Crystal Structures and Mechanical Properties of Ca₂C at High Pressure.
Recently, a new high-pressure semiconductor phase of Ca₂C (space group Pnma) was successfully synthesized, it has a low-pressure metallic phase (space group C2/m). In this paper, a systematic investigation of the pressure-induced phase transition of Ca₂C is studied on the basis of first-principles calculations. The calculated enthalpy reveals that the phase transition which transforms from C2/m-Ca₂C to Pnma-Ca₂C occurs at 7.8 GPa, and it is a first-order phase transition with a volume drop of 26.7%. The calculated elastic constants show that C2/m-Ca₂C is mechanically unstable above 6.4 GPa, indicating that the structural phase transition is due to mechanical instability. Both of the two phases exhibit the elastic anisotropy. The semiconductivity of Pnma-Ca₂C and the metallicity of C2/m-Ca₂C have been demonstrated by the electronic band structure calculations. The quasi-direct band gap of Pnma-Ca₂C at 0 GPa is 0.86 eV. Furthermore, the detailed analysis of the total and partial density of states is performed to show the specific contribution to the Fermi level.


Social health needs of Iranian male adolescents.
Adequate attention to adolescents' health is considered an investment for the future of any country. Adolescents face many social and cultural challenges when they enter a new stage of social life. The advancement of adolescent social health depends on the recognition of their needs. This study aimed to explain the concept of social health needs from the perspectives of male adolescents to improve the health of both adolescents and the society. In this qualitative study with a content analysis approach, 52 male adolescents aged 13-18 years participated in 10 semi-structured individual interviews and seven focus group discussions. They expressed their experiences and opinions regarding social health needs. Purposive sampling was performed to recruit the adolescents in different areas of Tehran in 2017. Collected data was analyzed using the conventional content analysis method. The findings were divided into four main themes and eight sub-themes including "need to have a healthy family (healthy family relationships and family responsibility)", "need to have a healthy society (favorable social status and favorable economic situation)", "need to have educational facilities (promoting productivity in schools and public education facilities)", "need to have communication with peers (healthy communication with peers and setting up for communication with peers of the opposite gender)". To promote social health in adolescents, it is necessary to plan for the empowerment of community, family, schools and mass media by health authorities and devise appropriate health policies.


Synthesis, degradation, and subcellular localization of proteins encoded by the primary response genes TIS7/PC4 and TIS21/PC3.
Murine TIS7 and TIS21 cDNAs were cloned from phorbol ester-induced Swiss 3T3 cells. The cognate rat cDNAs, PC4 and PC3, were cloned from nerve growth factor (NGF)-treated PC12 pheochromocytoma cells. The TIS7/PC4 and TIS21/PC3 primary response genes are rapidly and transiently induced in response to serum, phorbol esters, and polypeptide growth factors in quiescent Swiss 3T3 cells and by NGF and other ligands in PC12 cells. In both 3T3 and PC12 cells the appearance of the TIS21/PC3 message precedes that of TIS7/PC4 message following ligand stimulation, suggesting that the TIS21/PC3 protein is likely to be synthesized more rapidly than the TIS7/PC4 protein. Using antisera prepared against recombinant TIS21 and TIS7 proteins, we find that the TIS21/PC3 protein is, indeed, synthesized more rapidly than the TIS7/PC4 protein following stimulation in both 3T3 and PC12 cells. In addition, "pulse-chase" experiments demonstrate that the TIS21/PC3 protein is degraded much more rapidly than the TIS7/PC4 protein. The sequences of the predicted PC3 and PC4 proteins have lead to the speculation that these two proteins may both be secreted from cells following stimulation. The PC4 protein is reported to have some sequence similarity to interferons. The TIS21/PC3 protein contains a presumptive leader sequence. Using our antisera to the recombinant proteins, however, we cannot detect secretion of radiolabelled TIS7/PC4 or TIS21/PC3 protein. Immunohistochemical and subcellular fractionation experiments suggest that the TIS7 protein is a membrane associated, non-nuclear intracellular protein. The TIS21 protein, in contrast, is a non-nuclear, soluble intracellular protein.


Morphological predictors of survival in colorectal carcinoma: univariate and multivariate analysis.
In 150 curative resected adenocarcinomas of the large bowel we analyzed the morphological parameters of the primary tumor and lymph node involvement which most efficiently expressed the relationship to survival time. Using univariate survival analysis (product limit estimator according Kaplan-Meier), several macroscopical and microscopical parameters of the primary tumor and lymph node involvement significantly correlated with survival time. A multivariate survival analysis of covariates according to the Cox regression model revealed that the significant correlations of all these parameters were expressed by a set of five variables: pT stage, number of inflammatory cells, sex, age, and pN stage. As shown by the Kaplan-Meier test, this set of variables allowed a more precise prediction of survival time than mere staging according to the TNM system. Parametric multiple stepwise survival analysis was inefficient. No distinct relationship was found between the morphology of the primary tumor and the involvement of lymph nodes.


[Arteriovenous dissection for branch retinal vein occlusion].
Arteriovenous dissection (AVD) is a surgical maneuver to separate the retinal artery and vein at the crossing site in patients with branch retinal vein occlusion (BRVO). The published studies showed an evidence level 3. AVD seems to be maintainable in patients with recent onset of BRVO and decimal visual acuity < or =0.4.


TRPM4-dependent post-synaptic depolarization is essential for the induction of NMDA receptor-dependent LTP in CA1 hippocampal neurons.
TRPM4 is a calcium-activated but calcium-impermeable non-selective cation (CAN) channel. Previous studies have shown that TRPM4 is an important regulator of Ca(2+)-dependent changes in membrane potential in excitable and non-excitable cell types. However, its physiological significance in neurons of the central nervous system remained unclear. Here, we report that TRPM4 proteins form a CAN channel in CA1 neurons of the hippocampus and we show that TRPM4 is an essential co-activator of N-methyl-D-aspartate (NMDA) receptors (NMDAR) during the induction of long-term potentiation (LTP). Disrupting the Trpm4 gene in mice specifically eliminates NMDAR-dependent LTP, while basal synaptic transmission, short-term plasticity, and NMDAR-dependent long-term depression are unchanged. The induction of LTP in Trpm4 (-/-) neurons was rescued by facilitating NMDA receptor activation or post-synaptic membrane depolarization. Accordingly, we obtained normal LTP in Trpm4 (-/-) neurons in a pairing protocol, where post-synaptic depolarization was applied in parallel to pre-synaptic stimulation. Taken together, our data are consistent with a novel model of LTP induction in CA1 hippocampal neurons, in which TRPM4 is an essential player in a feed-forward loop that generates the post-synaptic membrane depolarization which is necessary to fully activate NMDA receptors during the induction of LTP but which is dispensable for the induction of long-term depression (LTD). These results have important implications for the understanding of the induction process of LTP and the development of nootropic medication.


Correction: Survivorship of Patients After Long Intensive Care Stay With Exploration and Experience in a New Zealand Cohort (SPLIT ENZ): Protocol for a Mixed Methods Study.
[This corrects the article DOI: 10.2196/35936.].


Long-term catheter-associated bacteriuria: species at low concentration.
Polymicrobial bacteriuria in patients with long-term (greater than or equal to 30 days) indwelling urethral catheters is common and is associated with potentially serious acute and long-term complications. The dynamics of organisms at low concentration (less than 10(5) cfu/mL) in this setting has not been well-characterized; however, in patients with short-term catheters organisms initially present at low concentration (less than 10(5) cfu/mL) usually grow to high concentration (greater than or equal to 10(5) cfu/mL). At the time of catheter replacement for 7 long-term catheterized patients who were not receiving antibiotics, we identified all species at greater than or equal to 10(2) cfu/mL in fresh urine aspirated from the old indwelling catheter and the new sterile replacement catheter and then determined which of these species were present at high concentration two weeks later. A total of thirty-seven species, nineteen at high and eighteen at low concentration were detected in either the old or the new catheters. Eighteen of the nineteen initially detected at high concentration but only one of the eighteen initially detected at low concentration (p less than 0.001) were present at high concentration two weeks later. In patients with long-term indwelling urethral catheters, the number and multiplicity of species causing bacteriuria at low concentration rival that of species at high concentration; however, species at low concentration usually do not grow to high concentration in the presence of other species at high concentration.


Fine structure of muscle in human disuse atrophy: significance of proximal muscle involvement in muscle disorders.
The universal occurrence of weakness of skeletal musculature on disuse, however produced, and the paucity of published reports on the fine structural changes in human disuse atrophy, prompted the present investigation. The quadriceps muscle of a leg immobilized in plaster cast (for fracture) and of the opposite non-immobilized limb was biopsied in four adult males, after periods of immobilization from 50 to 75 days. These 8 muscle specimens were examined for histopathological changes, and muscle fibre diameters were measured by micrometry from paraffin sections. The histograms revealed a larger proportion of small fibres (less than 20 micron) and a smaller proportion of large fibres (greater than 40 micron) in the immobilized limb compared to the opposite. Thus, light microscopy showed only atrophic changes. This was confirmed by electronmicroscopy, where atrophy of few to several muscle fibres was seen in the form of loss of myofibrils, collapse and folding of the basement membrane and prominence of glycogen or muscle nuclei. The atrophic change was more severe in the immobilized limbs, but it was also noticeable in all the non-immobilized limbs. Degenerative changes, especially disorganization and breakdown of myofibrils, and fragmentation of plasma membrane, were also seen in occasional atrophied muscle fibres, again more frequently in the immobilized limb. Lipofuscin was often found accumulated in muscle fibres and occasionally in endothelial cells of intramuscular blood vessels; the latter showed prominent pinocytotic vesicles or thickened basement membrane. It is concluded that both atrophy and degeneration of fibres of proximal muscles can occur as non-specific consequences of disuse of the limb in man, that degeneration is a latter and more severe change, that muscles even of the non-immobilized leg are subjected to disuse atrophy during bed-rest, and that the proximal muscles in man seem to have a natural susceptibility to atrophy and degeneration in any muscular disorders.


A potential membrane protein involved in pre-tRNA splicing of Schizosaccharomyces pombe.
We had previously isolated six pre-tRNA splicing mutants of Schizosaccharomyces pombe named ptp1 to ptp6. To investigate the molecular mechanism of tRNA splicing, we cloned the ptp4(+) gene by complementation of the temperature-sensitive growth defect. The ptp4(+) gene consists of three exons and encodes a putative protein of 218 amino acids with a molecular mass of 24.4 kDa. Analysis of the amino acid sequence reveals that the protein is a potential membrane protein with four membrane-spanning regions. The ptp4(+) shows significant similarity to the Saccharomyces cerevisiae putative protein YOR311C. Expression of the ptp4(+) gene in the ptp4(-) mutant restores the ability to splice tRNA. Northern blot analysis showed that the ptp4(+) gene is expressed in both mating-type cells of S. pombe. These results suggest that the Ptp4(+) could be a component involved in tRNA splicing.


