; nsP1, nsP2, nsP3 and nsP4, which are cleaved from a polyprotein of 2431 amino acids (SFV). The parental genome is copied to a full-length minus strand with poly(U) at the 5' end. The minus strand is used as template for the synthesis of 42 S RNA in membrane-bound replicative-intermediate (RI) structures. In addition to 42 S RNA, a 3'-coterminal subgenomic 26 S mRNA, coding for the structural proteins, is synthesized by internal initiation at the minus strand. Capping and methylation of both plus-strand RNAs occur concomitantly with their synthesis. Analysis of Sindbis virus temperature-sensitive RNA-negative mutants have shown that one complementation group (B) is specifically associated with the synthesis of minus strands. Another, group F, is involved in the polymerization step of both minus- and plus-strand 42 S RNA, and of the 26 S mRNA. The synthesis of minus strands is normally dependent on protein synthesis. There is a shut off of the minus-strand RNA synthesis at about 3 h post-infection. This is apparently regulated by a virus-specific protein, represented by the complementation group A. The same protein is involved in the regulation of the initiation of 26 S RNA together with a component represented by group G mutants. Comparative analysis of SFV and SIN RNAs and DI RNAs of both viruses suggests that perhaps only 19 nucleotides from the 3' end and about 150 nucleotides from the 5' end are needed for replication of the alphavirus RNAs. In some SIN DI RNAs the proposed secondary structure at the 5' end is replaced by a cellular tRNA(ASP) suggesting that the secondary structure rather than nucleotide sequence is sufficient for the recognition by the viral polymerase. Even when the primary structure of the four non-structural proteins of both SFV and SIN is known, the correlation of the genetic data with the individual proteins has not yet been possible.


Actin Isoform Composition and Binding Factors Fine-Tune Regulatory Impact of Mical Enzymes.
Mical family enzymes are unusual actin regulators that prime filaments (F-actin) for disassembly via the site-specific oxidation of M44/M47. Filamentous actin acts as a substrate of Mical enzymes, as well as an activator of their NADPH oxidase activity, which leads to hydrogen peroxide generation. Mical enzymes are required for cytokinesis, muscle and heart development, dendritic pruning, and axonal guidance, among other processes. Thus, it is critical to understand how this family of actin regulators functions in different cell types. Vertebrates express six actin isoforms in a cell-specific manner, but MICALs' impact on their intrinsic properties has never been systematically investigated. Our data reveal the differences in the intrinsic dynamics of Mical-oxidized actin isoforms. Furthermore, our results connect the intrinsic dynamics of actin isoforms and their redox state with the patterns of hydrogen peroxide (H2O2) generation by MICALs. We documented that the differential properties of actin isoforms translate into the distinct patterns of hydrogen peroxide generation in Mical/NADPH-containing systems. Moreover, our results establish a conceptual link between actin stabilization by interacting factors and its ability to activate MICALs' NADPH oxidase activity. Altogether, our results suggest that the regulatory impact of MICALs may differ depending on the isoform-related identities of local actin networks.


Maternal psychiatric and somatic illness, and the risk of unintentional injuries in children: variation by type of maternal illness, type of injury and child age.
Maternal mental illness appears to increase the risk of unintentional childhood injuries, which are a common cause of morbidity and mortality in early childhood. However, little is known about the variations in this association by type of injury and child's age, and studies on the effects of maternal somatic illness on children's injury risk are scarce. We used Finnish total population register data from 2000 to 2017 to link 1 369 325 children to their biological mothers and followed them for maternal illness and childhood injuries until the children's sixth birthday. Cox regression models were used to examine the associations between maternal illness and children's injuries by type of illness (neurological, psychiatric and cancer), type of injury (transport injuries, falls, burns, drowning or suffocations, poisonings, exposure to inanimate and animate mechanical forces) and child's age (<1 year-olds, 1-2 year-olds, 3-5 year-olds). After adjustment for family structure, maternal age at birth, maternal education, income, child's gender, native language and region of residence, children of unwell mothers showed a higher risk of injuries (HR: 1.21, 95% CI: 1.19 to 1.23). This association was clear for maternal neurological (HR: 1.31, 95% CI: 1.26 to 1.36) and psychiatric illnesses (HR: 1.20, 95% CI: 1.18 to 1.23) but inconsistent for cancer. Maternal illness predicted an increased risk of injury across all age groups. Maternal mental and somatic illness may both increase children's injury risk. Adequate social and parenting support for families with maternal illness may reduce childhood injury.


Synergistic interaction of selected marine animal anticancer drugs against human diffuse large cell lymphoma.
We studied the antitumor effects of dolastatin 10, its structural modification, auristatin PE (TZT-1027), and vincristine alone and in combination with bryostatin 1 on a human diffuse large cell lymphoma line (WSU-DLCL2) in vitro and in vivo. WSU-DLCL2 cells were cultured in RPMI 1640 at a concentration of 2 x 10(5)/ml using a 24-well plate. Agents were added to triplicate wells, and cell count, viability, mitosis and apoptosis were assessed. Dolastatin 10 showed no apparent inhibition of cell growth at concentrations less than 500 pg/ ml. Auristatin PE showed significant growth inhibition at concentrations as low as 10 pg/ml, while vincristine had a minimal effect at 50 pg/ml. Dolastatin 10, auristatin PE and vincristine-treated cultures, at 50 pg/ml, exhibited 11, 1.7; 45, 11.8%; and 39, 25% mitosis and apoptosis, respectively. In the WSU-DLCL2 SCID mouse xenograft model, the efficacy of these agents alone or in combination with bryostatin 1 was evaluated. Tumor growth inhibition (T/C), tumor growth delay (T-C) and log10 kill for dolastatin 10, auristatin PE, vincristine and bryostatin 1 were 30%, 14 days and 1.4; 0.0%, 55 days and 5.5; 29.6%, 16 days and 1.6; and 39%, 7 days and 0.7, respectively. When given in combination, two out of five mice treated with auristatin PE + bryostatin 1 were free of tumors for 150 days and were considered cured. Dolastatin 10 + bryostatin 1 and vincristine + bryostatin 1 combinations were highly active but no cure was observed. We conclude that: (i) auristatin PE is more effective in this model than dolastatin 10, vincristine or bryostatin 1, (ii) auristatin PE can be administered at a concentration 10 times greater than dolastatin 10, and (iii) there is a synergistic effect between these agents and bryostatin 1, which is more apparent in the bryostatin 1 + auristatin PE combination. The use of these agents should be further explored clinically in the treatment of lymphoma.


Implementation of Specialized Pharmaceutical Care Hospital Outpatient Clinics in a Hospital Pharmacy Department.
To describe the organization of patient care into Specialized Pharmaceutical Care Hospital Outpatient Clinics in a Hospital Pharmacy Department, to evaluate their healthcare quality, and the quality perceived by outpatients. A retrospective observational study in a High-Level Hospital Pharmacy Department during three periods (years 2010, 2013 and 2016); description of the organization at the levels of structure, human resources, material resources and working procedures; evaluation of healthcare quality through the analysis of three variables in terms of procedure: prior appointment compliance, waiting time and documentation of pharmaceutical care; evaluation of quality perceived by outpatients through a satisfaction survey; comparative statistical analysis of means (Student's t) and proportions (Pearson's chi square). Fifteen (15) specialized outpatient clinics were opened and managed by 18 pharmacists; between the initial and final periods of the study (2010 vs. 2016), the compliance with previous appointments was of 61.3% vs. 88.8% (p <0001), waiting time was 27.6±12.1 vs. 12.1±5.4 minutes (p <0.0001), documentation of pharmaceutical care in the clinical record was of 2.3% vs. 9.81% (p <0.0001), and the overall satisfaction perceived by the patients was 6.63±2.36 vs. 9.16±1.27 (p <0.01). The model of Specialized Pharmaceutical Care Hospital Outpatient Clinics exposed, focused on the patient and with continuity of care, has improved the quality of care and the quality perceived by the patients and it´s in optimal conditions to investigate its contribution on health outcomes and on the health system through a better quality, safety and efficiency of pharmacotherapy.


The importance of lactic acid bacteria for the prevention of bacterial growth and their biogenic amines formation: A review.
Foodborne pathogens (FBP) represent an important threat to the consumers' health as they are able to cause different foodborne diseases. In order to eliminate the potential risk of those pathogens, lactic acid bacteria (LAB) have received a great attention in the food biotechnology sector since they play an essential function to prevent bacterial growth and reduce the biogenic amines (BAs) formation. The foodborne illnesses (diarrhea, vomiting, and abdominal pain, etc.) caused by those microbial pathogens is due to various reasons, one of them is related to the decarboxylation of available amino acids that lead to BAs production. The formation of BAs by pathogens in foods can cause the deterioration of their nutritional and sensory qualities. BAs formation can also have toxicological impacts and lead to different types of intoxications. The growth of FBP and their BAs production should be monitored and prevented to avoid such problems. LAB is capable of improving food safety by preventing foods spoilage and extending their shelf-life. LAB are utilized by the food industries to produce fermented products with their antibacterial effects as bio-preservative agents to extent their storage period and preserve their nutritive and gustative characteristics. Besides their contribution to the flavor for fermented foods, LAB secretes various antimicrobial substances including organic acids, hydrogen peroxide, and bacteriocins. Consequently, in this paper, the impact of LAB on the growth of FBP and their BAs formation in food has been reviewed extensively.


