Perceptions of physiotherapy clinical educators' dual roles as mentors and assessors: Influence on teaching-learning relationships.
Central to clinical education is the teaching-learning (T-L) relationship that evolves between the clinical educator (CE) and the student. Within this T-L relationship, CEs may be expected to fulfil dual roles as mentors and assessors of students. Challenges for both parties may arise when CEs take on these different roles. The goal of this study was to ascertain how CEs perceived the influence of their dual roles as mentors and assessors on their T-L relationships with physiotherapy students. Individual interviews were semi-structured with nine CEs during this qualitative descriptive study at the Division of Physiotherapy, Faculty of Medicine and Health Sciences, Stellenbosch University. A content analysis followed to analyse the data obtained. An iterative process, aimed to understand the phenomena under study, was conducted via an interpretive approach in context. This revealed main themes that were identified and refined. Clinical educators experienced challenges when their role changed from being a mentor to that of assessor. These challenges affected the learning of students, as they influenced the T-L relationship. Clinical educators experienced ambiguities regarding their dual roles and, as a result, their expectations were often not fulfilled. Students' learning processes were negatively affected by the changing roles of CEs, who acted as mentors and later as assessors of clinical competence during the students' clinical rotations. The positioning theory was offered as a framework to resolve the challenges created by the dual roles and to manage expectations between CEs and students. The T-L encounters could be enhanced if students and CEs aligned themselves to a learning-centred paradigm where the focus was on learning and where the needs of the diverse students and the expectations of CEs were balanced. Further research should explore how a workshop with role play, demonstrating to CEs in practice how to reposition themselves, would impact the relationships between both parties. It is essential to ensure a positive T-L relationship between a CE and a student as this will improve the quality of learning in the clinical environment and, therefore, directly influence student's patient management. Implementing faculty development programmes to address this, should be further explored. physiotherapy; clinical education; teaching-learning relationship; learning-centred; dual roles.


Aerobic exercise training increases circulating insulin-like growth factor binding protein-1 concentration, but does not attenuate the reduction in circulating insulin-like growth factor binding protein-1 after a high-fat meal.
Insulin-like growth factor binding protein-1 (IGFBP-1) has metabolic effects throughout the body, and its expression is regulated in part by insulin. Circulating IGFBP-1 predicts development of cardiometabolic diseases in longitudinal studies, and low IGFBP-1 concentrations are associated with insulin resistance and consumption of a high-fat diet. Because of the favorable metabolic effects of regular aerobic exercise, we hypothesized that aerobic exercise training would increase plasma IGFBP-1 concentrations and attenuate the reduction in IGFBP-1 after a high-fat meal. Ten overweight (body mass index = 28.7 ± 0.9 kg/m(2)), older (61 ± 2 years) men and women underwent high-fat feeding and oral glucose tolerance tests at baseline and after 6 months of aerobic exercise training. In response to aerobic exercise training, subjects increased cardiorespiratory fitness by 13% (P < .05) and insulin sensitivity index by 28% (P < .05). Basal plasma concentrations of IGFBP-1 increased by 41% after aerobic exercise training (P < .05). The insulin response to an oral glucose tolerance test was a significant predictor of fasting plasma IGFBP-1 concentrations at baseline and after exercise training (P = .02). In response to the high-fat meal at baseline, plasma IGFBP-1 concentrations decreased by 58% (P < .001); a 61% decrease to similar postprandial concentrations was observed after exercise training (P < .001). Plasma insulin response to the high-fat meal was inversely associated with postprandial IGFBP-1 concentrations at baseline and after exercise training (P = .06 and P < .05, respectively). Although aerobic exercise training did not attenuate the response to a high-fat meal, the increase in IGFBP-1 concentrations after exercise training may be one mechanism by which exercise reduces risk for cardiometabolic diseases in older adults.


Preoperative fasting in children: An audit and its implications in a tertiary care hospital.
Prolonged preoperative fasting in children is a common problem, especially in highvolume centers. All international professional society guidelines for preoperative fasting recommend 2 h for clear fluids, 4 h for breast milk and 6 h for solids, nonhuman and formula milk in children. These guidelines are rarely adhered to in practice. An audit was undertaken to determine the length of preoperative fasting time in children and its causes. Cross-sectional study of 50 children below 15 years posted for elective surgeries. An initial audit was performed at our institution on preoperative fasting time in 50 children below 15 years of age for elective surgeries. The mean preoperative fasting times were found to be much longer than the recommended times. Ward nurses were then educated about internationally recommended preoperative fasting guidelines in children. Anesthesiologists started coordinating with surgeons and ward nurses to prescribe water for children waiting for more than 2 h based on changes in surgery schedule by instructing ward nurses through telephone on the day of surgery. A reaudit was done 6 months after the initial audit. SPSS 16 software. The initial audit revealed a mean preoperative fasting time of 11.25 h and 9.25 h for solids and water, respectively. Incorrect orders by ward nurses (74%) and change in the surgical schedule (32%) were important causes. After changing the preoperative system, mean preoperative fasting times in children decreased to 9 h and 4 h for solids and water, respectively in reaudit. Change in surgical schedule (30%) was the major cause for prolonged preoperative fasting in reaudit. Simple steps such as education of ward nurses and better coordination among the anesthesiologists, surgeons and nurses can greatly reduce unnecessary preoperative starvation in children.


Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation, and Bcl-X(L) levels in vivo.
The serine/threonine kinase protein kinase B (PKB)/Akt mediates cell survival in a variety of systems. We have generated transgenic mice expressing a constitutively active form of PKB (gag-PKB) to examine the effects of PKB activity on T lymphocyte survival. Thymocytes and mature T cells overexpressing gag-PKB displayed increased active PKB, enhanced viability in culture, and resistance to a variety of apoptotic stimuli. PKB activity prolonged the survival of CD4(+)CD8(+) double positive (DP) thymocytes in fetal thymic organ culture, but was unable to prevent antigen-induced clonal deletion of thymocytes expressing the major histocompatibility complex class I-restricted P14 T cell receptor (TCR). In mature T lymphocytes, PKB can be activated in response to TCR stimulation, and peptide-antigen-specific proliferation is enhanced in T cells expressing the gag-PKB transgene. Both thymocytes and T cells overexpressing gag-PKB displayed elevated levels of the antiapoptotic molecule Bcl-X(L). In addition, the activation of peripheral T cells led to enhanced nuclear factor (NF)-kappaB activation via accelerated degradation of the NF-kappaB inhibitory protein IkappaBalpha. Our data highlight a physiological role for PKB in promoting survival of DP thymocytes and mature T cells, and provide evidence for the direct association of three major survival molecules (PKB, Bcl-X(L), and NF-kappaB) in vivo in T lymphocytes.


Controlling fullerene addition sequences, regioselectivity and magic numbers via metal encapsulation.
A systematic density functional study of chlorine addition to C(70) up to C(70)Cl(12) confirms experimental observations of regioselectivity and stability of C(70)Cl(10). We show that K@C(70) follows an alternative addition sequence with different isomers and magic numbers to C(70) such as KC(70)Cl(3). This prediction is important for controlling functionalisation behaviour via encapsulation and endofullerene purification.


EblacZ tumor dormancy in bone marrow and lymph nodes: active control of proliferating tumor cells by CD8+ immune T cells.
A well-defined lacZ gene tagged DBA/2 lymphoma (EblacZ) was used to examine the role of host immune responses in controlling tumor dissemination and persistence, as well as metastasis. In s.c. and intra-ear pinna-inoculated mice, low numbers of EblacZ cells homed to the bone marrow and lymph nodes. The frequency of bone marrow-residing tumor cells did not change with the growth of primary tumor or with multiple inoculations of tumor cells. The bone marrow-residing tumor cells expressed the proliferation-associated Ki67 antigen and expanded upon CD8+ depletion. In contrast, inoculation of nu/nu or severe combined immunodeficiency mice or of immune-suppressed DBA/2 mice led to the rapid outgrowth of EblacZ cells in the bone marrow and their metastasis to other organs. Transfer of bone marrow from EblacZ immunized MHC congenic or syngeneic DBA/2 donors, but not from naive donors, protected s.c.-inoculated DBA/2 mice. Protection was abrogated by in vitro depletion of CD8+ T cells prior to transfer of bone marrow. These experiments show that bone marrow and lymph nodes are privileged sites where potentially lethal tumor cells are controlled in a dormant state by the immune system. Metastasis may be a consequence of the breakdown of this immune control.