Multilayer pixel super-resolution lensless in-line holographic microscope with random sample movement.
We report a multilayer lensless in-line holographic microscope (LIHM) with improved imaging resolution by using the pixel super-resolution technique and random sample movement. In our imaging system, a laser beam illuminated the sample and a CMOS imaging sensor located behind the sample recorded the in-line hologram for image reconstruction. During the imaging process, the sample was moved by hand randomly and the in-line holograms were acquired sequentially. Then the sample image was reconstructed from an enhanced-resolution hologram obtained from multiple low-resolution in-line holograms by applying the pixel super-resolution (PSR) technique. We studied the resolution enhancement effects by using the U.S. Air Force (USAF) target as the sample in numerical simulation and experiment. We also showed that multilayer pixel super-resolution images can be obtained by imaging a triple-layer sample made with the filamentous algae on the middle layer and microspheres with diameter of 2 μm on the top and bottom layers. Our pixel super-resolution LIHM provides a compact and low-cost solution for microscopic imaging and is promising for many biomedical applications.


Monocyte (macrophage)-specific antibodies in patients with systemic lupus erythematosus (SLE).
Antibodies reactive for monocytes (macrophages) were found in the sera of patients with systemic lupus erythematosus (SLE). These antibodies were present in both IgG and IgM fractions and worked under both warm (37 degrees C) and cold (4 degrees C) conditions. These antibodies were specific for monocytes, because cytotoxic antibodies for monocytes were absorbed with monocytes, but not with T cells, B cells, and granulocytes. Furthermore, their specificity is also different from anti-HLA-DR antibody. The presence of these antibodies correlated with the activity of disease. They were found in 12 of 14 active SLE and 7 of 16 inactive SLE patients. The treatment of normal monocytes with these SLE sera and complement resulted in the depletion of their accessory function for T-cell activation and their phagocytic activity. In the previous paper, we reported that the accessory function of monocytes for T-cell activation was impaired in SLE patients. These results suggest that monocyte-specific antibodies play an important role in the pathogenesis of SLE through disturbing the monocyte regulatory function for immune responses.


Mutual benefits: Combining reinforcement learning with sequential sampling models.
Reinforcement learning models of error-driven learning and sequential-sampling models of decision making have provided significant insight into the neural basis of a variety of cognitive processes. Until recently, model-based cognitive neuroscience research using both frameworks has evolved separately and independently. Recent efforts have illustrated the complementary nature of both modelling traditions and showed how they can be integrated into a unified theoretical framework, explaining trial-by-trial dependencies in choice behavior as well as response time distributions. Here, we review a theoretical background of integrating the two classes of models, and review recent empirical efforts towards this goal. We furthermore argue that the integration of both modelling traditions provides mutual benefits for both fields, and highlight promises of this approach for cognitive modelling and model-based cognitive neuroscience.


How do we best detect toxic effects of drugs taken during pregnancy? A EuroMap paper.
It is a major clinical and public health problem that there is no clear strategy as to how we best make use of information obtained when pregnant women take drugs. For this reason, some pregnant women are not treated as they should be and some are given drugs they should not use. We suggest a monitoring system that combines some of the available datasets in Europe. Using these sources as a starting point, one can develop a system that has sufficient power to detect even rare diseases like congenital malformations and sufficient diversity to detect several possible outcomes from spontaneous abortions to childhood disorders. We also suggest that case-crossover designs should be used in case-control monitoring systems that carry a high risk of recall bias. These considerations are based upon our results from a European Union-funded concerted action called EuroMaP (Medicine and Pregnancy).


[Diagnostic error and overdiagnosis in Primary Care. Proposals for the improvement of clinical practice family medicine].
Family doctors see a wide range of patients, with a wide range of complexity, in a short time and with few diagnostic resources. This situation makes primary care professionals more vulnerable to diagnostic errors. For this reason, an adequate clinical reasoning process is the most powerful tool family doctors have to safely guide the patient care process. Considering these errors as missed opportunities for a correct diagnosis, which may cause harm to the patient, leads us as professionals to review how to improve this process. The review includes, among other aspects, identifying cognitive biases, analysing the ways in which work is organised in primary care teams, and situations in the care context that may contribute to such errors. In this article we describe the most frequent diagnostic errors and their causal factors in primary care, the impact of cognitive process failures, situations of overdiagnosis and the diagnostic and therapeutic cascades associated with them. Finally, we propose a set of tools to improve decision-making in the diagnostic process in primary care.


Oncologic outcomes of pre-malignant and invasive germ cell tumors in patients with differences in sex development - A systematic review.
To describe the rates of GCNIS-free and GCT-free pathology based on age at gonadal surgery and to describe long-term oncologic outcomes in patients with DSD who have GCNIS or GCT at the time of gonadal surgery. A systematic review was conducted using MEDLINE to identify patients with DSD who underwent gonadal surgery. DSD diagnoses were stratified based on malignancy risk. GCNIS/GCT and GCT-free survival by age of gonadal surgery, RFS and OS were calculated using the Kaplan-Meier method, with groups compared using log-rank testing. 386 articles from 1951 to 2017 were included (2037 patients). Median age at gonadal surgery was 17 years (y) (IQR 11-20), median follow-up was 60 months (m) (IQR 30-68.1). GCNIS/GCT- and GCT-free survival at the time of gonadal surgery was lowest for those in the high/intermediate risk group (p < 0.001) but decreased sharply around age 15y, regardless of risk category. 5y RFS and OS was similar for those with no GCNIS/GCT and GCNIS and was worse for those with GCT (p < 0.001). When patients undergo gonadal surgery, regardless of indication (i.e. prophylactic vs. tumor), it appears that GCTs are more commonly found when surgery is done around age 15 y or older, despite risk category. This is similar to ovarian and testicular GCTs. Patients with GCNIS can be reassured that long-term oncologic outcomes are excellent. While RFS and OS for GCTs are not as good as for ovarian and testicular GCTs (95%), they are still >80%. This similar trend was found in a COG review of 9 patients with DSD and ovarian GCT. There were several limitations to this study. This is a retrospective analysis that included aa wide time frame of publications. The indication for surgical intervention was not addressed in the majority of publications. Thus these data provide pathologic outcomes based on age at gonadal surgery rather than the age at which GCNIS/GCT develops over a lifetime, if at all. The risk of GCNIS or GCT at the time of gonadal surgery appears to increase with age, accelerating between 15 and 20y regardless of risk category. 5y RFS and OS for those with GCNIS is equivalent to those without GCNIS/GCT but is worse for those with GCT. These data may be used when counseling families on timing of gonadal surgery and quantification of outcomes should GCNIS or malignancy be identified.


Effects of ultra-high pressure treatment on structure and bioactivity of polysaccharides from large leaf yellow tea.
In this study, the changes of structure and bioactivity of polysaccharides from large leaf yellow tea (LYTP) were investigated under ultra-high pressure (UHP). Native yellow tea polysaccharide were treatmented with ultra-high pressure (200, 400 and 600 MPa) for 5 min to yield yellow tea polysaccharide including 200 MPa-LYTP, 400 MPa-LYTP and 600 MPa-LYTP. It was found that the monosaccharide composition of LYTP changed significantly after the ultra-high pressure treatment. The molecular weight (Mw) of 200 MPa-LYTP (from 563.6 to 11.7 kDa), 400 MPa-LYTP (from 372.2 to 11.8 kDa) and 600 MPa-LYTP (from 344 to 11.6 kDa) sharply decreased upon ultra-high pressure treatment compared with LYTP (771.5 kDa), coincidentally particle size was also significantly reduced for 200 MPa-LYTP (23.2 %), 400 MPa-LYTP (40.2 %) and 600 MPa-LYTP (25.9 %). The results of the scanning electron microscope showed that ultra-high pressure also changed the surface and spatial morphology of LYTP. LYTP after ultra-high pressure treatment (UHP-LYTP) could further ameliorate alcohol-induced liver injury in mice. In addition, UHP treatment can more efficiently remove protein than the Sevages method. With the gradual removal of protein, its hepatoprotective effect increased. These findings demonstrated that UHP treatment could change the primary structure and spatial structure of LYTP, increase the content of acidic polysaccharides, and improve its bioactivity.


Pre-registration house officers and ward-based learning: a 'new apprenticeship' model.
The pre-registration house officer (PRHO) year can be seen as a formal apprenticeship into the profession of medicine, and as central to the identity construction of the doctor. The year characteristically involves rotation between specialties, including attachment to ward-based 'firms', where consultants teach PRHOs. Teaching and learning in ward-based environments is under-researched, and the current literature displays a bias towards a psychological model of pedagogy that focuses upon transmission of knowledge and skills from one individual to another. Such a model offers a necessary, but not sufficient, explanation of how work-based learning occurs. Understanding the PRHO apprenticeship year should include reference to cultural dimensions to learning, especially socialisation into the profession. This constitutes an 'extended' (or 'hidden') curriculum model that may be theorised through contemporary ideas of activity learning within a 'new apprenticeship' framework. The dominant psychological model can lead to an expectation for a uniform method of teaching and learning in ward round contexts that (a) ignores important differences in educational climate between established communities of practice, and (b) orients both teachers and learners to one-to-one transmission and reception, rather than sensitising to how knowledge may be held across members of a working group. The latter shifts emphasis away from reception to issues of active access. PRHOs, as novices, are not relegated to passive learning roles, but may actively co-construct knowledge with experts, offering potential transformation of the practices of ward groups.


[Dermoid cysts: epidemiological, clinical and pathological studies].
We retrospectively analyzed 31 cases of dermoid cysts surgically treated between January 1992 and October 2000. Mean patient age was 18.9 years. The preseptal localization predominated, with 29 cases. Two cases of intraorbital localization required orbitotomy. The surgical result was excellent.


Carbamazepine-induced facial burns caused by a photocopier.
A 36-year-old woman on long-term anticonvulsant therapy with carbamazepine (Tegretol) sustained superficial facial and corneal burns after using a photocopier for 2 h. Photosensitivity is a rare side-effect of carbamazepine therapy, and progression to a superficial burn has not been reported previously. Photocopiers emit a very low level of ultraviolet irradiation: this would not cause burns in a normal patient but could possibly do so in someone who is sensitive to ultraviolet light.