Seatbelts Save Lives, and Spines, in Motor Vehicle Accidents: A Review of the National Trauma Data Bank in the Pediatric Population.
Database study. The purpose of this study was to use a large, nationwide database to determine prevalence of pediatric spine fractures in the United States, associated injuries, mechanisms of injury (MOI), use of safety devices, and mortality rates. Spinal fractures account for 1% to 2% of pediatric injuries. However, they are associated with significant comorbidities and complications. Motor vehicle accidents (MVAs) are most responsible for increased incidence observed. Retrospective review of National Trauma Data Bank between 2009 and 2014 (analysis in 2019) for all vertebral fractures in patients under 18 years of age. Subanalysis included those in MVAs where protective device use data were available. Patient demographics, MOI, geographical and anatomical region of injury, concomitant musculoskeletal/organ injury, protective device usage, hospital length of stay, surgical procedures, and mortality were all analyzed. A total of 34,563 patients with 45,430 fractured vertebrae included. Median age was 15 years. Most fractures (63.1%) occurred in patients aged 15 to 17 years, most frequent MOI was MVA (66.8%), and most common geographic location was the South (38%). Males sustained more spine fractures than females, overall (58.4% vs. 41.6%; P < 0.001) and in MVAs (54.4% vs. 45.6%; P < 0.001). Those in MVAs wearing seatbelts had lower odds of cranial (29.6% vs. 70.4%; odds ratio [OR] = 0.85, 95% confidence interval [CI]: 0.82-0.89; P < 0.001) and thoracic (30.1% vs. 69.9%; OR = 0.88, 95% CI: 0.84-0.91; P < 0.001) organ injury, multivertebral (30% vs. 70%; OR = 0.78, 95% CI: 0.73-0.83; P < 0.001) and concomitant nonvertebral fractures (30.9% vs. 69.1%; OR = 0.89, 95% CI:0.73-0.83; P < 0.001), and 21% lower odds of mortality (29.3% vs. 70.7%; OR = 0.79, 95% CI: 0.66-0.94; P = 0.009). Over 70% of drivers were not restrained during MVA, with majority of seatbelt violations incurred by males, ages 15 to 17, in the South. Over 60% of pediatric spinal fractures occur in children aged 15 to 17 years, coinciding with the beginning of legal driving. MVA is the most common cause and has significant association with morbidity/mortality. Nearly two- thirds pediatric spinal fractures sustained in MVAs occurred without seatbelts. Absence of seatbelts associated with >20% greater odds of mortality. Ensuring new drivers wear protective devices can greatly reduce morbidity/ mortality associated with MVA.Level of Evidence: 3.


Measuring and Understanding the Health Impact of Greater Fatigability in Older Adults: A Call to Action and Opportunities.
Different from fatigue, an instantaneous state of tiredness, weakness and lack of energy, fatigability is a trait that contextualizes whole-body fatigue to the level of activity (i.e., intensity and duration) with which the fatigue is associated. Fatigability can be perceived or performance-related. Measuring fatigability improves upon traditional fatigue measures by accounting for self-pacing as older adults likely slow down or limit their daily activity to maintain fatigue in a tolerable range. Anchoring fatigue to activities/tasks improves sensitivity and allows for meaningful comparisons across individuals/between studies, as well as evaluating change over time and treatment effects. Two well-validated approaches are utilized to measure perceived fatigability: 1) a 5-minute slow-paced (1.5 mph/0.67 m/s, 0% grade) treadmill walk immediately followed by Borg rating of perceived exertion; and 2) a self-administered 10-item questionnaire, Pittsburgh Fatigability Scale, with both physical and mental subscales. Many walking-based performance fatigability measures are based on certain lap time or distance, while the Pittsburgh Performance Fatigability Index uses raw accelerometry data to quantify percent of cadence decline over the entire long distance walking tasks. Perceived fatigability prevalence ranges from 20-90% in older adults varying by assessment tool, and is higher with advancing age and in women compared to men. Fatigability is associated with physical and cognitive function, fall risk, mobility decline, and mortality. Unfortunately, the available research lacks representativeness in terms of racial and ethnic diversity. The time is now to incorporate our established sensitive and validated fatigability measures into global research and clinical practice to better understand mechanistic underpinnings and reveal intervention effects to reduce the burden and lessen the consequences of greater fatigability worldwide.


Help-seeking preferences for psychological distress in primary care: effect of current mental state.
There is much debate over when it is appropriate to intervene medically for psychological distress, and limited evidence on patients' perspectives about a broad range of possible treatment options. It is currently unclear whether preferences may differ for those patients with milder symptoms compared to those experiencing more severe distress. To determine patient preferences for professional, informal, and alternative help for psychological distress in primary care, and the impact of their current mental state on these. Cross-sectional survey in seven general practices across suburban/urban London. Participants were 1357 consecutive general practice attenders aged 18 years and over. The main outcome measure was the General Health Questionnaire 12-item version and a questionnaire on help-seeking preferences. Overall, only 47% of participants reported wanting 'some help' if feeling stressed, worried, or low and it was affecting their daily life. Those currently experiencing mild-to-moderate distress preferred informal sources of help such as friends/family support, relaxation/yoga, exercise/sport, or massage along with general advice from their GP and talking therapies. Self-help (books/leaflets or computer/internet) was not popular at any level of distress, and less favoured by those with mild-to-moderate distress (odds ratio [OR] = 0.50; 95% confidence interval [CI] = 0.35 to 0.70). Those experiencing severe distress were much more likely to want talking therapies (OR = 3.43, 95% CI = 2.85 to 4.14), tablets (OR = 3.07, 95% CI = 2.00 to 4.71), and support groups (OR = 3.07, 95% CI = 1.72 to 5.47). People with mild-to-moderate distress appear to prefer informal sources of help and those involving human contact, compared to medication or self-help. This has implications for the implementation of potential interventions for psychological distress in primary care.


Magnetic resonance imaging and pelvic malignancy.
The major advantages of magnetic resonance imaging include its multiplanar capability, the ability to obtain T1 and T2 information and the superior contrast resolution obtained compared with computed tomography. These advantages render the technique well suited to staging pelvic malignancy. Its potential to distinguish malignant tissue from fibrosis is an important feature which may have significance for monitoring response and detecting recurrent disease.


A flow quantification method using fluid dynamics regularization and MR tagging.
This paper presents a new method for improved flow analysis and quantification using MRI. The method incorporates fluid dynamics to regularize the flow quantification from tagged MR images. Specifically, the flow quantification is formulated as a minimization problem based on the following: 1) the Navier-Stokes equation governing the fluid dynamics; 2) the flow continuity equation and boundary conditions; and 3) the data consistency constraint. The minimization is carried out using a genetic algorithm. This method is tested using both computer simulations and MR flow experiments. The results are evaluated using flow vector fields from the computational fluid dynamics software package as a reference, which show that the new method can achieve more realistic and accurate flow quantifications than the conventional method.


Auditory memory decrements, without dissimulation, among patients with major depressive disorder.
Questions have been raised about whether poor performance on memory tasks by individuals with major depressive disorder (MDD) might be the result of poor or variable effort or disease-related disruption of neural circuits supporting memory functions. The present study examined performance on a measure of task engagement and on an auditory memory task among 45 patients with MDD (M age = 47.82, SD = 19.55) relative to 32 healthy controls (HC; M age = 51.03, SD = 22.09). One-hundred percent of HC and MDD volunteers performed above the threshold for adequate effort on a formal measure of task engagement. The MDD subjects performed significantly more poorly than the HC subjects on an auditory learning and memory test. The present results suggest that auditory memory difficulties do occur among those with MDD and that decrements in performance in this group may be related to factors other than lack of effort.


The hepatitis E virus ORF1 hypervariable region confers partial cyclophilin dependency.
Hepatitis E virus (HEV) is an emerging pathogen responsible for more than 20 million cases of acute hepatitis globally per annum. Healthy individuals typically have a self-limiting infection, but mortality rates in some populations such as pregnant women can reach 30 %. A detailed understanding of the virus lifecycle is lacking, mainly due to limitations in experimental systems. In this regard, the cyclophilins are an important family of proteins that have peptidyl-prolyl isomerase activity and play roles in the replication of a number of positive-sense RNA viruses, including hepatotropic viruses such as hepatitis C virus (HCV). Cyclophilins A and B (CypA/B) are the two most abundant Cyps in hepatocytes and are therefore potential targets for pan-viral therapeutics. Here, we investigated the importance of CypA and CypB for HEV genome replication using sub-genomic replicons. Using a combination of pharmacological inhibition by cyclosporine A (CsA), and silencing by small hairpin RNA we find that CypA and CypB are not essential for HEV replication. However, we find that silencing of CypB reduces replication of some HEV isolates in some cells. Furthermore, sensitivity to Cyp silencing appears to be partly conferred by the sequence within the hypervariable region of the viral polyprotein. These data suggest HEV is atypical in its requirements for cyclophilin for viral genome replication and that this phenomenon could be genotype- and sequence-specific.