Antioxidant and antiproliferative activities of Desmodium triflorum (L.) DC.
This study evaluated the antioxidant and antiproliferative activities of the crude extract and fractions of Desmodium triflorum (L.) DC. The total phenolic content, 1,1-diphenyl-2- picrylhydrazyl hydrate (DPPH) free radical scavenging activity, trolox equivalent antioxidant capacity (TEAC), reducing power, total flavonoid content of D. triflorum were evaluated for the exploration of its antioxidant activities. Furthermore, its antiproliferative activities were investigated through the MTT method. It was compared with the antioxidant capacities of known antioxidants, including catechin, alpha-tocopherol, trolox and ascorbic acid. Among all fractions, ethyl acetate fraction was the most active in scavenging DPPH and TEAC radicals, of which 0.4 mg was equivalent to 186.6 +/- 2.5 microg and 82.5 +/- 2.1 microg of alpha-tocopherol and trolox respectively. The total phenolic and flavonoid contents of the crude extract were equivalent to 36.60 +/- 0.1 mg catechin and 45.6 +/- 0.6 mg rutin per gram respectively. In the reducing power assay, 1.25 mg of crude extract was similar to 61.2 +/- 0.3 microg of ascorbic acid. For the assessment of the safety and toxicity of D. triflorum, LD(50) of the crude extract was greater than 10 g/kg when administered to mice through gastric intubation. The above experimental data indicated that D. triflorum was a potent antioxidant medicinal plant, and such efficacy may be mainly attributed to its polyphenolic compounds.


Vertebral pneumaticity is correlated with serial variation in vertebral shape in storks.
Birds and their ornithodiran ancestors are unique among vertebrates in exhibiting air-filled sinuses in their postcranial bones, a phenomenon called postcranial skeletal pneumaticity. The factors that account for serial and interspecific variation in postcranial skeletal pneumaticity are poorly understood, although body size, ecology, and bone biomechanics have all been implicated as influencing the extent to which pneumatizing epithelia invade the skeleton and induce bone resorption. Here, I use high-resolution computed-tomography to holistically quantify vertebral pneumaticity in members of the neognath family Ciconiidae (storks), with pneumaticity measured as the relative volume of internal air space. These data are used to describe serial variation in extent of pneumaticity and to assess whether and how pneumaticity varies with the size and shape of a vertebra. Pneumaticity increases dramatically from the middle of the neck onwards, contrary to previous predictions that cervical pneumaticity should decrease toward the thorax to maintain structural integrity as the mass and bending moments of the neck increase. Although the largest vertebrae sampled are also the most pneumatic, vertebral size cannot on its own account for serial or interspecific variation in extent of pneumaticity. Vertebral shape, as quantified by three-dimensional geometric morphometrics, is found to be significantly correlated with extent of pneumaticity, with elongate vertebrae being less pneumatic than craniocaudally short and dorsoventrally tall vertebrae. Considered together, the results of this study are consistent with the hypothesis that shape- and position-specific biomechanics influence the amount of bone loss that can be safely tolerated. These results have potentially important implications for the evolution of vertebral morphology in birds and their extinct relatives.


Automatic analysis of moving images.
Cine film and videotape are used to record a variety of natural processes in biology, medicine, meteorology, etc. This paper describes a system which detects and tracks moving objects from these records to obtain meaningful measures of their movements, such as linear and angular velocities. Features of the system are as follows. 1) In order to detect moving objects that are usually blurred, temporal differences of gray values (differences between consecutive frames) are used to separate moving objects from stationary objects, in addition to spatial differences of gray values. 2) The results of previous frames are used to guide feature extraction process of the next frame so that efficient processing of moving pictures which consists of a large number of frames is possible. 3) Uncertain parts in the current frame, such as occluded objects, are deduced using information of previous frames. 4) Misinterpreted or unknown parts in previous frames are reanalyzed using the results of later frames where those parts could be found.


Addison's other disease: primary biliary cirrhosis as a model autoimmune disease.
Thomas Addison described three of the classical autoimmune diseases, so can justifiably be regarded as one of the fathers of the study of autoimmunity. The least well recognised of these conditions, the autoimmune liver disease primary biliary cirrhosis (PBC), is in some ways the most interesting. As a result of the relatively advanced state of knowledge of its immunopathogenesis, it represents a good model for the study of autoimmune disease. The classical pathological lesion of PBC is apoptotic damage to the biliary epithelial cells lining the small intrahepatic bile ducts. The disease is typified by two symptom sets: fatigue and pruritus, which can occur at any stage of the disease process, and the features of advanced liver disease, which occur when secondary liver damage results from bile retention. Although autoantibodies directed at, in particular, pyruvate dehydrogenase complex (PDC) are almost universally present in PBC (and represent an important diagnostic tool), it appears likely that CD8+ cytotoxic T cells reactive with self-PDC derived epitopes are directly responsible for target cell damage. Recent studies in humans and a novel murine disease model have shed light on the mechanism of breakdown of immune tolerance to self-PDC; they provide important insights into the pathogenesis of PBC in particular and of autoimmunity in general.


Correction of intraocular pressure for changes in central corneal thickness following photorefractive keratectomy.
To investigate the relation between measurements of intraocular pressure (IOP) and central corneal thickness (CCT) in myopic patients undergoing photorefractive keratectomy (PRK). Descriptive study. University-affiliated eye care centre in Ottawa. A total of 481 consecutive eyes of 318 patients with a mean preoperative refractive error of -6.50 dioptres treated with excimer PRK between March 1993 and December 1996. IOP measured by Goldmann applanation tonometry and CCT before and 3, 6, 12, 18 and 24 months after surgery. CCT was a significant predictor of IOP only before PRK and 6 months after PRK (p < or = 0.05). The relation between IOP and CCT suggests corrections for CCT that are not clinically significant (0.81 mm Hg [standard error (SE) 0.33 mm Hg] and 1.00 mm Hg [SE 0.38 mm Hg] per 100 microns of corneal thinning preoperatively and at 6 months respectively). On average, there was a significant decrease in IOP after PRK (0.96 mm Hg and 1.24 mm Hg at 12 and 24 months respectively) (p < 0.05). There was a significant correlation between change in IOP and change in CCT (decrease of 2.1 mm Hg per 100 microns of corneal thinning) (p < 0.05). For a given change in CCT, individual changes in IOP were variable, with increases or decreases of more than 5 mm Hg in some cases. There are individual differences in IOP changes following PRK. Until further data are available we propose that the change in IOP between the preoperative visit (or the fellow eye, if healthy or untreated) and the 12-month visit be used as an individual correction factor to be applied to IOP measurements in the operated eye.