The surgical management of overcorrection in myopic epikeratophakia.
Three patients underwent myopic epikeratophakia that resulted in overcorrection. The surgical management of these cases involved resuturing the myopic lenticule to flatten the peripheral curvature and reduce the amount of minus power. A reduction in the overcorrection was achieved in all cases.


Outcomes After Arthroscopic Osteochondroplasty for Femoroacetabular Impingement Secondary to Slipped Capital Femoral Epiphysis: A Systematic Review.
To determine the efficacy of arthroscopic osteochondroplasty for patients with femoroacetabular impingement (FAI) secondary to slipped capital femoral epiphysis (SCFE). A systematic review was performed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using Embase, PubMed (Medline), and Cochrane Library up to November 1, 2019. Data including patient demographics, slip severity according to Southwick, outcomes, and complications were retrieved from eligible studies that reported a minimum 3-month follow-up of arthroscopic osteochondroplasty for FAI secondary to SCFE. Methodological Index for Non-Randomized Studies (MINORS) criteria was used to assess quality of studies. Heterogeneity and quality were evaluated using P values and the I2 statistic. Six studies (90 hips) were analyzed. The range of MINORS scores was 8 to 11. Most studies were level of evidence 4 (n = 4, 66.7%), with more men than women (n = 5, 83.3%). The ranges of age, body mass index, and follow-up length after surgery were 10 to 42 years, 17.5 to 32.3 kg/m2, and 3 to 56 months, respectively. The Modified Harris Hip Score (mHHS) was the most commonly used score to report on clinical outcomes (n = 2 studies, 28 hips) with a significant improvement following surgery. Three studies reported an improvement in internal rotation (IR) of the hip with a range of improvement of 17° to 32°, with low heterogeneity (I2 = 0% and P = .531). Five studies reported a significant correction of the α angle, with range of improvement of 19.9° to 37.3°. The range of postoperative α angle was 32° to 67°, and 3 studies achieved appropriate postoperative α angle (40° to 50°), with low heterogeneity (I2 = 8.4% and P = .336). The total number of complications was 8 (1 major complication) and there were 6 revisions, with low heterogeneity. Arthroscopic osteochondroplasty for FAI secondary to SCFE provides good short- to medium-term outcomes and improves IR of the hip, with the ability to potentially correct the α angle with a low rate of complications and revision. IV, systematic review of level II to IV studies.


[Diagnostic image (73). A man with atypical back and abdominal symptoms. Inflammation of abdominal aortic aneurysm].
In a 66-year-old man a typical inflammatory abdominal aortic aneurysm was diagnosed.


Estimated direct costs of non-small cell lung cancer by stage at diagnosis and disease management phase: A whole-disease model.
Non-small cell lung cancer (NSCLC) is the first cause of cancer-related death among men and the second among women worldwide. It also poses an economic threat to the sustainability of healthcare services. This study estimated the direct costs of care for patients with NSCLC by stage at diagnosis, and management phase of pathway recommended in local and international guidelines. Based on the most up-to-date guidelines, we developed a very detailed "whole-disease" model listing the probabilities of all potentially necessary diagnostic and therapeutic actions involved in the management of each stage of NSCLC. We assigned a cost to each procedure, and obtained an estimate of the total and average per-patient costs of each stage of the disease and phase of its management. The mean expected cost of a patient with NSCLC is 21,328 € (95% C.I. -20 897-22 322). This cost is 16 291 € in stage I, 19530 € in stage II, 21938 € in stage III, 22175 € in stage IV, and 28 711 € for a Pancoast tumor. In the early stages of the disease, the main cost is incurred by surgery, whereas in the more advanced stages radiotherapy, medical therapy, treatment for progressions, and supportive care become variously more important. An estimation of the direct costs of care for NSCLC is fundamental in order to predict the burden of new oncological therapies and treatments on healthcare services, and thus orient the decisions of policy-makers regarding the allocation of resources. SIGNIFICANT FINDINGS OF THE STUDY: The high costs of surgery make the early stages of the disease no less expensive than the advanced stages. An estimation of the direct costs of care is fundamental in order to orient the decisions of policy-makers regarding the allocation of resources.


Development of the dopaminergic innervation of the rat cerebral cortex. A light microscopic immunocytochemical study using anti-tyrosine hydroxylase antibodies.
A precise topographical analysis of the distribution of tyrosine hydroxylase-like immunoreactive processes was performed in the frontal, cingular and parietal cortex of the rat during late embryonic and early postnatal life. Until birth, labeled processes were only observed in the restricted cortical areas known to receive a dopaminergic innervation in the adult brain. Their distribution differed markedly from that of noradrenergic fibers as identified by their dopamine-beta-hydroxylase-like immunoreactivity. Thus we considered TH-like immunoreactivity to be a selective marker of the cortical dopaminergic innervation during late fetal life, at least with the antibody we used. With this marker, dopaminergic fibers were first detected in the anterior frontal cortex at day 16 of embryonic life (E16). They developed as two bundles passing medially and laterally to the ventricular layer without penetrating it. From E20 on, the terminal fields extended to the cingular and rhinal cortex, still being restricted to the intermediate zone. No fibers were visible in the lateral and dorsal frontal cortex at this time, nor in the cortical plate and molecular layer in any cortical area. At E21, rare labeled fibers were seen in the molecular layer of the medial frontal and cingular cortex. After birth, the terminal fields of the TH-containing fibers extended further caudally in the cingular cortex and also superficially in the cortical plate. Moreover, labeled axons now also appeared in the lateral frontal and parietal cortex where their density gradually increased. At P14, two different patterns of distribution were observed: a high density of TH-positive fibers in the cortical areas known to receive a dopaminergic innervation; a low density of fibers in the other cortical areas which represented noradrenergic fibers. Indeed these TH-containing presumed noradrenergic fibers were absent at P14 following a bilateral destruction of the locus coeruleus in 4-day-old pups.


Salvage photodynamic therapy for local failure after chemoradiotherapy for esophageal squamous cell carcinoma.
Photodynamic therapy (PDT) is a less-invasive salvage treatment option for local failure at the primary site after chemoradiotherapy (CRT) for esophageal squamous cell carcinoma. The objective of this study was to clarify the long-term outcomes and prognostic factors of salvage PDT. One hundred thirteen consecutive patients treated in our institution with PDT for local failure limited to within T2 without any metastases after definitive CRT performed between 1998 and 2008 were retrospectively enrolled. The complete response rate, adverse events, and survival outcomes were assessed and prognostic factors were investigated using a multivariate analysis. The complete response rate was 58.4% (95% confidence interval [CI], 49.3%-67.5%). The progression-free survival (PFS) and the overall survival (OS) rates at 5 years after salvage PDT were 22.1% (95% CI, 14.3%-30.0%) and 35.9% (95% CI, 26.7%-45.1%). N0 before CRT was significantly associated with OS (hazard ratio [HR], 0.54; 95% CI, 0.33-0.91, P = .020), whereas the impact of T1 or T2 before CRT on PFS (HR, 0.63; 95% CI, 0.38-1.04, P = .068) and that of a longer period between CRT and PDT on OS (HR, 0.64; 95% CI, 0.39-1.05, P = .078) were marginal. The treatment-related death rate was 1.8%. Salvage PDT was found to have a superior outcome and a satisfactory safety profile. An earlier clinical stage before CRT and a longer interval between CRT and PDT may be associated with a longer survival period.


Screening for sexually transmitted infections at a DeAddictions service in south India.
To estimate the lifetime prevalence of four sexually transmitted infections (STIs) and to identify correlates of these infections among patients seeking care for a substance use disorder at a specialized DeAddictions Unit in southern India. Consecutive inpatients (n=361; 98% male; M age=36.7 years) admitted to DeAddictions Unit of the National Institute of Mental Health and Neuro Sciences in Bangalore, India, participated in a structured interview to obtain demographic, psychiatric, sexual behavior, and substance use data; each patient also provided a blood sample for serologic testing for HIV, chlamydia, syphilis, and hepatitis B. One-quarter of all patients tested positive for at least one STI. Lifetime seroprevalence rates were 12.9% for syphilis, 10.3% for chlamydia, 3.1% for hepatitis B, and 1.1% for HIV. Analyses did not reveal any consistent pattern of associations between STI status and sociodemographic, psychiatric, and sexual behavioral characteristics. All patients should receive a comprehensive sexual assessment during standard care; for those patients who report risky sexual practices, we recommend voluntary counseling and testing for STIs. Although we do not recommend universal testing for STIs at this time, this should be revisited based upon national surveillance data.


Evaluation of pharmacy student empathy scores before and after a geriatrics advanced pharmacy practice experience (APPE).
Empathy from healthcare providers is associated with improved patient care and satisfaction, resulting in increased emphasis on empathy in pharmacy school curricula. Previous studies showed improvement in pharmacy student empathy after older adult-specific simulation activities in the didactic setting, but no such data exist for the practice environment. This study's purpose was to evaluate the impact of a geriatrics advanced pharmacy practice experience (APPE) on pharmacy student empathy toward older adults. All fourth-year pharmacy students in a geriatrics APPE at one of four participating sites were offered to participate in the study at the beginning of the rotation. Empathy was measured at baseline and end of the rotation using the Kiersma-Chen Empathy Scale (KCES). Wilcoxon matched-pairs signed-ranks test was used to test differences from pre- to post-rotation. Fifty-four of the 110 eligible students opted to participate in the study, and 46 completed both the pre- and post-surveys. Most students were female (55.6%), and the average age was 27.3 years. Mean empathy scores for all students increased significantly by 4.89 points (z = 4.17, P < .001, d = 0.97). Specific KCES items related to handling other's feelings and viewing another person's perspective also significantly improved. Empathy is a key component to professional development in healthcare students, and a geriatrics APPE provides an opportunity for students to grow this soft skill. Although further study is warranted, older adult focused rotations may be considered by schools of pharmacy to aid in preparing "graduate-ready" pharmacists.


Clinical, histologic, cytologic, and ultrastructural characteristics of the oral lesions from hereditary mucoepithelial dysplasia. A disease of gap junction and desmosome formation.
Hereditary mucoepithelial dysplasia is an autosomal, dominantly inherited disorder affecting all of the orificial mucosa with cataracts, follicular keratosis of skin, nonscarring alopecia, bouts of pneumonia, spontaneous pneumothorax, and terminal cor pulmonale. The oral lesion is a fiery red, flat or micropapillary-appearing mucosa most frequently involving the gingiva and hard palate. All oral and pharyngeal mucosa may be involved, however. Red scrotal mucosa of the tongue is common. Histologically, the oral mucosa shows a lack of cornified and keratinized cells, a decrease in the thickness of the epithelial cell layer, dyshesion, and dyskeratosis. Papanicolaou smears show lack of epithelial cell maturation, poikilocytosis, anisocytosis, large paranuclear cytoplasmic vacuoles, and cytoplasmic strand-shaped inclusions. Ultrastructural features include a paucity of desmosomes, intercellular accumulations of amorphous material, cytoplasmic vacuoles, and paranuclear lesions with strands of material resembling gap junctions and desmosomes. The condition most likely represents a basic defect in gap junction and desmosome formation.