Immunological evaluation of personalized peptide vaccination with gemcitabine for pancreatic cancer.
The aim of the present study was to investigate the safety and immune responses of personalized peptide vaccination when administered with gemcitabine (GEM) in advanced pancreatic cancer (APC) patients. Thirteen patients with APC were enrolled. Pre-vaccination with peripheral blood mononuclear cells and plasma was carried out to examine cellular and humoral responses to 25 or 23 peptides in human leukocyte antigen A24+(+) or A2++(+) patients, respectively. Only the reactive peptides (maximum of four) were then administered weekly at three different dose settings: 1, 2 and 3 mg of peptide. GEM was administered at 1000 mg/m(2) per week for 3 weeks, followed by 1 week of rest. The combination therapy was well tolerated. Grade 3 toxicities were: anemia (three patients), neutropenia (two patients) and thrombocytopenia (two patients). Of these 13 patients, 11 (85%) showed clinical responses, such as reduction in tumor size and/or level of tumor markers. Augmentation of peptide-specific cytotoxic T lymphocyte activity against pancreatic cancer cells was observed at each dose level, whereas the increment of peptide-specific IgG antibodies was dependent on peptide dose. GEM did not inhibit the immune responses induced by personalized peptide vaccinations, and this new type of immunochemotherapy combination is recommended for further clinical study in APC patients.


Population pharmacokinetic models of anti-PD-1 mAbs in patients with multiple tumor types: A systematic review.
A number of population pharmacokinetic (PPK) models of anti-programmed cell death-1 (PD-1) monoclonal antibodies (mAbs) in multiple tumor types have been published to characterize the influencing factors of their pharmacokinetics. This review described PPK models of anti-PD-1 mAbs that investigate the magnitude and types of covariate effects in PK parameters, provide a reference for building PPK models of other anti-PD-1 mAbs, and identify areas requiring additional research to facilitate the application of PPK models. A systematic search for analyses of PPK models of eleven anti-PD-1 mAbs on the market that were carried out in humans was conducted using PubMed, Embase, and the Cochrane Library. The search covered the period from the inception of the databases to April 2022. Currently, there are fourteen analyses on PPK models of anti-PD-1 mAbs summarized in this review, including seven models that refer to nivolumab, four referring to pembrolizumab, one referring to cemiplimab, one referring to camrelizumab, and one referred to dostarlimab. Most analyses described the pharmacokinetics of anti-PD-1 mAbs with a two-compartment model with time-varying clearance (CL) and a sigmoidal maximum effect. The estimated CL and volume of distribution in the central (VC) ranged from 0.179 to 0.290 L/day and 2.98 to 4.46 L, respectively. The median (range) of interindividual variability (IIV) for CL and VC was 30.9% (8.7%-50.8%) and 29.0% (4.32%-40.7%), respectively. The commonly identified significant covariates were body weight (BW) on CL and VC, and albumin (ALB), tumor type, sex, and performance status (PS) on CL. Other less assessed significant covariates included lactate dehydrogenase (LDH), immunoglobulin G (IgG), ipilimumab coadministration (IPICO) on CL, and body mass index (BMI), malignant pleural mesothelioma (MESO) on VC. This review provides detailed information about the characteristics of PPK models of anti-PD-1 mAbs, the effects of covariates on PK parameters, and the current status of the application of the models. ALB, BW, specific tumor type, sex, and PS should be considered for the future development of the PPK model of anti-PD-1 mAbs. Other potential covariates that were assessed less frequently but still have significance (e.g., LDH, IgG, and IPICO) should not be ignored. Thus, further research and thorough investigation are needed to assess new or potential covariates, which will pave the way for personalized anti-PD-1 mAbs therapy.


Systematic review of mammary analog secretory carcinoma of salivary glands at 7 years after description.
Mammary analog secretory carcinoma of the salivary glands (MASCSG ) is a newly introduced malignant tumor of the salivary glands. For decades, it has been confused with acinic cell carcinoma (ACC) of the salivary glands. All reported cases of MASCSG were surveyed from 2010 until January 2017. The collected data was compiled and computationally processed to describe the clinical parameters of MASCSG . Its epidemiology was also mapped. Moreover, inaccurate data was highlighted. Clinically implicating, this article tackles simply the several clinical findings of MASCSG so that our contemporary nosology, at 7 years after description, can be updated. The cytogenetic, histologic, and immunohistochemical details are also defined. The available data about MASCSG is sufficient enough to diagnose it with no need to investigate the ETV6-NTRK3 translocation. Although high-grade malignancy and distant metastases were rarely reported, a rapt attention should be paid both to the nature of this tumor and to the indicated close follow-up of such cases, especially when necrosis, increased mitotic activity, and other classic caveats are conspicuous. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1243-1248, 2017.


Weight gain among treatment-naïve persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada.
Weight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-naïve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Adult, treatment-naïve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4+ cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years. Among 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4+ cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI). PWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration.


The effects of periodic visual occlusion on ball catching.
Four experiments were conducted to examine the effects of periodic visual occlusion on one-handed ball catching. Tennis balls were projected one at a time over distances of 8-12 m, and liquid-crystal visual occlusion spectacles provided intermittent vision by opening and closing the lens shutters at different frequencies. As well as frequency, we manipulated duty cycle, or the proportion of time that the lenses were open. Generally, catching performance deteriorated as frequency was reduced. Although longer visual samples (i.e., increased duty cycle) mediated this effect to some extent, the most potent variable was the time between visual samples; performance deteriorated rapidly when this interval was greater than 80 ms (i.e., 10 Hz with 20-ms lens open times). Presumably this occurred because subjects had difficulty integrating visual information separated by longer temporal intervals.


Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study.
Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone. We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response. Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion. The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.


Ruxolitinib in patients with polycythemia vera resistant and/or intolerant to hydroxyurea: European observational study.
Hydroxyurea (HU) is a commonly used first-line treatment in patients with polycythemia vera (PV). However, approximately 15%-24% of PV patients report intolerance and resistance to HU. This phase IV, European, real-world, observational study assessed the efficacy and safety of ruxolitinib in PV patients who were resistant and/or intolerant to HU, with a 24-month follow-up. The primary objective was to describe the profile and disease burden of PV patients. In the 350 enrolled patients, 70% were >60 years old. Most patients (59.4%) had received ≥1 phlebotomy in the 12 months prior to the first dose of ruxolitinib. Overall, 68.2% of patients achieved hematocrit control with 92.3% patients having hematocrit <45% and 35.4% achieved hematologic remission at month 24. 85.1% of patients had no phlebotomies during the study. Treatment-related adverse events were reported in 54.3% of patients and the most common event was anemia (22.6%). Of the 10 reported deaths, two were suspected to be study drug-related. This study demonstrates that ruxolitinib treatment in PV maintains durable hematocrit control with a decrease in the number of phlebotomies in the majority of patients and was generally well tolerated.


Use of Telehealth in Substance Use Disorder Services During and After COVID-19: Online Survey Study.
Social distancing guidelines for COVID-19 have caused a rapid transition to telephone and video technologies for delivering treatment for substance use disorders (SUDs). This study examined the adoption of these technologies across the SUD service continuum, acceptance of these technologies among service providers, and intent of providers to use these technologies after the pandemic. Additional analysis using the validated technology acceptance model (TAM) was performed to test the potential applications of these technologies after the pandemic. The study objectives were as follows: (1) to assess the use of telehealth (telephone and video technologies) for different SUD services during COVID-19 in May-June 2020, (2) to assess the intended applications of telehealth for SUD services beyond COVID-19, (3) to evaluate the perceived ease of use and value of telehealth for delivering SUD services, and (4) to assess organizational readiness for the sustained use of telehealth services. An online survey on the use of telephonic and video services was distributed between May and August 2020 to measure the current use of these services, perceived organizational readiness to use these services, and the intent to use these services after COVID-19. In total, 8 of 10 regional Addiction Technology Transfer Centers representing 43 states distributed the survey. Individual organizations were the unit of analysis. In total, 457 organizations responded to the survey. Overall, the technology was widely used; >70% (n>335) of organizations reported using telephone or video platforms for most services. The odds of the intent of organizations to use these technologies to deliver services post COVID-19 were significantly greater for all but two services (ie, telephonic residential counseling and buprenorphine therapy; mean odds ratio 3.79, range 1.87-6.98). Clinical users preferred video technologies to telephone technologies for virtually all services. Readiness to use telephone and video technologies was high across numerous factors, though telephonic services were considered more accessible. Consistent with the TAM, perceived usefulness and ease of use influenced the intent to use both telephone and video technologies. The overall perceived ease of use and usefulness of telephonic and video services suggest promising post-COVID-19 applications of these services. Survey participants consistently preferred video services to telephonic services; however, the availability of telephonic services to those lacking easy access to video technology is an important characteristic of these services. Future studies should review the acceptance of telehealth services and their comparative impact on SUD care outcomes.


Economic aspects of sanitation in developing countries.
Improved sanitation has been shown to have great impacts on people's health and economy. However, the progress of achieving the Millennium Development Goals (MDGs) on halving the proportion of people without access to clean water and basic sanitation by 2015 has thus far been delayed. One of the reasons for the slow progress is that policy makers, as well as the general public, have not fully understood the importance of the improved sanitation solutions. This paper, by gathering relevant research findings, aims to report and discuss currently available evidence on the economic aspects of sanitation, including the economic impacts of unimproved sanitation and the costs and economic benefits of some common improved sanitation options in developing countries. DATA USED IN THIS PAPER WERE OBTAINED FROM DIFFERENT INFORMATION SOURCES: international and national journal articles and reports, web-based statistics, and fact sheets. We used both online search and hand search methods to gather the information. Scientific evidence has demonstrated that the economic cost associated with poor sanitation is substantial. At the global level, failure to meet the MDG water and sanitation target would have ramifications in the area of US$38 billion, and sanitation accounts for 92% of this amount. In developing countries, the spending required to provide new coverage to meet the MDG sanitation target (not including program costs) is US$142 billion (US$ year 2005). This translates to a per capita spending of US$28 for sanitation. Annually, this translates to roughly US$14 million. The evidence complied in this paper demonstrates that investing in sanitation is socially and economically worthwhile. For every US$1 invested, achieving the sanitation MDG target and universal sanitation access in the non-OECD countries would result in a global return of US$9.1 and US$11.2, respectively. Given the current state of knowledge, sanitation is undeniably a profitable investment. It is clear that achieving the MDG sanitation target not only saves lives but also provides a foundation for economic growth.