The measurement of functioning using the International Classification of Functioning, Disability and Health: comparing qualifier ratings with existing health status instruments.
The International Classification of Functioning, Disability and Health is the international standard for describing and monitoring functioning. While the categories, the units of the classification, were not designed with measurement in mind, the hierarchical structure of the classification lends itself to the possibility of summating categories into some higher order domain. Focusing on the chapters of d4 Mobility, d5 Self-Care and d6 Domestic Life, this study seeks to ascertain if qualifiers rating of categories (0-No problem to 4-Complete problem) within those chapters can be summated, and whether such derived measurement is consistent with estimates obtained from well-known instruments which purport to measure the same constructs. The current study applies secondary analysis to data previously collected in the context of validating Core Sets for stroke, rheumatoid arthritis, and osteoarthritis. Data included qualifier-based ratings of the categories in the Core Sets, and the physical functioning sub-scale of the Short-Form 36, and the World Health Organization Disability Assessment Schedule 2.0. To examine qualifier-comparator scale item agreement Kappa statistics were used. To identify whether appropriate gradients of the comparator scales were observed across qualifier levels, an Independent Sample Median Test of the ordinal scores was deployed. To investigate the internal validity of the summated ICF categories, the Rasch model was applied. Data from 2,927 subjects from Europe, Australasia, Middle East and South America were available for analysis; 36.3% had experienced a stroke, 35.8% osteoarthritis, and 27.9% had rheumatoid arthritis. The items from the Short-Form 36 could not match directly the qualifier categories as the former had only 3 response options. The Kappa between World Health Organization Disability Assessment Schedule 2.0 items and categories was low. For all qualifiers, a significant (<0.001) overall gradient was observed across the comparator scales. Only in few of the World Health Organization Disability Assessment Schedule 2.0 items could no discrete level be detected. The aggregation of the qualifiers at the Chapter and higher order levels mostly revealed fit to the Rasch model. Almost all ICF qualifiers showed ordered thresholds suggesting that the current structure and response options of the qualifiers worked as intended. The findings of this study provide supporting evidence for the use of the professionally rated categories and associated qualifiers to measure functioning. Implication for Rehabilitation This study provides evidence that functioning data can be collected directly with the International Classification of Functioning, Disability and Health (ICF) by using the ICF categories as items and the ICF qualifiers as rating scale. The findings of this study show the aggregated ratings of ICF categories from the chapters d4 Mobility, d5 Self-care, and d6 Domestic life capture a broader spectrum of the construct than the corresponding summated items from the SF36-Physical Function sub-scale and the corresponding items of the World Health Organization Disability Assessment Schedule 2.0. This study illustrates the potential of building quantitative measurement by aggregating ICF categories and their qualifier ratings into meaningful domains.


Study on cortisol, cortisone and prednisolone presence in urine of Chianina cattle breed.
The Chianina, one of the oldest and most important cattle breeds of Italy, is now reared all over the world. The Chianina has been known and appreciated since ancient times because, from a nutritional point of view, its meat has no proper rivals. To date, studies have been performed to evaluate the genetic profile of the breed, but knowledge about the chemical profile is generally lacking. Due to the increased interest from farmers regarding breeding of the Chianina, this study proposes a preliminary evaluation of main endogenous urinary corticosteroids (cortisol and cortisone) and most commonly used synthetic one (dexamethasone). Moreover, after recent findings regarding the presence of endogenous prednisolone in the urine of more popular breeds, particular attention was given to analysis of the presence of prednisolone and prednisone, as well. For this aim, the urine samples of 12 young cows and 30 young bulls was collected at the farms and analysed using a fit-for-purpose LC-MS/MS method. The preliminary results of this study show that prednisolone was found only in Chianina females (3 out of 12). Cortisol and cortisone were found at concentrations that showed a high inter-individual variability, and that were higher in female urine compared to that of males.


Field screening of blood lead levels in remote Andean villages.
Blood lead (PbB) levels were investigated in chronically lead (Pb) exposed Andean children and adults living in a highly Pb contaminated area of Ecuador where Pb glazing of ceramics is prevalent. A comparative study was made of the PbB levels of Pb-glazing and non-Pb-glazing families living in close proximity, using three PbB analysis techniques. Fifty-one, 50-microl blood samples from children and adults were analyzed in the field by a finger-stick capillary screening technique using the portable ESA LeadCare Blood Lead Testing System (LCS). Venous blood samples of 2-4 ml were collected from the same 51 participants and analyzed in the laboratory by inductively coupled plasma mass spectrometry (ICP-MS) and by graphite furnace atomic absorption spectrometry (AAS). The median PbB levels for the Pb-glazing group as determined by the ICP-MS, AAS and LCS techniques were 37.2 microg/dl (range 11.6-101.0), 32.0 microg/dl (range 8.0-70.0 microg/dl) and 44.0 microg/dl (range 19.0-105.0), respectively. The median PbB levels for the non-Pb-glazing group were 9.2 microg/dl (range 5.0-21.7) with ICP-MS, 9.0 microg/dl (range 4.3-32.0) with AAS, and 11.3 microg/dl (range 7.3-21.1) with LCS. The differences in PbB levels between the Pb glazing and non-Pb glazing groups were statistically significant (p = < .0001) for each PbB analysis method. Correlations between paired samples were: LCS and ICP-MS: r = 0.913, LCS and AAS: r = 0.829, and ICP-MS and AAS: r = 0.905. The results suggest that neighboring Pb glazing and non-Pb glazing families have significantly different PbB levels, and that the portable LCS field technique may be useful for screening and periodic monitoring of relatively low and high PbB levels of persons in remote high altitude Andean areas.


High circulating angiopoietin-2 levels exacerbate pulmonary inflammation but not vascular leak or mortality in endotoxin-induced lung injury in mice.
Elevated plasma levels of angiopoietin-2 (ANGPT2) have been reported in patients with acute lung injury (ALI); however, it remains unclear whether this increase contributes to, or just marks, the underlying vasculopathic inflammation and leak associated with ALI. Here we investigated the biological consequences of inducing high circulating levels of ANGPT2 in a mouse model of endotoxin-induced ALI. Transgenic mice (ANGPT2OVR) with elevated circulating levels of ANGPT2, achieved through conditional hepatocyte-specific overexpression, were examined from 3 to 72 hours following lipopolysaccharide (LPS)-induced ALI. An aptamer-based inhibitor was used to neutralise the effects of circulating ANGPT2 in LPS-exposed ANGPT2OVR mice. Total cells, neutrophils and macrophages, as well as inflammatory cytokines, were significantly higher in bronchoalveolar lavage (BAL) of ANGPT2OVR versus littermate controltTA mice at 48 hours and 6 hours post-LPS, respectively. In contrast, LPS-induced vascular leak, evidenced by total BAL protein levels and lung wet/dry ratio, was unchanged between ANGPT2OVR and controlstTA, while BAL levels of IgM and albumin were decreased in ANGPT2OVR mice between 24 hours and 48 hours suggesting a partial attenuation of vascular leak. There was no significant difference in LPS-induced mortality between ANGPT2OVR and controlstTA. An ANGPT2-neutralising aptamer partially attenuated alveolar cell infiltration while exacerbating vascular leak in LPS-exposed ANGPT2OVR mice, supported by underlying time-dependent changes in the lung transcriptional profiles of multiple genes linked to neutrophil recruitment/adhesion and endothelial integrity. Our findings suggest that high circulating ANGPT2 potentiates endotoxin-induced lung inflammation but may also exert other pleiotropic effects to help fine-tune the vascular response to lung injury.


Molecular and serological prevalence of Babesia bovis and Babesia bigemina in water buffaloes in the north region of Brazil.
Bovine babesiosis is a tick-borne disease caused mainly by Babesia bovis and Babesia bigemina, which are associated to considerable economic losses in cattle herds worldwide. Approximately 60% of buffalo herds in South America are located in Northern Brazil. Little is known about the impact of babesiosis on buffalo herds in Brazil. The present work aimed to verify the occurrence of B. bovis and B. bigemina in 542 water buffaloes in the state of Pará, Northern Brazil, using molecular and serological techniques. The percentage of seropositive animals for B. bovis and B. bigemina was 41.2% and 19.0%, respectively, by ELISA. B. bovis and B. bigemina DNA were detected in 15 and 16% of sampled buffaloes, respectively. A high correlation (Kappa index of 0.9) between serological and molecular tests suggests that the combination of the utilized techniques in the present study is suitable for babesiosis diagnosis in an endemic unstable area. Significantly difference of positivity for serological and molecular assays was verified to localities and reproductive status of sampled animals, but not between buffalo breeds. The immune status of sampled buffaloes associated to the circulation of babesiosis agents in sampled population suggests that the studied area is at risk to clinical babesiosis outbreaks. Furthermore, this study demonstrated that this region can be classified as endemically unstable.