The detection and clinical significance of antibodies to tumor-associated antigens in patients with renal cell carcinoma.
Antibodies against renal carcinoma cells were detected by a microcomplement fixation assay in the sera of 94 per cent of 75 patients with recently resected, localized or metastatic disease, and in 20 per cent of normal controls. Absorption of sera with pooled normal kidney cells abrogated reactivity against normal kidney cells but did not decrease reactivity significantly against the renal carcinoma cells. Analyses of sequential serum samples revealed that after nephrectomy in 9 of 10 patients free of tumor but a high risk for recurrence antibody levels decreased or disappeared by 1 year. However, these levels remained elevated in 2 patients who subsequently were found to have occult persistent tumor. Antibody titers in patients with metastatic renal cell carcinoma declined as the disease progressed. Patients with persistently elevated titers had the longest survival. Although the antibodies detected by this assay may not be specific for renal cell carcinoma, their detection may be of clinical significance with regard to the prognosis of the disease.


Co-cultures of enterocytes and hepatocytes for retinoid transport and metabolism.
Dietary retinoid bioavailability involves the interplay of the intestine (transport and metabolism) and the liver (secondary metabolism). To reproduce these processes in vitro, differentiated human intestinal Caco-2/TC7 cells were co-cultured with two hepatocyte cell lines. Murine 3A cells and the more highly differentiated human HepaRG hepatocytes were both shown to respond to β-carotene (BC) and retinol (ROH) treatment by secreting Retinol Binding Protein 4 (RBP4). In co-culture experiments, Caco-2/TC7 were differentiated on filter inserts and transferred for the time of the experiment to culture wells containing confluent 3A or differentiated HepaRG cells. Functionality of the co-cultures was assayed using as endpoints the retinol-dependent secretion of RBP4 and the retinoic acid-dependent induction of CYP26A1 in hepatocytes. BC and ROH added to intestinal Caco-2/TC7 induced a reduction in intracellular RBP4 levels in the underlying hepatocytes and its secretion into the medium. HepaRG hepatocytes were also shown to up-regulate the expression of CYP26A1 mRNA in response to retinoid treatment. This in vitro model represents a useful tool to analyze the absorption and metabolism of retinoids and could be further developed to investigate other dietary compounds and molecules of pharmacological interest.


Examining the impact of federally-funded syphilis elimination activities in the USA.
In 1999, the US Centers for Disease Control and Prevention (CDC) launched a national syphilis elimination plan. Using state-level syphilis incidence data from 1997 to 2005, we found that greater amounts of state-level funding for syphilis elimination in a given year were associated with lower state-level syphilis rates in subsequent years. The findings suggest that federally-funded syphilis elimination activities are having a notable impact on syphilis rates. The recent increases in syphilis in the United States might have been much more pronounced had there been no syphilis elimination activities.


COVID-19 infection leading to acute pustular dermatoses.
Viral infections, including SARS-CoV-2, the virus that causes COVID-19 infection, have been implicated in the development of pustular dermatoses, including generalized pustular psoriasis (GPP) and acute generalized exanthematous pustulosis (AGEP). We performed a literature review of existing cases of GPP and AGEP associated with COVID-19 infection and/or treatment reported over a period of 12 months. We summarize the clinical characteristics of these cases and report an additional six new cases of GPP and AGEP. Seven patients with COVID-19 infection were diagnosed with new-onset or exacerbated GPP, and 33 patients were diagnosed with AGEP. In 55% of the cases, no concomitant potential culprit drug trigger was identified. We present this review of cases of COVID-associated acute pustular dermatoses to further contribute to the spectrum of cutaneous eruption associated with SARS-CoV-2 infection.


High density lipoprotein cholesterol and arteriography in intermittent claudication.
Overnight fasting plasma lipoprotein and lipid concentrations were measured in a group of 76 patients with peripheral arterial disease (PAD)--main symptom: intermittent claudication--and compared to those of 21 controls, matched with the patients according to age, sex, body-mass index, alcohol and tobacco consumption, but without any signs of peripheral arterial disease. Significantly lower median values of high density lipoprotein cholesterols (HDL-C) (P less than 0.01), and significantly higher median values of low density lipoprotein cholesterols (LDL-C) (P less than 0.05) were found in the PAD group. The results also showed significantly lower ratios of HDL-C/LDL-C and HDL-C/total cholesterol in the PAD group when compared to the controls (both P less than 0.005). No significant differences were demonstrated concerning very low density lipoprotein, total cholesterol, or triglyceride plasma concentrations. Evaluation of arteriograms showed a significant negative correlation between HDL-C concentrations and the extent of arteriosclerotic lesions in the lower extremities (P less than 0.05). Thus, not only were the HDL-C and LDL-C levels different in the PAD group, but we also found a correlation between HDL-C and the severity of vascular disease.


Effects of different protocols of hydration on cardiorespiratory parameters during exercise and recovery.
Hydration plays a key role in the physiological maintenance required by exercise. To evaluate the behavior of heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure, pulse oxygen saturation (SpO2) and respiratory rate (RR) of young people during and after prolonged physical exercise, with and without the intake of water or isotonic solution. 31 young individuals (21.63 ± 1.86 years) were subjected to a four-step protocol with a 48-hour interval between each step, namely: i) a test to determine the incremental load used in subsequent steps, ii) a control protocol without hydration (CP), iii) an experimental protocol with water intake (PE1), iv) an experimental protocol with ingestion of isotonic (PE2). The protocols consisted of 10 min rest, 90 min of exercise on a treadmill at 60% of VO2peak and 60 min of recovery. The parameters HR, SBP, DBP, RR and SPO2 were measured at rest, at 30, 60 and 90 min of exercise, with the exception of RR; and at 1, 3, 5, 7, 10, 20, 30, 40, 50 and 60 min of recovery. The two-factor analysis of variance for repeated measures model was used for analysis (p<0.05). There was a moment effect for all variables in exercise (p<0.001), however, no effect was observed between the protocols (SBP, p=0.998; DBP, p=0.897; SpO2, p=0.077, HR=0.281) and in the interaction moment and protocol (SBP, p=0.058; DBP, p=0.191 and SpO2, p=0.510, HR=0.496). In recovery there was also a moment effect for all variables analyzed (p<0.001). There was no effect among protocols for SBP (p=0.986), DBP (p=0.536) and RR (p=0.539), however in the SpO2 (p=0.001) and HR (p=0.033) variables, effects were observed between the protocols. Regarding the moment and protocol interaction, an effect was observed for HR (SBP, p=0.431; DBP, p=0.086; SpO2, p=0.445, RR, p=0.147, HR, p=0.022). For the type of exercise performed, both the water and the isotonic solution influenced the behavior of cardiorespiratory parameters, and independent of the type of hydration given the behavior of the parameters studied was similar.


A reliable protocol for the manual segmentation of the human amygdala and its subregions using ultra-high resolution MRI.
The measurement of the volume of the human amygdala in vivo has received increasing attention over the past decade, but existing methods face several challenges. First, due to the amorphous appearance of the amygdala and the difficulties in interpreting its boundaries, it is common for protocols to omit sizable sections of the rostral and dorsal regions of the amygdala comprising parts of the basolateral complex (BL) and central nucleus (Ce), respectively. Second, segmentation of the amgydaloid complex into separate subdivisions is challenging due to the resolution of routinely acquired images and the lack of standard protocols. Recent advances in technology have made ultra-high resolution MR images available, and in this study we provide a detailed segmentation protocol for manually tracing the whole amygdala that incorporates a greater portion of the rostral and dorsal sections with techniques illustrated in detail to maximize reproducibility. In addition, we propose a geometrically-based protocol for segmenting the amygdala into four component subregions of interest (sROI), which correspond largely to amygdala subnuclear divisions: the BL sROI, centromedial (CM) sROI, basomedial (BM) sROI, and the amygdaloid cortical (ACo) sROI. We performed an intra- and inter-rater reliability study of our methods in 10 adults (5 young adults and 5 older adults). The results indicate that both protocols can be implemented with a high degree of reliability (the majority of intra-rater and inter-rater correlations were > 0.81). This protocol should aid further research into the alterations in amygdala anatomy, connectivity, and function that accompany normal aging and pathology associated with neuropsychiatric disorders.


Afatinib use in non-small cell lung cancer previously sensitive to epidermal growth factor receptor inhibitors: the United Kingdom Named Patient Programme.
Afatinib prolongs progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) who were previously sensitive to erlotinib or gefitinib. This study investigated experience of afatinib under a Named Patient Use (NPU) programme. Retrospective data for 63 patients were collected, including demographics, dose, toxicity and clinical efficacy. Response rate and median PFS were 14.3% and 2.6months, respectively. Diarrhoea and rash were the most common toxicities; 46% of patients required a dose reduction and 41% had a dose delay. Efficacy and safety in the NPU programme are consistent with the LUX-Lung 1 trial.


An outbreak of vulvovaginitis in goats caused by a caprine herpesvirus.
A caprine herpesvirus related to infectious bovine rhinotracheitis virus but immunologically distinct from that virus was isolated from an outbreak of vulvovaginitis in a herd of Saanen goats. The morbidity rate was 52.5%, with 21 of 40 does showing clinical signs. The lesions healed rapidly with only two goats showing lesions two weeks after the disease was first detected. No effect on subsequent reproductive performance was observed. The mode of transmission of the virus was believed to be venereal.


Homeostasis of naïve, effector and memory CD8 T cells.
Homeostatic control of CD8 T cell populations is essential for defense against infectious pathogens. Our understanding of the mechanisms that control naïve, effector and memory T cell populations in the intact animal has increased significantly over the last several years. There have been some surprises. For example, peripheral tissues have been found to harbor unexpectedly large numbers of effector memory T cells. Also unexpected was the finding of programmed T cell proliferation following very brief exposure to antigen. These and other recent advances are summarized in the following review.