New functional foods in the treatment of food allergy.
Over the last two decades atopic diseases have increased in prevalence and severity in the industrialized countries. Food allergy is frequently the first manifestation of these disorders. Currently food allergy is mainly treated with elimination diets. However, this approach to control allergic inflammation by empirical elimination diets has not proved totally satisfactory. Applying therapeutic elimination diets in clinically documented allergy to a specific food has been shown to alleviate symptoms and reverse some disturbances of humoral and cell-mediated immune response. These diets are, however, associated with the risk of inadequate nutrition in infants with allergies to foods of vital importance. New approaches to the management of food allergy, such as for example immunotherapy for counteracting the hypersensitivity process and for potentiating the gut barrier mechanisms, are therefore needed. Diet remains an important element in this approach as sensitization to dietary antigens is frequently transient and is reversed to antigen-specific hyporesponsiveness. However, it represents an initial link in the development of more permanent sensitization to aeroallergens.


Acute respiratory distress syndrome and multiple organ failure.
Despite improvements in outcome due to lung protective ventilation strategies using low tidal volumes, the mortality rate from acute respiratory distress syndrome (ARDS) remains unacceptably high, ranging from 34 to 64%. The predominant cause of death in ARDS is not severe hypoxemia, which is one of the defining criteria of ARDS, but multiple organ failure (MOF). In view of the relationship between ARDS and MOF, two different but complementary pathophysiological perspectives will be developed in this article: ARDS as a consequence of MOF, and ARDS as the cause of MOF. This framework may be useful in guiding the development of novel therapeutic strategies that ultimately improve the outcome of ARDS and sepsis patients. ARDS is a severe lung disease characterized by a very complex pathophysiology, involving not only the respiratory system but also nonpulmonary distal organs. Elucidation of the pathophysiological mechanisms bi-directionally linking MOF to ARDS appears to be a promising area of research that hopefully will lead to improved outcomes for these devastating conditions.


Dual contrast agents for fluorescence and photoacoustic imaging: evaluation in a murine model of prostate cancer.
Prostate-specific membrane antigen (PSMA) is a promising diagnostic and therapeutic target for prostate cancer (PC). Poly(amidoamine) [PAMAM] dendrimers serve as versatile scaffolds for imaging agents and drug delivery that can be tailored to different sizes and compositions depending upon the application. We have developed PSMA-targeted PAMAM dendrimers for real-time detection of PC using fluorescence (FL) and photoacoustic (PA) imaging. A generation-4, ethylenediamine core, amine-terminated dendrimer was consecutively conjugated with on average 10 lysine-glutamate-urea PSMA targeting moieties and a different number of sulfo-cyanine7.5 (Cy7.5) near-infrared dyes (2, 4, 6 and 8 denoted as conjugates II, III, IV and V, respectively). The remaining terminal primary amines were capped with butane-1,2-diol functionalities. We also prepared a conjugate composed of Cy7.5-lysine-suberic acid-lysine glutamate-urea (I) and control dendrimer conjugate (VI). Among all conjugates, IV showed superior in vivo target specificity in male NOD-SCID mice bearing isogenic PSMA+ PC3 PIP and PSMA- PC3 flu xenografts and suitable physicochemical properties for FL and PA imaging. Such agents may prove useful in PC cancer detection and subsequent surgical guidance during excision of PSMA-expressing lesions.


Isolation of a paramyxovirus from pigs in Israel and its antigenic relationships with avian paramyxoviruses.
During surveillance of the swine population in Israel a haemagglutinating agent was isolated and identified as a paramyxovirus (PMV). Serological studies based on haemagglutination and neuraminidase inhibition (HI and NI) tests displayed a close antigenic relationship between the isolate and the prototype strain of a variety of the avian PMV serotype 3 (PMV-3). However, comprehensive HI and NI cross-reaction tests between the isolate and PMV-3 reference strains, on the one hand, and the other eight avian PMV serotypes, on the other hand, showed that the viruses compared differed in terms of their antigenic interrelationships with the other avian PMVs and also in the quantitative values of the cross-reactivity. This is interpreted to mean that the swine isolate and the avain PMV-3 prototype strain are different viruses, although very closely related, but are not different isolations of the same virus from avian and mammalian hosts.


A Typology of Predictive Risk Factors for Non-Adherent Medication-Related Behaviors among Chronic Non-Cancer Pain Patients Prescribed Opioids: A Cohort Study.
There has been no previous prospective examination of the homogeneity of chronic non-cancer pain (CNCP) patients in risk factors for non-adherent opioid use. To identify whether latent risk classes exist among people with CNCP that predict non-adherence with prescribed opioids. Prospective cohort study. The Pain and Opioids IN Treatment prospective cohort comprises 1,514 people in Australia prescribed pharmaceutical opioids for CNCP interviewed 3 months apart. Risk factors were assessed in wave 1, and non-adherent behaviors in the 3 months prior to wave 1 and wave 2. Latent class analysis was used to examine groups with differing risk profiles. Logistic regression was used to examine predictors of non-adherence. A 4-class model was selected with classes described as: 1) Poor Physical Functioning group (27%); 2) Poor Coping/Physical Functioning group (35%); 3) Substance Use Problems group (14%); and 4) Multiple Comorbid Problems group (25%). The latter 2 groups had an increased risk of requesting increased opioid doses, early script renewals, using diverted medication, dose stock-piling, and unsanctioned dose alteration at wave 2. Risk factor onset prior to non-adherent behavior cannot be determined. Clusters of CNCP patients with distinct risk profiles for non-adherence exist. Each group was identified by at least one risk factor but the likelihood of non-adherent opioid use was higher in groups with particular clusters of multiple risk factors. Not all those with risk factors display non-adherence, emphasising the need for strategies to reduce risk for those patients displaying particular clusters of risks.


Transdermal insulin delivery using lipid enhanced electroporation.
Transdermal insulin transport by electroporation was measured using porcine epidermis and fluorescein-labeled insulin. Previous studies have shown that anionic lipids can enhance the electroporative transport of molecules up to 10 kDa in size. It was also shown that it is the charge and not the type of the phospholipid head group that influences transdermal transport under electroporation. Moreover, phospholipids with saturated acyl chains enhance the transport of larger molecules more as compared to those with unsaturated chains. In the current study, based on those earlier findings, the effect of 1,2-dimyristoyl-3-phosphatidylserine (DMPS) on the transdermal transport of insulin by electroporation was examined. Porcine epidermis was used as a model for skin. Transport was measured using glass vertical diffusion apparatus in which the epidermis separated the donor and receiver compartments. Negative pulses were applied across the epidermis using platinum electrodes. Results show that when electroporation was carried out in the presence of DMPS, there was greater than 20-fold enhancement of insulin transport. Furthermore, while in the presence of the phospholipid, almost all the transported insulin was detected in the receiver compartment; in the absence of added lipids, only about half the insulin transported was in the receiver compartment and an almost equal amount of insulin remained in the epidermis. Fluorescence microscopy revealed that the insulin transport was mainly through the lipid multilayer regions that surround the corneocytes.


Eating responses of obese and nonobese humans during dinner meals.
Observations of eating responses of obese and nonobese subjects were made in meal settings. Seven obese and seven nonobese male undergraduates were videotaped as they ate four dinner meals, two low and two high in preference, under low and high hunger conditions. As hunger and preferences increased, the amount of food eaten, the meal length, and the number of bites significantly increased. Time per bite decreased as hunger and preference increased. Obese subjects ate more grams per second than the nonobese subjects. Obese subjects also ate more high preference food and less low preference food than nonobese subjects. These findings are discussed in terms of Schachter's theory of differential stimulus orientation of obese and nonobese people and in terms of the set-point theories of Nisbett and Sclafani and Kluge.


Reduction of hexavalent chromium with the brown seaweed Ecklonia biomass.
A new type of biomass, protonated brown seaweed Ecklonia sp., was used for the removal of Cr(VI). When synthetic wastewater containing Cr(VI) was placed in contact with the biomass, the Cr(VI) was completely reduced to Cr(III). The converted Cr(III) appeared in the solution phase or was partly bound to the biomass. The Cr(VI) removal efficiency was always 100% in the pH range of this study (pH 1 to approximately 5). Furthermore, the Cr(VI) reduction was independent of the Cr(III) concentration, the reaction product, suggesting that the reaction was an irreversible process under our conditions. Proton ions were consumed in the ratio of 1.15 +/- 0.02 mol of protons/mol of Cr(VI), and the rate of Cr(VI) reduction increased with decreasing the pH. An optimum pH existed for the removal efficiency of total chromium (Cr(VI) plus Cr(III)), but this increased with contact time, eventually reaching approximately pH 4 when the reaction was complete. The electrons required for the Cr(VI) reduction also caused the oxidation of the organic compounds in the biomass. One gram of the biomass could reduce 4.49 +/- 0.12 mmol of Cr(VI). From a practical viewpoint, the abundant and inexpensive Ecklonia biomass could be used for the conversion of toxic Cr(VI) into less toxic or nontoxic Cr(III).