Real-time atlas-based stereotactic neuronavigation.
Surgery for tumors in eloquent brain faces immense challenges when attempting to maximize resection and avoid neurological deficits. In order to give the surgeon real-time atlas-based anatomic information linked to the patient's anatomy, we developed a software-based interface between deformable anatomic templates (DATs) and an intraoperative navigation system. Magnetic resonance imaging (MRI), diffusion tensor imaging, and/or functional MRI were performed on 3 patients preoperatively for the purposes of tumor resection by the use of neuronavigation. The DAT was registered to the patients' navigation coordinate system and utilized coordinates from the navigation system during surgery. This provided the surgeon with a list of proximal anatomic and functional structures and a real-time image of the atlas at that location fused to the patient's MRI. The clinical feasibility of this approach was evaluated during the resection of 3 eloquent tumors (right postcentral gyrus, left inferior frontal gyrus, and left occipital cuneus gyrus). Tumor resection was performed successfully in all 3 patients. With the use of the coordinates from the navigation system, anatomic and functional structures and their distances were visualized interactively during tumor resection by using the DAT. This is a proof of concept that an interactive atlas-based navigation can provide detailed anatomic and functional information that supplements MRI, diffusion tensor imaging, and functional MRI. The atlas-based navigation generated distances to important anatomic structures from the navigation probe tip. It can be used to guide direct electrical stimulation and highlight areas to avoid during tumor resection. DAT, deformable anatomic templateDES, direct electrical stimulationDTI, diffusion tensor imagingfMRI, functional magnetic resonance imaging.


Room temperature continuous-wave lasing in photonic crystal nanocavity.
We demonstrate room temperature continuous-wave laser operation at 1.3 mum in a photonic crystal nanocavity with InAs/GaAs self-assembled quantum dots by optical pumping. By analyzing a coupled rate equation and the experimental light-light characteristic plot, we evaluate the spontaneous emission coupling factor of the laser to be ~ 0.22. Three-dimensional carrier confinement and a low transparent carrier density due to volume effect in a quantum dot system play important roles in the cw laser operation at room temperature as well as a high quality factor photonic crystal nanocavity.


Evolutionary Scenarios and Primate Natural History.
Scenarios summarize evolutionary patterns and processes by interpreting organismal traits and their natural history correlates in a phylogenetic context. They are constructed by (1) describing phenotypes (including physiology and behavior), ideally with attention to formative roles of development, experience, and culture; (2) inferring homologies, homoplasies, ancestral character states, and their transformations with phylogenetic analyses; and (3) integrating those components with ecological and other ancillary data. At their best, evolutionary scenarios are factually dense narratives that entail no known falsehoods; their empirical and methodological shortcomings are transparent, they might be rejected based on new discoveries, and their potential ideological pitfalls are flagged for scrutiny. They are exemplified here by homoplastic foraging with percussive tools by humans, chimpanzees, capuchins, and macaques; homoplastic hunting with spears by humans and chimpanzees; and private experiences (e.g., sense of fairness, grief) among diverse animals, the homologous or homoplastic status of which often remains unexplored. Although scenarios are problematic when used to bolster political agendas, if constructed carefully and regarded skeptically, they can synthesize knowledge, inspire research, engender public understanding of evolution, enrich ethical debates, and provide a deeper historical context for conservation, including nature appreciation.


Individual monitoring of immune response in Atlantic salmon Salmo salar following experimental infection with piscine myocarditis virus (PMCV), agent of cardiomyopathy syndrome (CMS).
Piscine myocarditis virus (PCMV) is a double-stranded RNA virus structurally similar to the Totiviridae family. PCMV is the causative agent of cardiomyopathy syndrome (CMS), a severe cardiac disease that affects farmed Atlantic salmon (Salmo salar). A recent study characterized the host immune response in infected salmon through a transcriptome immune profiling, which confirmed a high regulation of immune and anti-viral genes throughout infection with PCMV. Previously we developed a novel model based on repeated non-lethal blood sampling, enabling the individual monitoring of salmonids during an infection. In the present work, we used this model to describe the host immune response in the blood cells of Atlantic salmon after intramuscular infection with PCMV-containing tissue homogenate over a 77-day period. At the final stage heart samples were also collected to verify the PCMV load, the pathological impact of infection and to compare the transcript profiles to blood. The expression level of a range of key immune genes was determined in the blood and heart samples by real-time PCR. Results indicated selected immune genes (mx, cd8α and γip) were up-regulated in the heart tissue of infected animals at the terminal time point, in comparison to the non-infected fish. When analyzing the blood samples over the course of infection, a significant n up-regulation of mx gene was also observed. The time and number of peaks in the kinetics of expression was different between individuals. The PCMV load and CMS pathology was verified by real-time PCR and histopathology, respectively. No pathogen and no pathology could be detected during the course of the experiment except at the terminal stage (viral load by qPCR and pathology by histology). This study emphasizes the value of non-lethal monitoring for evaluating the health status of fish at early stages of infection and in the absence of clinical signs.


Stillbirth following previous cesarean section in Bavaria/Germany 1987-2005.
An elevated risk for unexplained stillbirth in subsequent pregnancies after cesarean section was reported in 2003. This finding would imply renewed discussions about stronger indications for cesarean sections. To find out whether there is an elevated risk for stillbirth in subsequent pregnancies after cesarean section in our cohort in Bavaria. As data linkage of records is not possible in Germany, we devised a suitable adjustment for bias correction. Second pregnancies in Bavaria/Germany after previous vaginal birth and previous cesarean section from 1987 to 2005 were analyzed. Risk of unexplained stillbirth was estimated by time-to-event analysis. In our cohort of 629,815 second pregnancies, no elevated stillbirth risk in pregnancies after previous cesarean section compared to previous vaginal birth was noted (crude risk 0.22% in both groups; hazard ratio (HR) 1.00; P = 1.0). A slightly decreased risk for stillbirth after previous cesarean section for the period of 1994-2005 (HR 0.674; P = 0.04) could be shown. We found no elevated stillbirth risk in pregnancies after previous cesarean section. The significantly lower risk for stillbirths after previous cesarean section in the period 1994-2005 is interpreted as consequence of improved obstetric surveillance. With our adjustment for bias correction, we hope to have found a way to make our data largely comparable with other sources reported in the literature. However, because of the strict German data protection act, the Bavarian birth register is only of limited use for the presented study.


Risk of breast cancer following exposure to tetrachloroethylene-contaminated drinking water in Cape Cod, Massachusetts: reanalysis of a case-control study using a modified exposure assessment.
Tetrachloroethylene (PCE) is an important occupational chemical used in metal degreasing and drycleaning and a prevalent drinking water contaminant. Exposure often occurs with other chemicals but it occurred alone in a pattern that reduced the likelihood of confounding in a unique scenario on Cape Cod, Massachusetts. We previously found a small to moderate increased risk of breast cancer among women with the highest exposures using a simple exposure model. We have taken advantage of technical improvements in publically available software to incorporate a more sophisticated determination of water flow and direction to see if previous results were robust to more accurate exposure assessment. The current analysis used PCE exposure estimates generated with the addition of water distribution modeling software (EPANET 2.0) to test model assumptions, compare exposure distributions to prior methods, and re-examine the risk of breast cancer. In addition, we applied data smoothing to examine nonlinear relationships between breast cancer and exposure. We also compared a set of measured PCE concentrations in water samples collected in 1980 to modeled estimates. Thirty-nine percent of individuals considered unexposed in prior epidemiological analyses were considered exposed using the current method, but mostly at low exposure levels. As a result, the exposure distribution was shifted downward resulting in a lower value for the 90th percentile, the definition of "high exposure" in prior analyses. The current analyses confirmed a modest increase in the risk of breast cancer for women with high PCE exposure levels defined by either the 90th percentile (adjusted ORs 1.0-1.5 for 0-19 year latency assumptions) or smoothing analysis cut point (adjusted ORs 1.3-2.0 for 0-15 year latency assumptions). Current exposure estimates had a higher correlation with PCE concentrations in water samples (Spearman correlation coefficient = 0.65, p < 0.0001) than estimates generated using the prior method (0.54, p < 0.0001). The incorporation of sophisticated flow estimates in the exposure assessment method shifted the PCE exposure distribution downward, but did not meaningfully affect the exposure ranking of subjects or the strength of the association with the risk of breast cancer found in earlier analyses. Thus, the current analyses show a slightly elevated breast cancer risk for highly exposed women, with strengthened exposure assessment and minimization of misclassification by using the latest technology.