Enhanced growth of tumour cells in healing colonic anastomoses and laparotomy wounds.
In the past, it has been noted that experimental tumour cells inoculated into the peritoneal cavity or into the lumen of the bowel will grow at a recently formed colonic anastomosis. However, it has previously been unclear whether the healing process enhances tumour growth or whether the presence of a suture line merely allows the tumour cells to gain access to the tissues. In the present study, using the hooded Lister rat, we have confirmed these findings by showing that growth of the syngeneic MC28 sarcoma and OES5 breast carcinoma occurs preferentially at colonic anastomoses and laparotomy wounds after intraperitoneal injection, and at colonic anastomoses after intraluminal injection. In previous studies using the MC28 sarcoma and the OES5 breast carcinoma injected by the intracardiac route (so that tumour cells reach normal and healing tissues in approximately equal numbers) we have shown that tumour growth is enhanced in healing wounds but not in the surrounding normal tissues when cells reach a healing colonic anastomosis or laparotomy wound within 2 h of its formation. Furthermore, by studying the distribution of radiolabelled tumour cells after intracardiac injection, we have calculated that the probability of a tumour cell leading to a deposit in a healing anastomosis or laparotomy wound is increased 1,000 fold compared to normal tissue. No previous studies have combined the data for intracardiac, intraluminal and intraperitoneal injection of tumour cells using the same animal model. We conclude that the same phenomenon of tumour growth enhancement in colonic anastomoses and laparotomy wounds reported after intracardiac injection of tumour cells may well be enhancing tumour growth after intraperitoneal and intraluminal injection.(ABSTRACT TRUNCATED AT 250 WORDS)


The gut microbiota: a new perspective on the toxicity of malachite green (MG).
Gut microbiome critically contributes to host health status. Thus, investigating the relationship between the gut microbiome and toxic chemicals is a hot topic in toxicology research. Exposure to malachite green (MG) has been linked to various health disorders. Thus, exploring the gut microbiota changes in response to MG would provide a new perspective on the toxicity effects of this chemical substance. MG exposure resulted in the significantly lower alpha diversity (Mann-Whitney U test, z = - 6.83, p = 0.00) but higher beta diversity (Mann-Whitney U test, z = - 1.98, p = 0.04) of gut microbiota, and significantly decreased ecosystem stability (alpha and beta variability; Mann-Whitney U test, all p < 0.05) of gut microbial communities. Gut bacterial networks showed that the interactions became more complex and stronger after MG exposure, which could decrease the stability of the network. Changes in gut microbiota composition were mainly reflected in the enrichment of opportunistic bacteria (i.e., Aeromonas and Vibrio) and the depression of fermentative bacteria (i.e., Bacteroides and Paludibacter). MG exposure leads to a significantly increased gut permeability (lipopolysaccharide-binding protein; Mann-Whitney U test, z = - 6.92, p = 0.00), which could reduce the host selective pressures on particular bacterial species (such as members in Aeromonas and Vibrio). This result was further supported by the weakened importance of a deterministic microbial assembly after MG exposure. All these findings indicated that MG exposed fishes might have more possibilities to be infected, as demonstrated by the enrichment of opportunistic pathogenic bacteria, high-level immune responses, and increased gut permeability. These findings greatly improve our understanding of the toxicity effects of MG.


DNA of human cytomegalovirus: size heterogeneity and defectiveness resulting from serial undiluted passage.
The majority of DNA molecules associated with plaque-purified, low-multiplicity-passaged human cytomegalovirus (Towne strain) had a molecular weight of approximately 150 x 10(6) and a molecular complexity of approximately 140 x 10(6). Serial high-multiplicity passage resulted in the production of defective cytomegalovirions. An accumulation of smaller DNA molecules packaged into virions was directly correlated with a decrease in infectivity and an increase in the particle-to-PFU ratio. The majority of defective DNA molecules had a molecular weight of approximately 100 x 10(6). In addition, there were some viral DNA molecules of approximately 60 x 10(6). Restriction enzyme analysis of defective cytomegalovirus DNA detected unique DNA fragments, suggesting a specific alteration in the nucleotide sequence. Some reasons for the generation of defective cytomegalovirus DNA are discussed.


Serological diversity of antigens expressed on the surface of erythrocytes infected with Plasmodium falciparum.
We have studied the surface-antigen phenotypes of infected erythrocytes from children with acute falciparum malaria in the Punjab, Pakistan. Infected erythrocytes from 15 children and their homologous acute and convalescent sera, as well as hyperimmune sera from adults living in the same area, were used to analyse the serological diversity of parasite-associated antigens expressed on the surface of erythrocytes infected with Plasmodium falciparum. Analysis included agglutination, cytoadherence/inhibition of cytoadherence to melanoma cells, and rosette formation/disruption of rosettes formed between infected and non-infected erythrocytes. We found that isolate-specific antibodies were acquired by all children during convalescence and that there was a high degree of diversity of surface-antigen phenotypes. A majority of the sera either acquired or increased by 2- to 3-fold the capacity to inhibit cytoadherence and/or agglutinate the patient's own infected erythrocytes during convalescence and a strong correlation was found between these 2 activities. Hyperimmune sera from adults agglutinated and/or inhibited cytoadherence of many, but not all, of the isolates. Rosette formation was observed in 11 of the 15 isolates; 38% of the acute and 75% of the convalescent sera had anti-rosette activity on rosettes formed by the patient's own parasites. Among the isolates there was no correlation between rosette formation and binding of infected erythrocytes to melanoma cells. Our data provide good evidence that the children developed isolate-specific antibodies during convalescence from an acute attack of falciparum malaria and suggest that there was a high degree of heterogeneity of antigens expressed on the surface of infected erythrocytes.


Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety.
A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety were synthesized, and evaluated for their antiproliferative activity against 5 cancer cell lines (H460, HT-29, MKN-45, A549, and U87MG). Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 42 (c-Met/Flt-3 IC50=1.21/2.15nM) showed a 6.1-fold increase in activity against H460 cell line in vitro. The enzymatic assays (c-Met, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR) of compound 42 were evaluated in vitro. Docking analysis showed that compound 42 could form three hydrogen bonds with c-Met. Structure-activity relationship studies indicated that a more water-soluble cyclic tertiary amine and electron-withdrawing groups at 4-position of the phenyl ring contribute to the antitumour activity.


Electronic cigarettes: Ever use, current use and attitudes among alcohol and other drug clients.
Electronic cigarettes (e-cigarettes) are becoming popular and may be a potential harm reduction and quit smoking aid for people who use other drugs. Data on e-cigarette use and perceptions among people who use drugs is limited. The current study examines tobacco smoking status, use and attitudes towards e-cigarettes among people in drug and alcohol treatment. Data were collected through a standardised Patient Experience Tracking System device installed in the waiting room of six drug and alcohol clinical service programs located within one area health service in New South Wales, Australia during April to June 2017. Participants were clients of participating services aged 18 years and older. Five hundred and eleven participants completed the survey, 85% were current smokers, 9% were ex-smokers and 6% were non-smokers. Over half of all participants (53%) had tried e-cigarettes in their lifetime, 26% reported current use and 77% of those were using them with nicotine. Just less than half of all participants believed that e-cigarettes were helpful for quitting or cutting down smoking tobacco cigarettes (48%). More than half of all respondents (59%) believed that tobacco cigarettes were more harmful than e-cigarettes (59%) and believed that e-cigarettes were an acceptable quit smoking aid for patients of drug and alcohol services (64%). Most participants were current tobacco smokers and had tried an e-cigarette though a minority were currently using e-cigarettes. Participant attitudes were favourable towards the use of e-cigarettes as quit smoking aids.


Design and biological evaluation of ⁹⁹mTc-N₂S₂-Tat(49-57)-c(RGDyK): a hybrid radiopharmaceutical for tumors expressing α(v)β(3) integrins.
The α(ν)β(3) integrin is over-expressed in the tumor neovasculature and the tumor cells of glioblastomas. The HIV Tat-derived peptide has been used to deliver various cargos into cells. The aim of this research was to synthesize and assess the in vitro and in vivo uptake of (99m)Tc-N₂S₂-Tat(49-57)-c(RGDyK) ((99m)Tc-Tat-RGD) in α(ν)β(3) integrin positive cancer cells and compare it to that of a conventional (99m)Tc-RGD peptide ((99m)Tc-EDDA/HYNIC-E-[c(RGDfK)]2). The c(RGDyK) peptide was conjugated to a maleimidopropionyl (MP) moiety through Lys, and the MP group was used as the branch position to form a thioether with the Cys(12) side chain of the Tat(49-57)-spacer-N₂S₂ peptide. (99m)Tc-Tat-RGD was prepared, and stability studies were carried out by size exclusion HPLC analyses in human serum. The in vitro affinity for α(v)β(3) integrin was determined by a competitive binding assay. In vitro internalization was determined using glioblastoma C6 cells. Biodistribution studies were accomplished in athymic mice with C6 induced tumors that had blocked and unblocked receptors. Images were obtained using a micro-SPECT/CT. (99m)Tc-Tat-RGD was obtained with a radiochemical purity higher than 95%, as determined by radio-HPLC and ITLC-SG analyses. Protein binding was 15.7% for (99m)Tc-Tat-RGD and 5.6% for (99m)Tc-RGD. The IC50 values were 6.7 nM ((99m)Tc-Tat-RGD) and 4.6 nM ((99m)Tc-RGD). Internalization in C6 cells was higher in (99m)Tc-Tat-RGD (37.5%) than in (99m)Tc-RGD (10%). Biodistribution studies and in vivo micro-SPECT/CT images in mice showed higher tumor uptake for (99m)Tc-Tat-RGD (6.98% ± 1.34% ID/g at 3h) than that of (99m)Tc-RGD (3.72%±0.52% ID/g at 3h) with specific recognition for α(v)β(3) integrins. Because of the significant cell internalization (Auger and internal conversion electrons) and specific recognition for α(v)β(3) integrins, the hybrid (99m)Tc-N₂S₂-Tat(49-57)-c(RGDyK) radiopharmaceutical is potentially useful for the imaging and possible therapy of tumors expressing α(v)β(3) integrins.