An event-related functional magnetic resonance imaging study of voluntary and stimulus-driven orienting of attention.
Attention can be voluntarily directed to a location or automatically summoned to a location by a salient stimulus. We compared the effects of voluntary and stimulus-driven shifts of spatial attention on the blood oxygenation level-dependent signal in humans, using a method that separated preparatory activity related to the initial shift of attention from the subsequent activity caused by target presentation. Voluntary shifts produced greater preparatory activity than stimulus-driven shifts in the frontal eye field (FEF) and intraparietal sulcus, core regions of the dorsal frontoparietal attention network, demonstrating their special role in the voluntary control of attention. Stimulus-driven attentional shifts to salient color singletons recruited occipitotemporal regions, sensitive to color information and part of the dorsal network, including the FEF, suggesting a partly overlapping circuit for endogenous and exogenous orienting. The right temporoparietal junction (TPJ), a core region of the ventral frontoparietal attention network, was strongly modulated by stimulus-driven attentional shifts to behaviorally relevant stimuli, such as targets at unattended locations. However, the TPJ did not respond to salient, task-irrelevant color singletons, indicating that behavioral relevance is critical for TPJ modulation during stimulus-driven orienting. Finally, both ventral and dorsal regions were modulated during reorienting but significantly only by reorienting after voluntary shifts, suggesting the importance of a mismatch between expectation and sensory input.


Using non-reversible context-dependent evolutionary models to study substitution patterns in primate non-coding sequences.
We discuss the importance of non-reversible evolutionary models when analyzing context-dependence. Given the inherent non-reversible nature of the well-known CpG-methylation-deamination process in mammalian evolution, non-reversible context-dependent evolutionary models may be well able to accurately model such a process. In particular, the lack of constraints on non-reversible substitution models might allow for more accurate estimation of context-dependent substitution parameters. To demonstrate this, we have developed different time-homogeneous context-dependent evolutionary models to analyze a large genomic dataset of primate ancestral repeats based on existing independent evolutionary models. We have calculated the difference in model fit for each of these models using Bayes Factors obtained via thermodynamic integration. We find that non-reversible context-dependent models can drastically increase model fit when compared to independent models and this on two primate non-coding datasets. Further, we show that further improvements are possible by clustering similar parameters across contexts.


Perinatally acquired HIV infection in adolescents from sub-Saharan Africa: a review of emerging challenges.
Worldwide, more than three million children are infected with HIV, 90% of whom live in sub-Saharan Africa. As the HIV epidemic matures and antiretroviral treatment is scaled up, children with HIV are reaching adolescence in large numbers. The growing population of adolescents with perinatally acquired HIV infection living within this region presents not only unprecedented challenges but also opportunities to learn about the pathogenesis of HIV infection. In this Review, we discuss the changing epidemiology of paediatric HIV and the particular features of HIV infection in adolescents in sub-Saharan Africa. Longstanding HIV infection acquired when the immune system is not developed results in distinctive chronic clinical complications that cause severe morbidity. As well as dealing with chronic illness, HIV-infected adolescents have to confront psychosocial issues, maintain adherence to drugs, and learn to negotiate sexual relationships, while undergoing rapid physical and psychological development. Context-specific strategies for early identification of HIV infection in children and prompt linkage to care need to be developed. Clinical HIV care should integrate age-appropriate sexual and reproductive health and psychological, educational, and social services. Health-care workers will need to be trained to recognise and manage the needs of these young people so that the increasing numbers of children surviving to adolescence can access quality care beyond specialist services at low-level health-care facilities.


The G protein-coupled receptor GPRC5B contributes to neurogenesis in the developing mouse neocortex.
Neural progenitor cells in the developing brain give rise to neurons and glia. Multiple extrinsic signalling molecules and their cognate membrane receptors have been identified to control neural progenitor fate. However, a role for G protein-coupled receptors in cell fate decisions in the brain remains largely putative. Here we show that GPRC5B, which encodes an orphan G protein-coupled receptor, is present in the ventricular surface of cortical progenitors in the mouse developing neocortex and is required for their neuronal differentiation. GPRC5B-depleted progenitors fail to adopt a neuronal fate and ultimately become astrocytes. Furthermore, GPRC5B-mediated signalling is associated with the proper regulation of β-catenin signalling, a pathway crucial for progenitor fate decision. Our study uncovers G protein-coupled receptor signalling in the neuronal fate determination of cortical progenitors.


Non-digestible oligosaccharides and calcium absorption in girls with adequate calcium intakes.
Non-digestible oligosaccharides such as inulin and oligofructose have been shown to consistently increase calcium absorption in experimental animals, but data in humans are less clear-cut. The objective of this study was to assess the effect of 8 g/d of oligofructose or a mixture of inulin and oligofructose on calcium absorption in girls at or near menarche. A total of fifty-nine subjects were studied using a balanced, randomized, cross-over design. They received, in random order, 8 g/d placebo (sucrose), oligofructose or the mixture inulin+oligofructose for 3 weeks, separated by a 2-week washout period. Throughout the study, subjects consumed a total of approximately 1500 mg/d dietary calcium, by adding two glasses of calcium-fortified orange juice to their diet. Four grams of placebo, oligofructose or the mixture inulin+oligofructose was added to each glass of orange juice immediately before it was consumed. At the end of each 3-week adaptation period, calcium absorption was measured, using a dual stable isotope technique, from the cumulative fractional excretion of an oral and an intravenous tracer over 48 hours. Calcium absorption was significantly higher in the group receiving the inulin+oligofructose mixture than in the placebo group v. P=0.01), but no significant difference was seen between the oligofructose group and the placebo group v. P=NS). We conclude that modest intakes of an inulin+oligofructose mixture increases calcium absorption in girls at or near menarche.


SEARCHBreast: a new resource to locate and share surplus archival material from breast cancer animal models to help address the 3Rs.
Animal models have contributed to our understanding of breast cancer, with publication of results in high-impact journals almost invariably requiring extensive in vivo experimentation. As such, many laboratories hold large collections of surplus animal material, with only a fraction being used in publications relating to the original projects. Despite being developed at considerable cost, this material is an invisible and hence an underutilised resource, which often ends up being discarded. Within the breast cancer research community there is both a need and desire to make this valuable material available for researchers. Lack of a coordinated system for visualisation and localisation of this has prevented progress. To fulfil this unmet need, we have developed a novel initiative called Sharing Experimental Animal Resources: Coordinating Holdings-Breast (SEARCHBreast) which facilitates sharing of archival tissue between researchers on a collaborative basis and, de facto will reduce overall usage of animal models in breast cancer research. A secure searchable database has been developed where researchers can find, share, or upload materials related to animal models of breast cancer, including genetic and transplant models. SEARCHBreast is a virtual compendium where the physical material remains with the original laboratory. A bioanalysis pipeline is being developed for the analysis of transcriptomics data associated with mouse models, allowing comparative study with human and cell line data. Additionally, SEARCHBreast is committed to promoting the use of humanised breast tissue models as replacement alternatives to animals. Access to this unique resource is freely available to all academic researchers following registration at https://searchbreast.org.


Facilitating taxonomy and phylogenetics: An informative and cost-effective protocol integrating long amplicon PCRs and third-generation sequencing.
Phylogenetic inference has become a standard technique in integrative taxonomy and systematics, as well as in biogeography and ecology. DNA barcodes are often used for phylogenetic inference, despite being strongly limited due to their low number of informative sites. Also, because current DNA barcodes are based on a fraction of a single, fast-evolving gene, they are highly unsuitable for resolving deeper phylogenetic relationships due to saturation. In recent years, methods that analyse hundreds and thousands of loci at once have improved the resolution of the Tree of Life, but these methods require resources, experience and molecular laboratories that most taxonomists do not have. This paper introduces a PCR-based protocol that produces long amplicons of both slow- and fast-evolving unlinked mitochondrial and nuclear gene regions, which can be sequenced by the affordable and portable ONT MinION platform with low infrastructure or funding requirements. As a proof of concept, we inferred a phylogeny of a sample of 63 spider species from 20 families using our proposed protocol. The results were overall consistent with the results from approaches based on hundreds and thousands of loci, while requiring just a fraction of the cost and labour of such approaches, making our protocol accessible to taxonomists worldwide.


Regulation and localization of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the mouse ovary during gonadotropin-induced ovulation.
At the time of ovulation, proteolytic degradation of the follicular wall is required to release the mature oocyte. Extracellular proteases, such as serine proteases and matrix metalloproteinases (MMPs), are thought to play important roles in this process. In this study we have examined the regulation of 11 MMPs and 3 tissue inhibitors of metalloproteinases (TIMPs) during gonadotropin-induced ovulation in the mouse. Northern blot hybridization showed that messenger RNA for several MMPs and TIMPs, including gelatinase A, MT1-MMP, stromelysin-3, MMP-19, TIMP-1, TIMP-2, and TIMP-3, were present at detectable levels in the mouse ovary. In addition, ovarian extracts contained gelatinolytic activities corresponding to the inactive proforms of gelatinase A and gelatinase B. Most of the MMPs and TIMPs were expressed at a constitutive level throughout the periovulatory period. However, MMP-19 and TIMP-1 revealed a different expression pattern; they were both induced 5-10 times by hCG and reached their maximum levels at 12 h after hCG treatment, corresponding to the time of ovulation. At this time point, MMP-19 and TIMP-1 messenger RNA were localized to the granulosa and thecal-interstitial cells of large preovulatory and ovulating follicles. This temporal and spatial regulation pattern suggests that MMP-19 might be involved in the tissue degradation that occurs during follicular rupture and that TIMP-1 could have a role in terminating MMP activity after ovulation.