Dynamics of cortical oxygenation during immediate adaptation to extrauterine life.
The neonatal transition involves physiological modifications as a consequence of the complexity of the perinatal period. Various strategies can be used to attain the same level of postnatal cerebral oxygenation, depending on the status of the infant at birth. We evaluated such strategies by recording 20 full-term newborns by near-infrared spectroscopy during the first 10 min of life. The acid-base status at birth revealed two clustered profiles of cerebral oxygenation dynamics. Lower pH and base excess and higher lactate levels were associated with more rapid attainment of the 95% maximal tissue oxygenation index value. These results suggest that metabolic mechanisms drive initial cerebral oxygenation dynamics during this critical period. These results confirm the capacity of newborns to develop multiple strategies to protect the brain.


Prognostic significance of architectural patterns in non-Hodgkin lymphomas.
Clinical data and lymphoma biopsies were analyzed in 651 patients with non-Hodgkin lymphoma in order to describe the prognostic influence of different grades of follicular architecture compared to diffuse architecture. The follicularity was graded qualitatively according to the distinctness of the pattern (intra-follicular, infiltrative follicular and traceably follicular patterns). The partially follicular pattern, with co-existence of follicular and diffuse areas in the same biopsy, was graded quantitatively according to the proportion of these areas. The median survival of patients with diffuse pattern was 1.2 years, while that of patients with follicular patterns ranged from 2.5 to 7.3 yr. The prognosis for those with partially follicular pattern was not affected, whether or not more or less than 50% of the lymphoma was diffuse. For cytologically identical lymphomas, only the intra- and infiltrative follicular patterns influenced the prognosis favourably. This conclusion was further substantiated by means of multivariate analysis.


Dissecting the cytomegalovirus CC chemokine: Chemokine activity and gHgLchemokine-dependent cell tropism are independent players in CMV infection.
Like all herpesviruses, cytomegaloviruses (CMVs) code for many immunomodulatory proteins including chemokines. The human cytomegalovirus (HCMV) CC chemokine pUL128 has a dual role in the infection cycle. On one hand, it forms the pentameric receptor-binding complex gHgLpUL(128,130,131A), which is crucial for the broad cell tropism of HCMV. On the other hand, it is an active chemokine that attracts leukocytes and shapes their activation. All animal CMVs studied so far have functionally homologous CC chemokines. In murine cytomegalovirus (MCMV), the CC chemokine is encoded by the m131/m129 reading frames. The MCMV CC chemokine is called MCK2 and forms a trimeric gHgLMCK2 entry complex. Here, we have generated MCK2 mutant viruses either unable to form gHgLMCK2 complexes, lacking the chemokine function or lacking both functions. By using these viruses, we could demonstrate that gHgLMCK2-dependent entry and MCK2 chemokine activity are independent functions of MCK2 in vitro and in vivo. The gHgLMCK2 complex promotes the tropism for leukocytes like macrophages and dendritic cells and secures high titers in salivary glands in MCMV-infected mice independent of the chemokine activity of MCK2. In contrast, reduced early antiviral T cell responses in MCMV-infected mice are dependent on MCK2 being an active chemokine and do not require the formation of gHgLMCK2 complexes. High levels of CCL2 and IFN-γ in spleens of infected mice and MCMV virulence depend on both, the formation of gHgLMCK2 complexes and the MCK2 chemokine activity. Thus, independent and concerted functions of MCK2 serving as chemokine and part of a gHgL entry complex shape antiviral immunity and virus dissemination.


Human luteinized granulosa cells secrete apoB100-containing lipoproteins.
Thus far, liver, intestine, heart, and placenta have been shown to secrete apolipoprotein (apo)B-containing lipoproteins. In the present study, we first investigated lipoproteins in human follicular fluid (FF), surrounding developing oocytes within the ovary, as well as in corresponding plasma samples (n = 12). HDL cholesterol within FF correlated well with plasma HDL cholesterol (r = 0.80, P < 0.01), whereas VLDL cholesterol did not, indicating that VLDL in FF might originate directly from the granulosa cells producing FF. Primary human granulosa cells expressed apoB, microsomal triglyceride transfer protein, and apoE, but not the apoB-editing enzyme apobec-1. Using (3)H-leucine, we show that granulosa cells secrete apoB100-containing lipoproteins and that secretion can be stimulated by adding oleate to the medium (+83%). With electron microscopy, apoB-containing lipoproteins within the secretory pathway of human granulosa cells were directly visualized. Finally, we found a positive relationship between apoB levels in FF and improved fertility parameters in a population of 27 women undergoing in vitro fertilization. This study demonstrates that human granulosa cells assemble and secrete apoB100-containing lipoproteins, thereby identifying a novel cell type equipped with these properties. These results might have important implications for female infertility phenotypes as well as for the development of drugs targeting the VLDL production pathway.


Erythrocyte alkaline phosphatase in patients with myotonic muscle disorders.
The allosteric behaviour of the p-nitrophenyl-phosphatase (E.C.220.127.116.11.) from membrane erythrocytes was investigated in the following multisystemic diseases: myotonic dystrophy, limb-girdle muscular dystrophy, Charcot-Marie-Tooth and juvenile spinal muscular atrophy; in myotonia congenita, which is not a multisystemic disease, and in healthy controls. The Hill coefficient in F inhibition in controls was different from that in multisystemic diseases patients but not from that in myotonia congenita patients. Changes in the cooperative type kinetics would suggest that the interaction membrane-enzyme in controls and in patients with neuromuscular disorders is only different for multisystemic diseases.


Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100.
Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.


Designing nanosensors based on charged derivatives of gramicidin A.
Detection of chemical processes on a single molecule scale is the ultimate goal of sensitive analytical assays. We recently reported the possibility to detect chemical modifications on individual molecules by monitoring a change in the single ion channel conductance of derivatives of gramicidin A (gA) upon reaction with analytes in solution. These peptide-based nanosensors detect reaction-induced changes in the charge of gA derivatives that were engineered to carry specific functional groups near their C-terminus.1 Here, we discuss five key design parameters to optimize the performance of such chemomodulated ion channel sensors. In order to realize an effective sensor that measures changes in charge of groups attached to the C-terminus of a gA pore, the following conditions should be fulfilled: (1) the change in charge should occur as close to the entrance of the pore as possible; (2) the charge before and after reaction should be well-defined within the operational pH range; (3) the ionic strength of the recording buffer should be as low as possible while maintaining a detectable flow of ions through the pore; (4) the applied transmembrane voltage should be as high as possible while maintaining a stable membrane; (5) the lipids in the supporting membrane should either be zwitterionic or charged differently than the derivative of gA. We show that under the condition of high applied transmembrane potential (>100 mV) and low ionic strength of the recording buffer (< or =0.10 M), a change in charge at the entrance of the pore is the dominant requirement to distinguish between two differently charged derivatives of gA; the conductance of the heterodimeric gA pore reported here does not depend on a difference in charge at the exit of the pore. We provide a simple explanation for this asymmetric characteristic based on charge-induced local changes in the concentration of cations near the lipid bilayer membrane. Charge-based ion channel sensors offer tremendous potential for ultrasensitive functional detection since a single chemical modification of each individual sensing element can lead to readily detectable changes in channel conductance.