Comparative evaluation of bone chars derived from bovine parts: Physicochemical properties and copper sorption behavior.
With the increasing demand for beef worldwide, a considerable amount of bovine bone is discharged as solid waste. Therefore, in this study, the physicochemical properties of chars from bovine bones (ribs, scapulae, vertebrae, and legs) and their copper sorption behavior in aqueous solutions were investigated. The bone chars were pyrolyzed at 500 °C and the ash contents were approximately 85.08%, although the leg bone char had significantly higher values. The rib bone char showed a larger specific surface area (172 m2/g), smaller average pore diameter (7.7 nm), and more basic functional groups than the other char types. The maximum sorption capacity varied from 72.53 to 83.71 g/kg, with the rib bone char exhibiting the best adsorption characteristics, followed by the scapulae, vertebrae, and legs. A correlation analysis demonstrated that the adsorption capacity of Cu(II) on bone char is closely related to surface pore characteristics. An adsorption kinetic analysis and physicochemical characterization of the chars indicate that the Cu(II) adsorption mechanism in bovine bone char is primarily surface chemisorption. Based on the different of physicochemical properties and sorption behavior, bone chars pyrolyzed from bovine ribs are most suitable for adsorption-related applications. The results of this study demonstrate the potential for classified utilization of animal bones, including the use of graded bone chars as low-cost adsorbents requiring no chemical pre-treatment.


Pharmacokinetics of betamethasone in twin and singleton pregnancy.
The aims of the study were to compare the pharmacokinetics of betamethasone in singleton pregnancy with the pharmacokinetics in twin pregnancy and to assess the adrenal suppression produced by betamethasone. We measured serial betamethasone and cortisol levels in 30 singleton and 21 twin pregnancies after the first dose of betamethasone and calculated the pharmacokinetic parameters for betamethasone including volume of distribution, half-life, and clearance. We also measured cord and maternal blood levels of betamethasone at the birth of infants of 13 singleton and 9 twin pregnancies. The half-life of betamethasone in mothers with twin pregnancies was significantly shorter than that in mothers with singleton pregnancies (7.2 +/-2.4 versus 9.0 +/- 2.7 hours; P <.017). Clearance of betamethasone in the twin pregnancies appeared greater than in singleton pregnancies (8.4 +/- 6.4 versus 5.7+/- 3.1 L/h; P =.06) but did not reach statistical significance. Volume of distribution was similar in the two groups. Because the time between the last dose of betamethasone and birth varied widely (range, 2-158 hours), mothers with a longer interval after treatment tended to have a higher cord-to-maternal betamethasone ratio than did mothers with a shorter interval in both twin and singleton pregnancies. This finding indicated delayed fetal clearance, but the correlation was weak (R (2) = 0.29 for twins and 0.08 for singletons). The shorter half-life of betamethasone in twin pregnancy than in singleton pregnancy may cause the level of betamethasone to be subtherapeutic for lung maturation in twin pregnancy.


Correlations of in vivo mediator release with late cutaneous allergic responses in humans. I. Kinetics of histamine release.
To evaluate the contribution of mast cell-derived mediators in the late cutaneous allergic response, the duration and quantity of antigen-induced histamine release was compared to the intensity of the antigen-induced skin reactions in atopic volunteers. Chambers containing either pollen extract or buffer were appended to denuded bases for 1 hr and were replaced hourly with buffer for 3 additional hr. These were compared to the extinction dilution skin test titer and to the mean diameters of the 20-minute wheal and induration at 6 and 8 hr after intradermal injection of antigen. Chamber-fluid histamine levels were significantly higher at antigen than at buffer sites throughout the 4 hr. The hourly histamine levels correlated with the size of the induration at 6 and 8 hr but not with the wheal size or skin test titer. We conclude that (1) histamine is released for at least 4 hr at skin sites of antigen challenge as a consequence of prolonged release either from individual or sequentially activated mast cells, and (2) the quantity of histamine released correlates with the intensity of the late-phase skin response. We hypothesize that histamine might be a marker for prolonged release from the mast cell of other mediators that are responsible for the late-phase response.


Multi-dimensional visualization of ingestion, biological effects and interactions of microplastics and a representative POP in edible jellyfish.
Due to their ubiquity and potential risks, microplastics (MPs) and nanoplastics (NPs) are concerning environmental issues. Yet there are still significant knowledge gaps in understanding the tissue-specific accumulation and dynamic change of MPs and NPs in the aquatic organism and how these micro/nano-scale emerging contaminants interact with other environmental pollutants such as persistent organic pollutants (POPs). Here, in vivo imaging systems (IVIS), radioisotope tracing, and histological staining were innovatively used to reveal the fate and toxicity of fluorescently-labeled MPs/NPs and 14C-labeled 2,4,4'-trichlorobiphenyl (PCB28) in edible jellyfish Rhopilema esculentum. These contaminants' ingestion, biological effects, and interactions were visualized at cellular, tissue, and whole-body multidimensional levels. Both MPs and NPs were shown to be preferentially accumulated in the mouthlets of oral arms, and most ingested MPs/NPs were present in the extracellular environment instead of being internalized into the mesoglea. Moreover, the presence of MPs or NPs in the seawater significantly inhibited the bioaccumulation of PCB28 in the jellyfish tissue, thus alleviating physiological alteration, gastric damage, and apoptosis caused by PCB28. This study provides a multi-dimensional visualization strategy to display the distribution and biological effects of typical pollutants in marine organisms and offers new insights for understanding the impacts of MPs/NPs and POPs on marine ecosystems.


Magnetic Resonance Imaging Findings of Intraspinal Tuberculoma in Children.
Intraspinal tuberculoma is a rare disease in children, and its imaging findings have been described in only a few case reports. This study aimed to investigate the magnetic resonance imaging (MRI) features of pediatric intraspinal tuberculoma and to explore the possible pathogenesis of the disease. The clinical and MRI data of 24 child patients with intraspinal tuberculoma (such as 6 cases of intramedullary tuberculoma, 8 cases of intradural extramedullary tuberculoma, and 10 cases of epidural tuberculoma) were retrospectively analyzed. All patients underwent plain and contrast-enhanced MR scans. The diagnosis was confirmed by surgical pathology or by antituberculous treatment and follow-up data. Intramedullary tuberculoma had a round shape, while intradural extramedullary tuberculoma and epidural tuberculoma presented long-fusiform or en plaque shapes. Regarding MRI signals, intramedullary tuberculoma and extramedullary tuberculoma were mainly isointense on T1-weighted imaging (T1WI) and hypointense or isointense on T2WI. Rim enhancement was observed in intramedullary tuberculoma, and marked homogeneous enhancement was dominant in extramedullary tuberculoma. Ten (10/24) tuberculomas occurred during antituberculous therapy, with intradural extramedullary tuberculoma accounting for 7 cases (7/8), which was significantly more frequent than intramedullary tuberculoma (1/6) or epidural tuberculoma (2/10). MRI is important in the diagnosis of intraspinal tuberculoma, which is characterized by isointensity on T1WI, isointensity, or hypointensity on T2WI, and rim or obvious homogeneous enhancement. Some intraspinal tuberculomas, especially intradural extramedullary tuberculomas, might be associated with the "paradoxical response" mechanism during the tuberculosis treatment.


Rational modification of a dendrimeric peptide with antimicrobial activity: consequences on membrane-binding and biological properties.
Peptide-based antibiotics might help containing the rising tide of antimicrobial resistance. We developed SB056, a semi-synthetic peptide with a dimeric dendrimer scaffold, active against both Gram-negative and Gram-positive bacteria. Being the mechanism of SB056 attributed to disruption of bacterial membranes, we enhanced the amphiphilic profile of the original, empirically derived sequence [WKKIRVRLSA-NH2] by interchanging the first two residues [KWKIRVRLSA-NH2], and explored the effects of this modification on the interaction of peptide, both in linear and dimeric forms, with model membranes and on antimicrobial activity. Results obtained against Escherichia coli and Staphylococcus aureus planktonic strains, with or without salts at physiological concentrations, confirmed the added value of dendrimeric structure over the linear one, especially at physiological ionic strength, and the impact of the higher amphipathicity obtained through sequence modification on enhancing peptide performances. SB056 peptides also displayed intriguing antibiofilm properties. Staphylococcus epidermidis was the most susceptible strain in sessile form, notably to optimized linear analog lin-SB056-1 and the wild-type dendrimer den-SB056. Membrane affinity of all peptides increased with the percentage of negatively charged lipids and was less influenced by the presence of salt in the case of dendrimeric peptides. The analog lin-SB056-1 displayed the highest overall affinity, even for zwitterionic PC bilayers. Thus, in addition to electrostatics, distribution of charged/polar and hydrophobic residues along the sequence might have a significant role in driving peptide-lipid interaction. Supporting this view, dendrimeric analog den-SB056-1 retained greater membrane affinity in the presence of salt than den-SB056, despite the fact that they bear exactly the same net positive charge.


Functional roles of Phe of deacetyl-thymosin beta4 in the impaired blastogenic response of uraemic T-lymphocytes.
Phe(12) of deacetyl-thymosin beta(4) is one of the structural essentials for restorative effect on the impaired blastogenic response of uraemic T-lymphocytes. In order to evaluate the functional roles of this phenyl group in the restorative effect on impaired T-lymphocytes, two analogues, [1- Nal(12)]deacetyl-thymosin beta(4) and [Cha(12)]deacetyl4 thymosin beta(4), were synthesized by a solid-phase method and evaluated for restorative effect on the impaired blastogenic response of uraemic T-lymphocytes. The results indicated that [1-Nal(12)]deacetyl-thymosin beta(4) which had a bulky naphthyl ring showed a stronger restorative effect than that of deacetyl-thymosin beta(4), but it was slightly weaker than that of [Phe(4F)(12)]deacetyl-thymosin beta(4). However, [Cha(12)]deacetyl-thymosin beta(4) showed no restorative effect on the impaired blastogenic response of uraemic T-lymphocytes.


Central respiratory stimulant effect of bombesin in the cat.
Bombesin (0.62-6.2 nmol) was administered into the cisterna magna of chloralose-anesthetized cats while monitoring tracheal airflow with a pneumotachograph. The peptide produced dose-related increases in respiratory activity which were seen primarily as increases in tidal volume. Intravenous administration of bombesin (6.2 nmol) did not cause any respiratory effects. These results indicate that bombesin acts in the brain to stimulate respiration.


MATERNAL DEPRESSION AND CHILD OXYTOCIN RESPONSE; MODERATION BY MATERNAL OXYTOCIN AND RELATIONAL BEHAVIOR.
Maternal postpartum depression (PPD) carries long-term detrimental effects on children's well-being, yet the mechanisms of transmission remain unclear. One possible pathway of vulnerability involves the oxytocinergic (OT) system, which is transferred from mother to child via sensitive caregiving and is disrupted in PPD. A large birth cohort (N = 1983) of women were repeatedly assessed for depression from birth to 6 years. Utilizing an extreme case design, two matched cohorts were formed; mothers chronically depressed from birth to 6 years and nondepressed controls (N = 97, depressed = 41, nondepressed; N = 56). At 6 years, mothers and children underwent psychiatric diagnosis, urinary OT was assayed from mother and child before and after social contact, and mother-child interactions were coded. Baseline OT and OT response of mother and child were interrelated and children of depressed mothers showed low baseline OT and attenuated OT response. Child OT response was negatively predicted by maternal depression, child Axis-I psychopathology, maternal expressed negative affect, and child social withdrawal. Interaction effect of maternal baseline OT and depression emerged. Slope analysis indicated that when maternal OT was medium or low, child OT response was negatively impacted by maternal depression. However, when maternal OT was high, child OT was unaffected, suggesting that maternal OT functionality buffers the effects of depression on the child. Results suggest involvement of the OT system in the cross-generational transfer of vulnerability, as well as resilience, from depressed mothers to their children. Because the OT system is open to interventions that enhance maternal touch and contact, findings have important implications for targeted early dyadic inventions.