Finite-element analysis of material and parameter effects in laser-based thermoelastic ultrasound generation.
Laser-based, thermoelastic transduction methods have potential in very high frequency (>50 MHz), high-density two-dimensional (2-D) arrays for a variety of very high-resolution superficial imaging applications, including in vivo tissue sectioning. Previous studies of these transducers generally have been based on experimental measurements or theoretical analyses using various simplifying assumptions. These theoretical models are mostly 1-D and best matched to simple geometries with a minimum number of component materials. In this work, we use a new thermoelastic solver in a commercially available finite-element analysis (FEA) software package to analyze multidimensional effects in laser-based devices of arbitrary geometry with the potential for use with arbitrary material properties. The FEA approach was verified first against experimental data. Thereafter, we explored the impact of various design variables, including laser spot size and laser penetration depth.


Collagen microstructural factors influencing optic nerve head biomechanics.
Previous studies have suggested that the lamina cribrosa (LC) and its surrounding sclera are biomechanically important in the pathogenesis of glaucoma, but many were limited by assumptions of tissue isotropy and homogeneity. Here, we used an improved biomechanical model driven by experimental measurements of scleral and LC collagen fiber organization to more accurately evaluate optic nerve head (ONH) biomechanics. Collagen fiber organization was quantitatively mapped across human ONH cryosections (three normal and three glaucomatous) using small-angle light scattering (SALS) and fed into two-dimensional finite element models loaded under biaxial stress to simulate raised intraocular pressure. Effects of artificial variations in collagen fiber microstructure and stiffness on LC and scleral strains were also investigated. Scleral collagen fibers were circumferential and exhibited the highest alignment in a region not immediately adjacent to, but at a distance (400-500 μm) away from, the LC. In models, such a fiber arrangement yielded rings of low strain (second principal and effective) in the scleral region immediately adjacent to the LC. Further sensitivity analyses showed that scleral fiber alignment was crucial in determining LC strain levels. Moderate scleral anisotropy (as observed physiologically) was more effective than isotropy or high anisotropy in limiting LC and scleral strain magnitude. The presence of a heterogeneous collagen fiber organization in the peripapillary sclera appears effective in limiting LC strain and is able to reduce strain levels at the scleral canal boundary: a transition zone prone to LC disinsertion, focal lamina cribrosa defects, and optic disc hemorrhages in glaucoma.


Maintenance of behavior by ketamine and related compounds in rhesus monkeys with different self-administration histories.
Rhesus monkeys lever-pressed under a fixed-ratio 30 time-out 600 sec schedule of i.v. injection of codeine (0.32 mg/kg/injection) or, in a second group of monkeys, ketamine (1.0 mg/kg/injection). During single session substitutions, the maintenance drug was replaced with saline or doses of various other drugs. At appropriate doses, ketamine maintained responding when substituted for ketamine. Phencyclidine, dexoxadrol and dextrorphan maintained responding when substituted for ketamine but did not maintain responding when substituted for codeine. Cyclazocine and SKF-10,047 (N-allyl-normetazocine) did not maintain responding when substituted for either ketamine or codeine; ethylketazocine did not maintain responding when substituted for ketamine. For those drugs maintained under behavior, fixed-ratio response rate and the number of injection dose and then decreased at higher injection doses. Substituted drugs maintained maximum response rates at the following injection doses: codeine, 0.32 mg/kg; ketamine, 1.0 mg/kg; phencyclidine, 0.03 mg/kg, dexoxadrol, 0.32 mg/kg; and dextrorphan, 1.0 mg/kg. Under only the ketamine maintenance schedule, the rate of responding during the timeout component varied as a function of the substitution dose of ketamine, codeine, phencyclidine and dexoxadrol, with the dose that maintained maximal fixed-ratio rates also engendering the highest rates of timeout responding.


Characterization of a novel heat shock protein (Hsp22.5) involved in the pathogenesis of Mycobacterium tuberculosis.
Tuberculosis is a worldwide health problem, given that one-third of the world's population is currently infected with Mycobacterium tuberculosis. Understanding the regulation of virulence on the molecular level will provide a better understanding of how M. tuberculosis can establish chronic infection. Using in vivo microarray analysis (IVMA), we previously identified a group of genes that are activated in BALB/c mouse lungs compared to in vitro cultures, including the rv0990c gene. Our analysis indicated that this gene is a member of the heat shock regulon and was activated under other stress conditions, including survival in macrophages or during the late phase of chronic tuberculosis in the murine lungs. Deletion of rv0990c from the genome of M. tuberculosis strain H37Rv affected the transcriptional profiles of many genes (n = 382) and operons involved in mycobacterial survival, including the dormancy regulon, ATP synthesis, respiration, protein synthesis, and lipid metabolism. Comparison of the proteomes of the mutant to those of the wild-type strain further confirmed the differential expression of 15 proteins, especially those involved in the heat shock response (e.g., DnaK and GrpE). Finally, the rv0990c mutant strain showed survival equivalent to that of the isogenic wild-type strain during active tuberculosis in guinea pigs, despite showing significant attenuation in BALB/c mice during the chronic phase of the disease. Overall, we suggest that rv0990c encodes a heat shock protein that plays an important role in mycobacterial virulence. Hence, we renamed rv0990c heat shock protein 22.5 (hsp22.5), reflecting its molecular mass.


The Cholesterol Metabolite 27HC Increases Secretion of Extracellular Vesicles Which Promote Breast Cancer Progression.
Cholesterol has been implicated in the clinical progression of breast cancer, a disease that continues to be the most commonly diagnosed cancer in women. Previous work has identified the cholesterol metabolite 27-hydroxycholesterol (27HC) as a major mediator of the effects of cholesterol on breast tumor growth and progression. 27HC can act as an estrogen receptor (ER) modulator to promote the growth of ERα+ tumors, and as a liver X receptor (LXR) ligand in myeloid immune cells to establish an immune-suppressive program. In fact, the metastatic properties of 27HC require the presence of myeloid cells with neutrophils (polymorphonuclear neutrophils; PMNs) being essential for the increase in lung metastasis in murine models. In an effort to further elucidate the mechanisms by which 27HC alters breast cancer progression, we made the striking finding that 27HC promoted the secretion of extracellular vesicles (EVs), a diverse assortment of membrane bound particles that includes exosomes. The resulting EVs had a size distribution that was skewed slightly larger than EVs generated by treating cells with vehicle. The increase in EV secretion and size was consistent across 3 different subtypes: primary murine PMNs, RAW264.7 monocytic cells, and 4T1 murine mammary cancer cells. Label-free analysis of 27HC-EVs indicated that they had a different metabolite composition to those from vehicle-treated cells. Importantly, 27HC-EVs from primary PMNs promoted tumor growth and metastasis in 2 different syngeneic models, demonstrating the potential role of 27HC-induced EVs in the progression of breast cancer. EVs from PMNs were taken up by cancer cells, macrophages, and PMNs, but not T cells. Since EVs did not alter proliferation of cancer cells, it is likely that their protumor effects are mediated through interactions with myeloid cells. Interestingly, RNA-seq analysis of tumors from 27HC-EV-treated mice do not display significantly altered transcriptomes, suggesting that the effects of 27HC-EVs occur early on in tumor establishment and growth. Future work will be required to elucidate the mechanisms by which 27HC increases EV secretion, and how these EVs promote breast cancer progression. Collectively, however, our data indicate that EV secretion and content can be regulated by a cholesterol metabolite, which may have detrimental effects in terms of disease progression, important findings given the prevalence of both breast cancer and hypercholesterolemia.


Transfection of promyelocytic leukemia in retrovirus vector inhibits growth of human bladder cancer cells.
To construct a recombinant retrovirus vector carrying human promyelocytic leukemia (PML) cDNA and identify its expression and biology role in bladder cancer UM-UC-2 cells for future gene therapy. PML full-length cDNA was inserted into the EcoR I and BamH I site of pLXSN vector containing the long terminal repeat (LTR) promoter. The vector was identified by restriction enzyme digestion and then transfected into PA317 packaging cell line by calcium phosphate coprecipitation. PML cDNA was detected by polymerase chain reaction (PCR) and the protein was identified by laser confocal microscopy and Western blot in bladder cancer cells, respectively. The morphology was observed by inverted phase contrast microscope, and MTT assay determined growth curve of the bladder cancer cells. Restriction enzyme digestion proved that a 2.1 kb PML cDNA was inserted into the pLXSN vector. PCR assay demonstrated that 304 bp fragments were found in UM-UC-2/pLPMLSN transfects. Laser confocal microscopy showed speck dots fluorescence in the UM-UC-2/pLPMLSN nucleus. A 90 kD specific brand was found by Western blot. MTT assay demonstrated the UM-UC-2/pLPMLSN bladder cancer growth inhibition. The retrovirus pLPMLSN vector was successfully constructed and could generate high effective expression of human PML in bladder cancer cell UM-UC-2, suggesting that PML recombinant retrovirus have potential utility in the gene therapy for bladder cancer.