[Do the isocyanate monomer standards still protect against attacks of occupational asthma? Should a standard including polyisocyanates be evolved?].
Field surveys of diisocyanates at the workplaces in Switzerland and particularly in car repair shops, where HDI was the most used, showed that the monomer levels comply with the Swiss permissible exposure limit (PEL) in the great number of situations. Cases of medical surveillance associated with industrial hygiene measurements demonstrate that occupational asthma was also observed in situations where the monomer concentrations are low although high peaks of prepolymers are often recorded. From the statistical data on compensations, the annual incidence of occupational asthma over the period 1988 to 1992 remains around 54 cases with a mean cost of 21,000 sFr. per case per year. It is suggested that a PEL on the prepolymers should be introduced in the Swiss PEL list to enhance the efficiency of prevention policy.


The dynamic interaction of water with four dental impression materials during cure.
The purpose of this work was to investigate the interaction of water with four different dental impression materials: Aquasil (Ultra XLV Type 3), Take 1 (Wash Regular Set), Genie (Light Body, Standard Set), and Impregum Garant (Soft Light Bodied Consistency). Apparent contact angles of de-ionized water made against thin horizontal sample films of the different materials under different conditions were measured from analysis of profile images of symmetrical sessile drops of water placed on the sample films using a Model FTA200 dynamic drop shape analysis system, which included a JAI M30 high speed CCD camera combined with a zoom microscope. Data were taken for specimens of dry ages (times following mixing) from a minimum of 20 seconds up to 1220 seconds. Imaging was started before the initial water/impression material contact, and lasted for at least 420 seconds in each case. The interval at the beginning of each run was 0.033 second, and then increased by a factor of 1.012 to the end. During the initial 3 seconds following the drop deposition, the drop's shape oscillated due to inertial effects, so apparent contact angle data during this period were neglected in all cases. All measurements were made at room temperature. The drops were enclosed in a humidified chamber that suppressed evaporation. All data were repeated at least five times, and results were analyzed where appropriate using one-way ANOVA. Microscopic images of the water/impression material interactions for fresh (uncured) materials were acquired to reveal the destructive interactions that resulted from such contact. Finally, surface tension measurements were made of water that had been contacted with material of varying dry age using the pendant drop method capability of the drop shape analysis system. These helped to assess the origin of hydrophilicity development for the different materials. For short curing times (dry ages), water showed a destructive effect on the integrity of all of the impression materials, as evidenced by the formation of a crater beneath the water drop and a scum of material at its surface. These effects diminished with dry age until a critical curing time was reached, beyond which such destructive interactions were no longer detectable. These critical curing times were determined to be 80, 140, 110, and 185 seconds for Aquasil, Take 1, Genie, and Impregum, respectively. The initial contact angle following the respective critical curing time was lowest for Impregum, at 66 degrees ; while values for Aquasil, Genie, and Take 1 were 93 degrees , 104 degrees , and 110 degrees , respectively. Beyond the critical curing times for the different materials, different degrees of hydrophilicity were observed. Aquasil showed the lowest final contact angle (<10 degrees ), with Impregum, Take 1, and Genie showing 31 degrees , 34 degrees , and 40 degrees , respectively. Measurements of the surface tension of water after contact with the different materials suggested that for Aquasil, hydrophilicity appears to be developed through the leaching of surfactant from the material, whereas for Impregum, Take 1, and Genie, hydrophilicity is developed at least in part through a change in surface structure in contact with water. Impregum and Aquasil materials of dry ages well beyond the critical curing time exhibited a stick-slip behavior in their interline movement or contact angle evolution. This was believed to be due to the slowness in the leaching of surfactant (in the case of Aquasil) or the re-orientation of unleachable surface groups (in the case of the other materials) in comparison to the inherent kinetics of water drop spreading. All materials investigated in the fresh, uncured state showed qualitative decomposition when put in contact with water through the formation of a crater beneath the water drop and a scum of material at its surface. These effects diminished with curing time until beyond a critical value, no such effects were evident. The initial hydrophilicity of the materials as determined by the contact angles obtained at their respective critical dry ages was greatest for Impregum. Beyond the critical curing time, different degrees of hydrophilicity were observed, with Aquasil showing the lowest final contact angle.


Lesbian, gay, bisexual, and transgender hate crimes and suicidality among a population-based sample of sexual-minority adolescents in Boston.
We examined whether past-year suicidality among sexual-minority adolescents was more common in neighborhoods with a higher prevalence of hate crimes targeting lesbian, gay, bisexual, and transgender (LGBT) individuals. Participants' data came from a racially/ethnically diverse population-based sample of 9th- through 12th-grade public school students in Boston, Massachusetts (n = 1292). Of these, 108 (8.36%) reported a minority sexual orientation. We obtained data on LGBT hate crimes involving assaults or assaults with battery between 2005 and 2008 from the Boston Police Department and linked the data to the adolescent's residential address. Sexual-minority youths residing in neighborhoods with higher rates of LGBT assault hate crimes were significantly more likely to report suicidal ideation (P = .013) and suicide attempts (P = .006), than were those residing in neighborhoods with lower LGBT assault hate crime rates. We observed no relationships between overall neighborhood-level violent and property crimes and suicidality among sexual-minority adolescents (P > .05), providing evidence for specificity of the results to LGBT assault hate crimes. Neighborhood context (i.e., LGBT hate crimes) may contribute to sexual-orientation disparities in adolescent suicidality, highlighting potential targets for community-level suicide-prevention programs.


The molecular architecture of glucose-1-phosphate uridylyltransferase.
Glucose-1-phosphate uridylyltransferase, also referred to as UDP-glucose pyrophosphorylase or UGPase, catalyzes the formation of UDP-glucose from glucose-1-phosphate and UTP. Not surprisingly, given the central role of UDP-glucose in glycogen synthesis and in the production of glycolipids, glycoproteins, and proteoglycans, the enzyme is ubiquitous in nature. Interestingly, however, the prokaryotic and eukaryotic forms of the enzyme are unrelated in amino acid sequence and structure. Here we describe the cloning and structural analysis to 1.9 A resolution of the UGPase from Escherichia coli. The protein is a tetramer with 222 point group symmetry. Each subunit of the tetramer is dominated by an eight-stranded mixed beta-sheet. There are two additional layers of beta-sheet (two and three strands) and 10 alpha-helices. The overall fold of the molecule is remarkably similar to that observed for glucose-1-phosphate thymidylyltransferase in complex with its product, dTDP-glucose. On the basis of this similarity, a UDP-glucose moiety has been positioned into the active site of UGPase. This protein/product model predicts that the side chains of Gln 109 and Asp 137, respectively, serve to anchor the uracil ring and the ribose of UDP-glucose to the protein. The beta-phosphoryl group of the product is predicted to lie within hydrogen bonding distance to the epsilon-nitrogen of Lys 202 whereas the carboxylate group of Glu 201 is predicted to bridge the 2'- and 3'-hydroxyl groups of the glucosyl moiety. Details concerning the overall structure of UGPase and a comparison with glucose-1-phosphate thymidylyltransferase are presented.