Class I antigens of the bovine major histocompatibility system and resistance to the cattle tick (Boophilus microplus) assessed in three different seasons.
Two consecutive calf crops consisting of 141 three-quarters Brahman/one-quarter Shorthorn cattle were assessed for resistance to the Australian cattle tick Boophilus microplus in May, July and October 1983. Although the level of expressed resistance to artificial infestation varied considerably between seasons, the animals maintained very similar rankings for resistance in all three seasons, and the repeatability of tick resistance ranged from 0.59 to 0.82. The cattle were typed for 30 bovine class I lymphocyte antigens. Antigens W6 and CA31 were associated with susceptibility to artificial tick infestation but none of the other lymphocyte antigens showed strong associations with resistance or susceptibility.


Microbiological and Clinical Effects of a Proanthocyanidin-enriched Extract from Rumex acetosa in Periodontally Healthy Carriers of Porphyromonas gingivalis: a Randomized Controlled Pilot Study.
Rumex acetosa significantly inhibits the adhesion of Porphyromonas gingivalis (P. g.) to eukaryotic host cells in vitro. The objective of this randomized placebo-controlled pilot-trial was to analyze effects of a mouth rinse containing 0.8% (w/w) of a quantified proanthocyanidin-enriched extract from Rumex acetosa (RA1) on microbiological, clinical, and cytological parameters in systemically healthy individuals without history of periodontitis, harboring P. g. intraorally. 35 subjects received a supragingival debridement (SD) followed by mouth rinsing (3 times daily) with either RA1 mouth rinse solution (test) or placebo (control) for 7 days as adjunct to routine oral hygiene. Supragingival biofilm samples were taken at screening visit, baseline (BL), 2, 4, 7 and 14 days after SD. P. g. and 11 other oral microorganisms were detected and quantified by rtPCR. Changes in the oral microbiota composition of one test and one control subject were assessed via high throughput 16S rRNS gene amplicon sequencing. Approximal Plaque Index (API) and the modified Sulcular Bleeding Index (SBI) were assessed at BL, 7- and 14-days following SD. Brush biopsies were taken at BL and 14 d following SD. Intergroup comparisons revealed no significant microbiological, cytological, and clinical differences at any timepoint. However, a significant reduction in SBI at day 14 (p = 0.003) and API at day 7 (p = 0.02) and day 14 (p = 0.009) was found in the test group by intragroup comparison. No severe adverse events were observed. The results indicate that RA1 mouth rinse is safe but does not seem to inhibit colonization of P. g. or improve periodontal health following SD.


Development of immunity to incoming radiolabelled larvae in lambs continuously infected with Ostertagia circumcincta.
Infective larvae of Ostertagia circumcincta were radiolabelled with 75selenium by a method which did not affect their viability. Three groups of five-month-old lambs were infected daily with 1000 unlabelled infective larvae for four, eight and 12 weeks, respectively. After each period one of these groups and a group of worm-free controls were challenged with three consecutive daily doses of 1000 radiolabelled third stage larvae. The lambs were killed 13 days after the first dose of challenge larvae and their worm burdens examined. The first indication of immunity was retardation of developing worms observed at four weeks. Resistance to the establishment of incoming worms developed between four and eight weeks and a brief period of population turnover probably took place at this time. Simultaneously a greater inhibition of worm development occurred resulting in an increase in the number of parasites recovered as early fourth stage larvae. By 12 weeks the animals were almost completely immune to incoming worms. The development of resistance to incoming worms correlated with a rise in serum antibody titre and an increase in the number of intraepithelial globule leucocytes in the gastric mucosa.


User acceptance of smart home voice assistant: a comparison among younger, middle-aged, and older adults.
Voice assistants are widely used in smart home environments. This study aimed to investigate user acceptance of a smart home voice assistant. A questionnaire was designed, and 471 Chinese adults were recruited to complete the questionnaire. The data were analyzed using exploratory factor analysis and regression analysis. The results revealed that user requirements of adults were composed of six factors: hedonic motivation and trust (β = .41, p < .001), social influence (β = .22, p < .001), performance expectancy (β = .15, p < .001), effort expectancy (β = .08, p = .018), product features (β = .15, p = .009), and facilitating conditions (β = .06, p = .049). Among these six factors, hedonic motivation and trust are considered the most important. Younger, middle-aged, and older adults differed significantly in their requirements and acceptance of a smart home voice assistant. These findings have implications for the design of smart home voice assistants so that they are more acceptable to younger and older adults. The online version contains supplementary material available at 10.1007/s10209-022-00936-1.


Potassium uptake in the unicellular cyanobacterium Synechocystis sp. strain PCC 6803 mainly depends on a Ktr-like system encoded by slr1509 (ntpJ).
The molecular basis of potassium uptake in cyanobacteria has not been elucidated. However, genes known from other bacteria to encode potassium transporters can be identified in the genome of Synechocystis sp. strain PCC 6803. Mutants defective in kdpA and ntpJ were generated and characterized to address the role of the Kdp and KtrAB systems in this strain. KtrAB is crucial for K(+) uptake, as the DeltantpJ mutant shows slowed growth, slowed potassium uptake kinetics, and increased salt sensitivity. The DeltakdpA mutant has the same phenotype as the wild type even at limiting potassium, but a DeltakdpADeltantpJ double mutant is not viable, indicating a role of Kdp for potassium uptake when the Ktr system is not functioning.


Development of multiscale complexity and multifractality of fetal heart rate variability.
During fetal development a complex system grows and coordination over multiple time scales is formed towards an integrated behavior of the organism. Since essential cardiovascular and associated coordination is mediated by the autonomic nervous system (ANS) and the ANS activity is reflected in recordable heart rate patterns, multiscale heart rate analysis is a tool predestined for the diagnosis of prenatal maturation. The analyses over multiple time scales requires sufficiently long data sets while the recordings of fetal heart rate as well as the behavioral states studied are themselves short. Care must be taken that the analysis methods used are appropriate for short data lengths. We investigated multiscale entropy and multifractal scaling exponents from 30 minute recordings of 27 normal fetuses, aged between 23 and 38 weeks of gestational age (WGA) during the quiet state. In multiscale entropy, we found complexity lower than that of non-correlated white noise over all 20 coarse graining time scales investigated. Significant maturation age related complexity increase was strongest expressed at scale 2, both using sample entropy and generalized mutual information as complexity estimates. Multiscale multifractal analysis (MMA) in which the Hurst surface h(q,s) is calculated, where q is the multifractal parameter and s is the scale, was applied to the fetal heart rate data. MMA is a method derived from detrended fluctuation analysis (DFA). We modified the base algorithm of MMA to be applicable for short time series analysis using overlapping data windows and a reduction of the scale range. We looked for such q and s for which the Hurst exponent h(q,s) is most correlated with gestational age. We used this value of the Hurst exponent to predict the gestational age based only on fetal heart rate variability properties. Comparison with the true age of the fetus gave satisfying results (error 2.17±3.29 weeks; p<0.001; R(2)=0.52). In addition, we found that the normally used DFA scale range is non-optimal for fetal age evaluation. We conclude that 30 min recordings are appropriate and sufficient for assessing fetal age by multiscale entropy and multiscale multifractal analysis. The predominant prognostic role of scale 2 heart beats for MSE and scale 39 heart beats (at q=-0.7) for MMA cannot be explored neither by single scale complexity measures nor by standard detrended fluctuation analysis.


Role of membrane sialic acid content in the adhesiveness of aged erythrocytes to human cultured endothelial cells.
Following our previous observation that the oldest normal red blood cells were the most adherent to human cultured endothelial cells, we attempted to simulate this age-related adherence. Among all the membrane modifications experienced by erythrocytes during their life-span, loss of sialic acids has attracted considerable attention. Using two different preparations of neuraminidase, we performed a sialic acid depletion on the youngest erythrocytes to reach a sialic acid content similar to that observed in physiologically aged erythrocytes. These pretreated youngest cells displayed limited increase in the adhesiveness to endothelial cells, lower than that found with intact oldest cells. To obtain an adhesiveness of pretreated cells similar to that of naturally aged cells, it was necessary to exceed 80% of sialic acid depletion. At this extent of desialation, modifications of the electrophoretic pattern of glycophorins were observed as well as the appearance of peanut agglutinin reactivity which were never found in physiologically aged erythrocytes. Therefore, the sialic acid loss cannot be considered as being a single determinant factor of the naturally aged red cell adhesiveness.


Optimal interdependence between networks for the evolution of cooperation.
Recent research has identified interactions between networks as crucial for the outcome of evolutionary games taking place on them. While the consensus is that interdependence does promote cooperation by means of organizational complexity and enhanced reciprocity that is out of reach on isolated networks, we here address the question just how much interdependence there should be. Intuitively, one might assume the more the better. However, we show that in fact only an intermediate density of sufficiently strong interactions between networks warrants an optimal resolution of social dilemmas. This is due to an intricate interplay between the heterogeneity that causes an asymmetric strategy flow because of the additional links between the networks, and the independent formation of cooperative patterns on each individual network. Presented results are robust to variations of the strategy updating rule, the topology of interdependent networks, and the governing social dilemma, thus suggesting a high degree of universality.


Application of autologous stem cell transplantation in various adult and pediatric rheumatic diseases.
In the past 15 years, more than 1,500 patients worldwide have received a hematopoietic stem cell transplant, mostly autologous, as treatment for a severe autoimmune disease (AD). A recent retrospective analysis of 900 patients showed that the majority had multiple sclerosis, systemic sclerosis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and juvenile idiopathic arthritis (JIA; n = 65) and idiopathic cytopenic purpura. An overall 85% 5-year survival and 43% progression-free survival was seen, with 100-day transplant-related mortality (TRM) ranging between 1% (RA) and 11% (SLE and JIA). Around 30% of patients in all disease subgroups had a complete response, despite full immune reconstitution. In many patients, morphological improvement was documented beyond any predicted known effects of intense immunosuppression alone. It is hoped that the results of three ongoing large prospective, randomized, controlled trials will allow modification of the protocols to reduce the high TRM, which relates to regimen intensity, age of patient, and comorbidity. Multipotent mesenchymal stromal cells (MSCs), including autologous MSCs, have recently been tested in various ADs, exploiting their immune-modulating properties and apparent low acute toxicity. Despite encouraging small phase I/II studies, no positive data from randomized, prospective studies are as yet available in the peer-reviewed literature.