Lacking power impairs executive functions.
Four experiments explored whether lacking power impairs executive functioning, testing the hypothesis that the cognitive presses of powerlessness increase vulnerability to performance decrements during complex executive tasks. In the first three experiments, low power impaired performance on executive-function tasks: The powerless were less effective than the powerful at updating (Experiment 1), inhibiting (Experiment 2), and planning (Experiment 3). Existing research suggests that the powerless have difficulty distinguishing between what is goal relevant and what is goal irrelevant in the environment. A fourth experiment established that the executive-function impairment associated with low power is driven by goal neglect. The current research implies that the cognitive alterations arising from powerlessness may help foster stable social hierarchies and that empowering employees may reduce costly organizational errors.


The Influence of Carbon Dioxide Pneumoperitoneum on Systemic Inflammatory Response Syndrome and Bacterial Translocation in Patients With Bacterial Peritonitis Caused by Acute Appendicitis.
To explore the influence of carbon dioxide pneumoperitoneum (CDP) on system inflammatory response syndrome (SIRS) and bacterial translocation (BT) in patients with bacterial peritonitis (BP) caused by acute appendicitis (AA). Eighty-six consecutive subjects were randomly divided into the laparoscopy and laparotomy groups (n = 44 and n = 42, respectively). The levels of white blood cells (WBC), C-reactive protein (CRP), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) of the 2 groups were tested preoperatively and at days 1, 2, and 4 after surgery. Blood and secretion culture was performed to verify whether septicemia or incision infection occurred, respectively. And the abdominal ultrasound or computed tomography scanning was used to diagnose peritoneal abscess for the suspected patients. The essential risk factors related to the aggravation of SIRS were analyzed through analysis of variance and binary logistic regression. The postoperative blood levels of WBC, CRP, TNF-α, and IL-6 on day 4 in the laparoscopy group were significantly lower than those in the control group (all Ps < .05). The differences in incidence rates of septicemia and peritoneal abscess between the CDP and control groups were not statistically significant ( P > .05). Nevertheless, the incision infection rate in the laparoscopy group was apparently lower than that in the control group (4.55% vs 19.04%, P = .047). Analysis of variance and binary logistic regression showed that the non-pneumoperitoneum, pathological type of appendicitis, and multidrug resistant infections were the 3 major risk factors for SIRS (the P values were .001, .019, and .012, respectively). It was found that CDP is safe for BP and could be a potential protective factor to mitigate BP effectively, indicating that the performance of laparoscopy operation under CDP is feasible to control SIRS; at the same time, CDP would not raise the incidence rate of BT.


Extracardiac findings at cardiac CT: a practical approach.
Noncardiac findings occur in 10% to 60% of cases depending on the patient population studied. Although most of the abnormalities will turn out to be benign, important findings such as pulmonary embolism and lung cancer occur. Not all important abnormalities will occur within the coned down field-of-view for evaluating the coronary arteries, and the entire study should also be reviewed with an expanded field-of-view. In particular, the typical screen detected cancer occurs in the lung periphery. It is important to have a practical approach in detecting and evaluating incidental findings so as not to cause undue cost or patient anxiety, while ensuring timely management of critical diseases.


Neuroblastoma with superficial soft tissue mass as the first symptom: case reports with atypical ultrasonic image and literature review.
Neuroblastoma is one of the most common tumors in children. Cases where an isolated soft-tissue metastasis mass is the initial symptom are rare, with only four such cases reported to date. We describe the imaging findings of ten cases of neuroblastoma patients in our hospital with superficial soft tissue mass (SSTM) as the primary symptom. The main ultrasound finding of SSTM was hypoechoic masses or scattered speck-like hyperechoic masses. However, when this type of SSTM is caused by soft tissue metastasis, the location is often atypical, and ultrasound findings are difficult to distinguish from other benign diseases. Therefore, this research should remind clinicians to recognize atypical presentations of this common childhood malignant tumor. Radiologists should also consider the possibility of neuroblastoma when finding this type of SSTM with atypical ultrasound features.


[Ultrastructural changes in middle ear and cochlea caused by respiratory syncytial virus in guinea pigs].
Respiratory syncytial virus (RSV) was inoculated into the middle ear of guinea pigs. Preyer's reflex began to decrease since 21st day. The positive rate of RSV culture from middle ear mucosa within the first week was 50%. The titer of IgG antibody against RSV in sera rose gradually. Electron microscopy showed enlarged rough endoplasmic reticulum, swelling mitochondria and pyknosis of nuclei in the epithelial and mononuclear cells of middle ear. The surface of Corti's organ was covered with exudate; hair cells had their hairs distorted or desquamated. The results indicate that the RSV can cause acute infection of middle ear and degeneration of hair cells of the cochlea.


Interdisciplinary evidence for early domestic horse exploitation in southern Patagonia.
The introduction of domestic horses transformed Indigenous societies across the grasslands of Argentina, leading to the emergence of specialized horse cultures across the Southern Cone. However, the dynamics of this introduction are poorly chronicled by historic records. Here, we apply archaeozoological and biomolecular techniques to horse remains from the site of Chorrillo Grande 1 in southern Argentina. Osteological and taphonomic analyses suggest that horses were pastorally managed and used for food by Aónikenk/Tehuelche hunter-gatherers before the onset of permanent European settlement, as early as the mid-17th century. DNA-based sex identifications suggest consumption of both male and female horses, while ceramic residue also shows use of guanaco products. Sequential isotope analyses on horse dentition reveal an origin in southern Patagonia and movement of these animals between the Río Coig and Río Gallegos basins. These results reinforce emerging evidence for rapid Indigenous-mediated dispersal of horses in the Americas and demonstrate that horses catalyzed rapid economic and social transformations.


Health care providers' adherence to tobacco treatment for waterpipe, cigarette and dual users in Vietnam.
Almost half of adult men in Vietnam are current cigarette smokers. Recent surveys also suggest a high prevalence of water pipe use, particularly in rural areas. Yet services to treat tobacco dependence are not readily available. The purpose of this study was to characterize current tobacco use treatment patterns among Vietnamese health care providers and factors influencing adherence to recommended guidelines for tobacco use screening and cessation interventions for water pipe, cigarette and dual users. We conducted cross sectional surveys of 929 male current tobacco users immediately after they completed a primary care visit at one of 18 community health centers. Thirty-four percent of smokers used cigarettes only, 24% water pipe only, and 42% were dual users. Overall 12% of patients reported that a provider asked them if they used tobacco products during the visit. Providers were significantly more likely to screen cigarette smokers compared with water pipe or dual users (16%, 9% and 11% respectively). Similarly, 9% of current cigarette smokers received advice to quit compared to 6% of water pipe and 5% of dual users. No patients reported that their health care provider offered them assistance to quit (e.g., self-help materials, referral). Despite ratifying the Framework Convention on Tobacco Control, Vietnam has not made progress in implementing policies and systems to ensure smokers are receiving evidence-based treatment. High rates of water pipe and dual use indicate a need for health care provider training and policy changes to facilitate treatment for both cigarette and water pipe use.


How can we identify and communicate the ecological value of deep-sea ecosystem services?
Submarine canyons are considered biodiversity hotspots which have been identified for their important roles in connecting the deep sea with shallower waters. To date, a huge gap exists between the high importance that scientists associate with deep-sea ecosystem services and the communication of this knowledge to decision makers and to the wider public, who remain largely ignorant of the importance of these services. The connectivity and complexity of marine ecosystems makes knowledge transfer very challenging, and new communication tools are necessary to increase understanding of ecological values beyond the science community. We show how the Ecosystem Principles Approach, a method that explains the importance of ocean processes via easily understandable ecological principles, might overcome this challenge for deep-sea ecosystem services. Scientists were asked to help develop a list of clear and concise ecosystem principles for the functioning of submarine canyons through a Delphi process to facilitate future transfers of ecological knowledge. These ecosystem principles describe ecosystem processes, link such processes to ecosystem services, and provide spatial and temporal information on the connectivity between deep and shallow waters. They also elucidate unique characteristics of submarine canyons. Our Ecosystem Principles Approach was successful in integrating ecological information into the ecosystem services assessment process. It therefore has a high potential to be the next step towards a wider implementation of ecological values in marine planning. We believe that successful communication of ecological knowledge is the key to a wider public support for ocean conservation, and that this endeavour has to be driven by scientists in their own interest as major deep-sea stakeholders.


Starfish ApDOCK protein essentially functions in larval defense system operated by mesenchyme cells.
In larvae of the starfish, Asterina pectinifera, mesenchyme cells operate in the defense system through various behaviors. We have investigated mesenchyme cell dynamics during the immune response by identifying ApDOCK, a new member of the DOCK180 superfamily protein. In 4-day-old bipinnaria larvae processed for morpholino oligonucleotide-mediated knockdown of ApDOCK, injection of inorganic foreign substances revealed that (1) mesenchyme cells fail to undergo either directed migration toward a large oil-droplet or persistent spreading on the oil-droplet after contact; (2) neither uptake of micro-beads nor cell-to-cell fusion on the large oil-droplet differed from that of mesenchyme cells from control larvae. Similar behaviors were also recorded in experiments where bacteria were injected. Under culture conditions, the expression level of ApDOCK mRNA was significantly associated with the immunological behavior of mesenchyme cells. Apparently, the mesenchyme cells from ApDOCK loss-of-function larvae exhibited insufficient lamellipodium formation via lack of fibrous form of actin organization at the leading edge. These results suggest that the migratory congregation and persistence of encapsulation of larval mesenchyme cells are intracellularly regulated by ApDOCK protein, and this regulation is associated with organization of cytoskeletal actin.