Risk of Liver Enzyme Elevation During Treatment With Ritonavir-Boosted Protease Inhibitors Among HIV-Monoinfected and HIV/HCV-Coinfected Patients.
The risk of liver enzyme elevation (LEE) after different ritonavir-boosted protease inhibitors (PI/r) has not been fully assessed in real-life settings and in populations with high rates of hepatitis C virus (HCV) coinfection. Patients introducing a new PI/r between 1998 and 2012 were included, if transaminases and HCV antibody (Ab) were assessed before treatment initiation. Time to grade 3 and 4 LEE were assessed using univariable and multivariable conditional Cox analyses, stratified by HCV serostatus. A total of 6193 HIV-infected patients (3242 HCV-Ab negative and 2951 HCV-Ab positive) were included. Incidence of grade 3 LEE was 1.05, 7.66, and 8.08 per 100 patient-years of follow-up among HCV-Ab negative, HCV-Ab-positive and HCV-RNA-positive patients, respectively. Among HCV-Ab-negative patients, no differences were detected between different PI/r. Use of darunavir/ritonavir was not associated with LEE among HCV-coinfected patients. Atazanavir/ritonavir use was associated with grade 3 LEE but only among HCV-Ab-positive patients (versus LPV/r, hazard ratio: 1.39; 95% confidence interval: 1.1 to 1.75). This risk was not confirmed in a subanalysis restricted to HCV-RNA-positive patients (versus LPV/r, hazard ratio: 1.16; 95% confidence interval: 0.87 to 1.55). Other independent predictors of grade 3 LEE among HCV-Ab-positive patients were older age, male gender, being treatment naive, nonnucleoside reverse transcriptase inhibitor coadministration, increased aspartate aminotransferase at baseline, overweight, positive HCV-RNA, and advanced estimated liver fibrosis. Occurrence of hepatotoxicity was a rare finding among HCV-Ab-negative patients and was not influenced by the type of PI/r. In particular, the use of darunavir/ritonavir, previously linked with severe cases of hepatotoxicity, was not associated with a greater risk of LEE, irrespective from HCV serostatus.


Intracellular electrophysiological study of suprachiasmatic nucleus neurons in rodents: excitatory synaptic mechanisms.
1. To study the synaptic mechanisms of excitatory transmission in the suprachiasmatic nucleus (SCN), we assessed the effects of excitatory amino acid receptor antagonists on excitatory postsynaptic potentials (EPSPs) recorded from SCN neurons in horizontal and parasagittal hypothalamic slice preparations from rats and guinea-pigs. The EPSPs were evoked by electrical stimulation of either optic nerve or a site near the SCN. 2. When evoked at membrane potentials between -60 and -100 mV, the EPSPs from optic nerve stimulation were conventional in shape; they rose to the peak quickly (6.2 +/- 0.5 ms, mean +/- S.E.M.; n = 45) and decayed gradually over 50-250 ms. When evoked at membrane potentials between -20 and -55 mV after blockade of outward K+ currents and fast Na+ spikes by intracellular injection of Cs+ and QX-314 (n = 5 neurons), a slow depolarizing potential emerged near the fast peak of the EPSP. This slow potential, unlike the fast peak, was not linearly related to membrane potential. 3. An antagonist for kainate- and quisqualate-type excitatory amino acid receptors, 6,7-dinitroquinoxaline-2,3-dione (DNQX 1-10 microM), depressed in a concentration-dependent and reversible manner the EPSPs evoked by optic nerve stimulation at membrane potentials between -60 and -100 mV (n = 9). The effects of DNQX were not associated with any significant changes in the baseline input resistance or membrane potential of the postsynaptic neurons. The selective N-methyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (AP5, 50-100 microM), did not affect significantly and consistently the EPSPs evoked at these membrane potentials (n = 7). On the other hand, AP5 (50 microM) blocked or depressed the slow depolarizing component of the EPSPs evoked at membrane potentials between -20 and -55 mV (n = 4). No significant changes in baseline input resistance or membrane potential accompanied the effects of AP5. 4. Stimulation of a site lateral or dorsocaudal to the SCN evoked EPSPs distinct from those evoked by optic nerve stimulation. Again, DNQX (0.3-10 microM) depressed the EPSPs evoked at membrane potentials between -60 and -100 mV (n = 4) whereas AP5 (50 microM) had no effect (n = 5). When evoked at less negative membrane potentials (i.e. -20 to -55 mV) after intracellular injection of Cs+ and QX-314, the EPSPs had a slow depolarizing potential, similar to the EPSPs from optic nerve stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)


Role of immunological factors in the pathophysiology and diagnosis of bipolar disorder: comparison with schizophrenia.
Several lines of evidence point to the key role of neurobiological mechanisms and shared genetic background in schizophrenia and bipolar disorder. For both disorders, neurodevelopmental and neurodegenerative processes have been postulated to be relevant for the pathogenesis as well as dysregulation of immuno-inflammatory pathways. Inflammation is a complex biological response to harmful stimuli and it is mediated by cytokines cascades, cellular immune responses, oxidative factors and hormone regulation. Cytokines, in particular, are supposed to play a critical role in infectious and inflammatory processes, mediating the cross-talk between the brain and the immune system; they also possibly contribute to the development of the central nervous system. From this perspective, even though mixed results have been reported, it seems that both schizophrenia and bipolar disorder are associated with an imbalance in inflammatory cytokines; in fact, some of these could represent biological markers of illness and could be possible targets for pharmacological treatments. In light of these considerations, the purpose of the present paper was to provide a comprehensive and critical review of the existing literature about immunological abnormalities in bipolar disorder with particular attention to the similarities and differences with schizophrenia.


Delayed dural laceration by hydroxyapatite spacer causing tetraparesis following double-door laminoplasty.
The authors describe 4 cases of delayed dural laceration by hydroxyapatite (HA) spacer causing tetra-paresis following double-door laminoplasty. There are few reports of iatrogenic spinal cord lesions developing after double-door laminoplasty, although some complications such as postoperative C-5 paralysis or axial symptoms have been reported. The purpose of this report is to draw attention to the possibility of delayed dural laceration and its triggering mechanism. One hundred thirty patients treated for cervical myelopathy were followed up for an average of 2 years and 9 months after laminoplasty. Four patients experienced aggravation of cervical myelopathy. Anterior dislodgement of HA spacers was shown on plain lateral radiographs. Follow-up T2-weighted magnetic resonance imaging demonstrated that the dislodged HA spacers were surrounded by cerebrospinal fluid at the time of aggravation. The dislodged HA spacers were removed and the dural membrane defects were repaired by patching with the fascia of the gluteus maximus muscle. The preoperative symptoms improved after the second operation in all patients. It is hypothesized that the loosening of the HA spacer in split spinous processes could occur with the movement of the cervical spine and/or the breakage of the suture before bone bonding. Anterior dislodgement of the HA spacer toward the spinal canal would cause dural laceration by direct friction between the dural membrane and the dislodged HA spacer, resulting in clinical aggravation. Despite the well-documented advantages of using HA spacers for double-door laminoplasty, possible laceration due to a dislodged HA spacer should be considered as a late complication.


Presence of osteoclast-like multinucleated giant cells in the bone and nonostotic lesions of Langerhans cell histiocytosis.
Langerhans cell histiocytosis (LCH) is a disease that can involve one or multiple organ systems characterized by an accumulation of CD1a(+) Langerhans-like cells as well as several other myeloid cell types. The precise origin and role of one of these populations, the multinucleated giant cell (MGC), in this disease remains unknown. This work shows that in three different lesional tissues, bone, skin, and lymph node, the MGCs expressed the characteristic osteoclast markers, tartrate-resistant acid phosphatase and vitronectin receptor, as well as the enzymes cathepsin K and matrix metalloproteinase-9. Although, in bone lesions, the osteoclast-like MGCs were only CD68(+), in the nonostotic sites, they coexpressed CD1a. The presence of osteoclast-like MGCs may be explained by the production of osteoclast-inducing cytokines such as receptor activator of nuclear factor kappaB ligand and macrophage colony-stimulating factor by both the CD1a(+) LCH cells and T cells in these lesions. As osteoclast-derived enzymes play a major role in tissue destruction, the osteoclast-like nature of MGCs in all LCH lesions makes them a potential target for the treatment of this disease.


Endovascular therapy for steno-occlusive subclavian and innominate artery disease.
This study investigated the safety and outcome of endovascular therapy for steno-occlusive subclavian or innominate artery disease at a single center over a long period of more than 2 decades. METHODS AND RESULTS: We retrospectively analyzed all endovascular procedures of stenosis or occlusion of the subclavian or innominate artery between January 1990 and October 2013. During the observation period, a total of 130 procedures were attempted in 127 mostly symptomatic patients with stenosis (n=108; 83%) or occlusion (n=22; 17%) of the subclavian (n=119; 92%) and innominate (n=11; 8%) artery. The overall technical success rate was 97.7% (n=127/130). Accounting for the type of lesion, the success rate for stenosis was 100% (n=108/108) and for total occlusion, 86% (n=19/22). The periprocedural complication rate was low and included stroke, transient ischemic attack, and access site complications of 0.8%, 1.5%, and 3.8%, respectively. During a mean follow-up of 28 months the rate of restenosis (>70%) was 12%. Due to the overall low event rate no significant lesion or procedural risk factor for the development of restenosis could be identified. Stenosis and occlusion of the subclavian and innominate artery can be treated safely and successfully by endovascular therapy with excellent long-term patency.