Comparison of vestibular input statistics during natural activities and while piloting an aircraft.
The present study investigates the statistics and spectral content of natural vestibular stimuli experienced by healthy human subjects during three unconstrained activities. More specifically, we assessed how the characteristics of vestibular inputs are altered during the operation of a complex human-machine interface (a flight in a helicopter simulator) compared with more ecological tasks, namely a walk in an office space and a seated visual exploration task. As previously reported, we found that the power spectra of vestibular stimuli experienced during self-navigation could be modeled by two power laws but noted a potential effect of task intensity on the transition frequency between the two fits. In contrast, both tasks that required a seated position had power spectra that were better described by an inverted U shape in all planes of motion. Taken together, our results suggest that 1) walking elicits stereotyped vestibular inputs whose power spectra can be modeled by two power laws that intersect at a task intensity-dependent frequency; 2) body posture induces changes in the frequency content of vestibular information; 3) pilots tend to operate their aircraft in a way that does not generate highly nonecological vestibular stimuli; and 4) nevertheless, human-machine interfaces used as a means of manual navigation still impose some unnatural, contextual constraints on their operators.NEW & NOTEWORTHY Building upon previously published research, this study assesses and compares the vestibular stimuli experienced by healthy subjects in natural tasks and during the interaction with a complex machine: a helicopter simulator. Our results suggest the existence of an anatomical filter, meaning that body posture shapes vestibular spectral content. Our findings further indicate that operators control their machine within a constrained operating range such that they experience vestibular stimulations that are as ecological as possible.


A reversed-phase high-performance liquid chromatographic method for the determination of Clanfenur in rat and human plasma.
A selective and specific high-pressure liquid chromatographic (HPLC) method for the simultaneous assay of Clanfenur and its metabolites in biological fluids of interest has been developed which is suitable for routine analysis, using micro volumes (0.1 ml) of plasma samples only. After protein precipitation the extract is analysed by reversed-phase HPLC with UV detection. Excellent recovery, linearity, accuracy and precision (less than 5% for plasma) are achieved by the assay which is able to quantify Clanfenur and its metabolites in plasma at concentrations between 0.025 and 5.0 mg l-1.


Schiff base-functionalized metal-organic frameworks as an efficient adsorbent for the decontamination of heavy metal ions in water.
Adsorptive removal of heavy metal ions from water is an energy- and cost-effective water decontamination technology. Schiff base functionalities can be incorporated into the pore cages of metal-organic frameworks (MOFs) via direct synthesis, post-synthetic modification, and composite formation. Such incorporation can efficiently enhance the interactions between the MOF adsorbent and target heavy metal ions to promote the selective adsorption of the latter. Accordingly, Schiff base-functionalized MOFs have great potential to selectively remove a particular metal ion from the aqueous solutions in the presence of coexisting (interfering) metal ions through the binding sites within their pore cages. Schiff base-functionalized MOFs can bind divalent metal ions (e.g., Pb(II), Co(II), Cu(II), Cd (II), and Hg (II)) more strongly than trivalent metal ions (e.g., Cr(III)). The adsorption capacity range of Schiff base-functionalized MOFs for divalent ions is thus much more broad (22.4-713 mg g-1) than that of trivalent metal ions (118-127 mg g-1). To evaluate the adsorption performance between different adsorbents, the two parameters (i.e., adsorption capacity and partition coefficient (PC)) are derived and used for comparison. Further, the possible interactions between the Schiff base sites and the target heavy metal ions are discussed to help understand the associated removal mechanisms. This review delivers actionable knowledge for developing Schiff-base functionalized MOFs toward the adsorptive removal of heavy metal ions in water in line with their performance evaluation and associated removal mechanisms. Finally, this review highlights the challenges and forthcoming research and development needs of Schiff base-functionalized MOFs for diverse fields of operations.


Mechanisms of carbachol-induced alterations in K+ transport across the rat colon.
The effect of carbachol, an agonist of the Ca2+ pathway, on K+ transport in rat proximal and distal colon was studied by measuring unidirectional fluxes, uptake, and efflux of Rb+, a marker for K+, in mucosa-submucosa preparations. Unidirectional ion flux measurements revealed that carbachol stimulated K+ secretion in the proximal colon by a marked increase in the serosa-to-mucosa flux (J(Rb)sm) and a more moderate rise in the mucosa-to-serosa flux (J(Rb)ms). In the distal colon carbachol had no effect on J(Rb)ms but J(Rb)sm was reduced after a transient increase finally resulting in an inhibition of K+ secretion. Carbachol caused a stimulation of mucosal Rb+ uptake in the distal colon, which was diminished in the presence of inhibitors of the apical H+-K+-ATPase, vanadate and ouabain. In contrast, in the proximal colon the serosal Rb+ uptake was enhanced by carbachol, an effect, which could be prevented by bumetanide, an inhibitor of the basolateral Na+-K+-2Cl(-)-cotransporter. Efflux experiments revealed that carbachol caused a transient increase of apical and basolateral Rb+ permeability in both colonic segments. In the distal colon, stimulated K+ efflux to the serosal side was reduced by quinine, efflux to the mucosal side was blocked by tetraethylammonium. In the proximal colon, carbachol-activated apical and basolateral K+ efflux were inhibited by Ba2+. In conclusion, these data suggest that in the distal colon carbachol stimulates the H+-K+-ATPase and the basolateral K+ efflux through quinine-sensitive K+ channels, whereas in the proximal colon carbachol induces K+ secretion due to a stimulation of the basolateral Na+-K+-2Cl(-)-cotransporter and an increased efflux to the luminal side via Ba2+-sensitive apical K+ channels.


Brain regions mediating alpha3beta4 nicotinic antagonist effects of 18-MC on methamphetamine and sucrose self-administration.
The novel iboga alkaloid congener 18-methoxycoronaridine (18-MC) is a putative anti-addictive agent that has been shown, in rats, to decrease the self-administration of several drugs of abuse. Previous work has established that 18-MC is a potent antagonist at alpha3beta4 nicotinic receptors. Because high densities of alpha3beta4 nicotinic receptors occur in the medial habenula and the interpeduncular nucleus and moderate densities occur in the dorsolateral tegmentum, ventral tegmental area, and basolateral amygdala, the present study was conducted to determine if 18-MC could act in these brain areas to modulate methamphetamine self-administration in rats. Local administration of 18-MC into either the medial habenula, the interpeduncular area or the basolateral amygdala decreased methamphetamine self-administration. Similar results were produced by local administration into the same brain areas of two other alpha3beta4 nicotinic antagonists, mecamylamine and alpha-conotoxin AuIB. Local administration of 18-MC, or the other antagonists, into the dorsolateral tegmentum or the ventral tegmental area had no effect on methamphetamine self-administration. In contrast, local administration of 18-MC and the other antagonists decreased sucrose self-administration when administered into the dorsolateral tegmentum or basolateral amygdala but had no effect when infused into the medial habenula, interpeduncular nucleus, or ventral tegmental area. These data are consistent with the hypothesis that 18-MC decreases methamphetamine self-administration by indirectly modulating the dopaminergic mesolimbic pathway via blockade of alpha3beta4 nicotinic receptors in the habenulo-interpeduncular pathway and the basolateral amygdala. The data also suggest that the basolateral amygdala along with a different pathway involving alpha3beta4 receptors in the dorsolateral tegmentum mediate the effect of 18-MC on sucrose self-administration.


Solution-oriented research for paediatric burn prevention in Mongolia: An assessment of prevention tools.
Child burn injuries in Mongolia are often caused by electric cooking appliances used on the floor or low table in traditional tent-like dwellings (called a ger) which have no separate kitchen. To prevent these injuries, we developed a context-specific kitchen rack to make electric appliances inaccessible to children, and the rack was provided to 50 families with children aged 0-3 years living in gers for a pilot test. In the present study, we investigated their opinions about the rack after they used it for about 10 months through semi-structured interviews, their willingness-to-pay (WTP) for the rack using a contingent valuation method, and their preference for potential modifications of the rack using best-worst scaling. The estimated median WTP was about USD 40 (which was higher than USD 37 at the baseline when they started to use the rack). The highest priority of modifications of the rack was to enclose the lower section of the rack with doors (which was originally open without doors to reduce the production cost). A few families did not use the rack in winter because they used heating stoves instead of electric appliances for cooking, but we found a unanimous view that the rack reduces burn injuries to children, which may be reflected in their increased WTP for the rack. These findings would guide us to make our burn prevention efforts more relevant to real-life situations and socially acceptable in Mongolia.


Separation and maintenance of normal cells from human embryonic stem cells with trisomy 12 mosaicism.
Human embryonic stem cells (hESCs) are pluripotent and hold great promise as useful tools in basic scientific research and in the field of regenerative medicine. However, several studies have recently reported chromosomal abnormalities such as gains of chromosomes 12, 17 and X in hESCs. This genetic instability presents an obstacle in the application of hESCs as sources of cell therapies. We found that trisomy 12 was correlated with changes in hESC colony morphology during hESC maintenance. In this study, we investigated whether normal and trisomy 12 cells could be separated in hESC cultures displaying trisomy 12 mosaicism with two types of colony morphology using a mechanical transfer technique. Eight sublines were cultured from eight hESC colonies displaying normal or abnormal morphology. Four sublines with normal morphology had normal chromosome 12 numbers, whereas the four sublines with abnormal morphology displayed trisomy 12. These results indicate that a hESC colony with a minor degree of chromosomal mosaicism and normal morphology could proceed to a colony with normal chromosomes after prolonged cultures with mechanical transfer. Therefore, analysis of cultures for chromosomal abnormalities when changes in colony morphology are observed during culture is essential for maintaining normal hESC lines.


Sources of stress among families caring for relatives with Alzheimer's disease.
We have described the different sources of stress and burden that are imposed by caring for a family member with AD. We have provided an approach to assessing each of these possible sources of stress and burden and have indicated how such assessments must take a family-based approach and consider the broader social roles and family dynamics that may color the way in which family members view and carry out their caregiving roles.