Synaptic connections between primary afferents and motoneurons in the spinal cord of anuran larvae.
The relationship between dorsal root afferents and lumbar motoneurons has been studied in the isolated spinal cord of Rana ridibunda tadpoles. It was found that primary afferents do not form direct contacts with "primary" motoneurons innervating the axial musculature used by the larvae in swimming. Monosynaptic connections were revealed only between afferent fibres and lateral motor column motoneurons which innervate the developing hindlimb. The transmission in these synapses was dual: electrical and chemical. During the metamorphic stages when the locomotion is gradually taken over by the developing hindlimbs, an increase of the percentage of motoneurons receiving direct synaptic input from the primary afferents was observed.


Bovine Mastitis: Prevalence, Risk Factors, and Bacterial Pathogens Isolated in Lactating Cows in Gamo Zone, Southern Ethiopia.
Mastitis is a disease known to cause a great deal of loss of production and has a major economic impact. In the study area, there is little current information on bovine mastitis. Therefore, this study aimed to determine the overall prevalence of bovine mastitis and its associated risk factors and isolate the major pathogenic bacteria. A cross-sectional study was conducted from February 2020 to September 2020 in selected dairy farms of Gamo Zone, southern Ethiopia. A total of 422 lactating cows were diagnosed for mastitis using the California mastitis test, clinical examination, and bacteriological methods. The overall prevalence of bovine mastitis determined in the area was 17.1% (72 of 422), of which 1.9% (eight of 422) was clinical and 15.2% (64 of 422) subclinical. Of 1,662 quarters examined, 7.94% (132) were positive. Bacteriological methods were also used to isolate the major pathogenic bacterial species associated with bovine mastitis. From 72 composite milk samples, growth of six different groups of bacteria was recorded in 64 (88.9%) samples. The most predominant bacterial pathogens isolated were Staphylococcus aureus (42.6%), ahead of Streptococcus spp. (26.2%), non-aureus staphylococci (14.8%), and Escherichia coli (11.5%). Salmonella spp. (3.3%) and Klebsiella pneumoniae (1.6%) were the least isolated bacterial pathogens. Among risk factors, breed, parity, udder depth, and tick infestation of the udder showed statistically significant differences (P<0.05) regarding the occurrence of mastitis. The current study revealed that mastitis is one of the health problems affecting dairy cows in Gamo. Enhancing the awareness of dairy farmers, regular screening, and improving hygienic conditions are critically important to control and prevent bovine mastitis in the study area.


Neural responses to salient visual stimuli.
The neural mechanisms involved in the selective processing of salient or behaviourally important stimuli are uncertain. We used an aversive conditioning paradigm in human volunteer subjects to manipulate the salience of visual stimuli (emotionally expressive faces) presented during positron emission tomography (PET) neuroimaging. Increases in salience, and conflicts between the innate and acquired value of the stimuli, produced augmented activation of the pulvinar nucleus of the right thalamus. Furthermore, this pulvinar activity correlated positively with responses in structures hypothesized to mediate value in the brain right amygdala and basal forebrain (including the cholinergic nucleus basalis of Meynert). The results provide evidence that the pulvinar nucleus of the thalamus plays a crucial modulatory role in selective visual processing, and that changes in perceptual salience are mediated by value-dependent plasticity in pulvinar responses.


C1 esterase inhibitor protein associated with human cancer: a tumour marker.
The concentration of a cancer-associated serum C1 esterase inhibitor protein was determined in 194 cases of human cancer, grouped according to their clinical activity. As control groups healthy blood donors and patients having non neoplastic chronic lung and liver diseases were included in the study. The results showed highly significant differences when the values obtained for "active" malignant tumors were compared with the two control groups and the quiescent tumours. The authors conclude that C1 esterase inhibitor protein measurement may be useful as a clinical tumour marker.


Double-blind assessment of the activity of minaprine (30038-CB) in child psychiatry.
A double-blind, crossover trial was carried out in 26 children with psychiatric disorders to assess the effectiveness of treatment with minaprine (100 mg per day) or placebo, each treatment being given in random order for 4 weeks. Patients were assessed before treatment and at 14 day intervals using a modified 34-item Hamilton rating scale. The results showed a definite therapeutic superiority of minaprine over placebo and a good response was achieved in over 50% of the children, including those showing signs of the "hyperactive syndrome'. Minaprine was well tolerated by all the patients.


Material Mismatch Effect on the Fracture of a Bone-Composite Cement Interface.
The interfacial mechanics at the bone-implant interface is a critical issue for implant fixation and the filling of bone defects created by tumors and/or their excision. Our previous study found that micron and nano sizes MgO particles improved the fracture toughness of bone-cement interfaces under tension loading. The strength of bonding of different types of bone with different types of implants may not be the same. The aims of this research were to determine the influences of material mismatch due to bone orientation and a magnesium oxide (MgO) filler material for PMMA bone cement on the mechanical strength between bone and bone cement specimens. This research studied the longitudinal and transverse directions bovine cortical bone as different bone materials and poly Methyl MethAcrylate (PMMA) bone cement with and without MgO additives as different implant materials. The scope of work for this study was: (1) to determine the bending strength and modulus of different bone and bone cement specimens, (2) to determine whether inclusion of MgO particles on PMMA has any influence on these mechanical properties of PMMA, and (3) to determine whether bone orientation and inclusion of MgO particles with PMMA has any influence on the interface strength between bone and PMMA. This study showed that bone orientation has statistically significant effect on the bonding strength between bone and bone cement specimens (P value<0.05). This study also found that while MgO additive decreased the bending strength and modulus of PMMA bone cement, but the inclusion of MgO additives with PMMA bone cement has no statistically significant effect on the bonding strength between bone and bone cement specimens (P value>0.05).


Does vasopressin contribute to salt-induced hypertension in the Dahl strain?
A humoral factor has been implicated in Dahl salt-sensitive genetically hypertensive rats. The goal of this study was to evaluate the pressor role of vasopressin (AVP) in Dahl rats. Salt-sensitive (S) and resistant (R) rats were fed either high (8%) or low (.04%) NaCl diets for 6 to 8 weeks. Blood pressure was elevated in S rats fed high salt diets (p less than 0.05). Plasma AVP increased with high salt diet in both groups (p less than 0.05), but was higher in S than R rats (2.0 +/- 0.3 and 1.3 +/- 0.2 microU/ml respectively, mean +/- SE, p less than 0.05). With low salt diet, plasma AVP did not differ significantly in S and R rats (1.0 +/- 0.2 and 0.7 +/- 0.2 microU/ml respectively). Pressor responses to intravenous injection of AVP were greater in S than R rats (p less than 0.05), but this difference was also observed with pressor responses to norepinephrine (S greater than R, p less than 0.05); there was no difference in pressor responses to AVP in S rats fed high vs low salt diet. Injection of 50 micrograms of d(CH2)5 VDAVP, which selectively inhibits vasoconstrictor effects of AVP, failed to lower blood pressure in S and R rats fed high or low salt diets despite the fact that this dose decreased pressor responses to 8 microU of AVP more than 90%. Although plasma AVP and vasopressor responses to AVP and NE are slightly elevated in S rats fed high salt, results with d(CH2)5 VDAVP suggest that vasoconstrictor effects of AVP do not play an important role in the maintenance of hypertension in Dahl S rats.


Association of Prenatal Alcohol Exposure With Psychological, Behavioral, and Neurodevelopmental Outcomes in Children From the Adolescent Brain Cognitive Development Study.
Data on the neurodevelopmental and associated behavioral effects of light to moderate in utero alcohol exposure are limited. This retrospective investigation tested for associations between reported maternal prenatal alcohol use and psychological, behavioral, and neurodevelopmental outcomes in substance-naive youths. Participants were 9,719 youths (ages 9.0 to 10.9 years) from the Adolescent Brain Cognitive Development Study. Based on parental reports, 2,518 (25.9%) had been exposed to alcohol in utero. Generalized additive mixed models and multilevel cross-sectional and longitudinal mediation models were used to test whether prenatal alcohol exposure was associated with psychological, behavioral, and cognitive outcomes, and whether differences in brain structure and resting-state functional connectivity partially explained these associations at baseline and 1-year follow-up, after controlling for possible confounding factors. Prenatal alcohol exposure of any severity was associated with greater psychopathology, attention deficits, and impulsiveness, with some effects showing a dose-dependent response. Children with prenatal alcohol exposure, compared with those without, displayed greater cerebral and regional volume and greater regional surface area. Resting-state functional connectivity was largely unaltered in children with in utero exposure. Some of the psychological and behavioral outcomes at baseline and at the 1-year follow-up were partially explained by differences in brain structure among youths who had been exposed to alcohol in utero. Any alcohol use during pregnancy is associated with subtle yet significant psychological and behavioral effects in children. Women should continue to be advised to abstain from alcohol consumption from conception throughout pregnancy.