Enhanced recovery after surgery (ERAS) in colorectal surgery: implementation is still beneficial despite modern surgical and anesthetic care.
Enhanced recovery after surgery (ERAS) protocols have shown beneficial outcomes in the last 20 years. Nevertheless, simultaneously implemented technical improvements such as minimally invasive access or modified anesthesia care may play a crucial role in optimizing patient outcome. The aim of the study was to investigate the effect of ERAS implementation in a highly specialized colorectal center. This is a propensity score matched single-center study comparing the short-term outcomes of patients undergoing elective colorectal surgery in a society-indepedent ERAS program from January 2021 to August 2022 to standard perioperative care from January 2019 to December 2020. Four hundred fifty-six patients were included in the propensity score matched analysis with 228 patients per group (ERAS vs. standard care). Minimally invasive access was used in 80.2% vs. 77.6% (p = 0.88), and there were 16.6% vs. 18.8% (p = 0.92) rectal procedures in the ERAS and standard care group, respectively. Major complications occurred in 10.1% vs. 11.4% (p = 0.65) and anastomotic leakage demanding operative revision in 2.2% vs. 2.6% (p = 0.68) in the ERAS and standard care group, respectively. ERAS lead to a lower number of non-surgical complications compared to standard care (57 vs. 79; p = 0.02). Mean length of stay (LOS) and mean costs per case were lower in ERAS compared to standard care (9.2 ± 5.6 days vs. 12.7 ± 7.4 days, p < 0.01; costs 33,727 ± 15,883 USD vs. 40,309 ± 29,738 USD, p < 0.01). The implementation of an ERAS protocol may lead to a reduction of LOS, costs, and a lower number of non-surgical complications even in a highly specialized colorectal unit using modern surgical and anesthetic care. ( ClinialTrials.gov number NCT05773248).


Type 2 diabetes prevalence, health status and quality of care among the North African immigrant population living in France.
This report is an overview of type 2 diabetes (DT2) in the North African immigrant population living in France. Data were collected in two separate cross-sectional national surveys. DT2 prevalence was estimated using a population-based survey involving 13 959 people aged ≥ 45 years (EDS), while health status and quality of care were evaluated using a sample of 3894 DT2 patients (ENTRED). Prevalence of DT2 and obesity was 14.0% [CI 95%: 9.9; 18.0] and 20.5% [15.7; 25.3], respectively, in participants born in North Africa (BNA) and 7.5% [7.0; 8.0] and 15.8% [14.7; 16.8], respectively, in those born in France (BIF). DT2 was associated with region of birth in women after adjusting for age, body mass index and income or occupation, but not after adjusting for education level. In men, DT2 was not associated with region of birth. BNA and BIF patients with diabetes frequently benefited from free medical coverage (88% vs. 84%, respectively), although BNA diabetic patients visited a general practitioner less frequently than BIF (8.5 vs. 9.0 visits/year, respectively). The percentage of BNA vs. BIF diabetes patients tested three times a year for HbA1c was lower (39% vs. 44%), while HbA1c was higher in BNA vs. BIF diabetics (> 8%: 30% vs. 15%). Ophthalmological complications were also more frequent in BNA vs. BIF patients with diabetes (25% vs. 18%, respectively). The greater prevalence of DT2 in BNA women and the poorer glycaemic control observed in the BNA population overall both probably contribute to disparity in diabetes mortality compared with BIF diabetics, a fact that has been observed in previous studies.


Safety, efficacy, and persistence of long-term mirabegron treatment for overactive bladder in the daily clinical setting: Interim (1-year) report from a Japanese post-marketing surveillance study.
To report interim 1-year results from a 3-year surveillance study evaluating safety, efficacy, and persistence of long-term mirabegron for overactive bladder (OAB). Patients starting treatment with mirabegron for urinary urgency, daytime frequency, and urgency incontinence associated with OAB were registered and followed up for 3 years. Data were collected on adverse drug reactions (ADR), changes in OAB symptoms, changes in Overactive Bladder Symptom Score (OABSS), and treatment discontinuations. Treatment persistence rates were calculated by Kaplan-Meier analysis. Eighty-one ADR were observed in 72/1139 patients (6.3%) through 1 year of mirabegron treatment, with the incidence highest during the first month. No significant change in residual urine volume was observed at any observation point up to 1 year of mirabegron treatment. Mirabegron was deemed "effective" in 883/1091 patients (80.9%) at 1 year/discontinuation. Total OABSS was decreased with statistical significance at 3, 6 months, and 1 year, or at discontinuation (P < 0.001 at each time point). Kaplan-Meier treatment persistence rates were 84.8% at 3 months, 77.6% at 6 months, and 66.0% at 1 year. Treatment persistence rates were similar for male and female patients but significantly higher for patients aged ≥65 years (67.3%; n = 908) compared with those aged <65 years (59.8%; n = 231; log-rank test: P = 0.032). Long-term OAB treatment with mirabegron was well-tolerated, with effectiveness maintained through 1 year. Mirabegron treatment persistence was higher than has been previously reported, and was greater in patients aged ≥65 years compared with those aged <65 years.


Neuroprotective effects of tamoxifen on experimental spinal cord injury in rats.
The aim of this study was to evaluate the effects of tamoxifen on tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) levels and ultrastructural changes in rats with spinal cord injury. Rats were divided into four groups: control group (laminectomy only), trauma group (laminectomy+spinal trauma), tamoxifen group (laminectomy+spinal trauma+tamoxifen), and vehicle group (laminectomy+spinal trauma+vehicle). Spinal cords were extirpated at the T(7)-T(12) level and tissue samples from the spinal cords were gathered for TNF-alpha and IL-1beta measurements at 1 and 6hours. Spinal cords harvested at 6 hours were evaluated for ultrastructural changes. TNF-alpha and IL-1beta levels at 6 hours were significantly lower in the tamoxifen group than in the trauma group. Electron microscopic examination of tissue from the trauma group revealed gross cell deformities with widespread edema of all structures as well as severe edema in the neuropil. At 6 hours after trauma, these ultrastructural changes were less marked in the tamoxifen group. Our findings support a neuroprotective and restorative role for tamoxifen in the context of secondary pathological biochemical events after SCI.


The natural agent rhein induces β-catenin degradation and tumour growth arrest.
The natural agent rhein is an ananthraquinone derivative of rhubarb, which has anticancer effects. To determine the mechanisms underlying the anticancer effects of rhein, we detected the effect of rhein on several oncoproteins. Here, we show that rhein induces β-catenin degradation in both hepatoma cell HepG2 and cervical cancer cell Hela. Treatment of HepG2 and Hela cells with rhein shortens the half-life of β-catenin. The proteasome inhibitor MG132 blunts the downregulation of β-catenin by rhein. The induction of β-catenin degradation by rhein is dependent on GSK3 but independent of Akt. Treatment of HepG2 and Hela cells with GSK3 inhibitor or GSK3β knockdown abrogates the effect of rhein on β-catenin. GSK3β knockdown compromises the inhibition of HepG2 and Hela cell growth by rhein. Furthermore, rhein dose not downregulate β-catenin mutant that is deficient of phosphorylation at multiple residues including Ser33, Ser37, Thr41 and Ser45. Moreover, rhein induces cell cycle arrest at S phase in both HepG2 and Hela cells. Intraperitoneal administration of rhein suppresses tumour cells proliferation and tumour growth in HepG2 xenografts model. Finally, the levels of β-catenin are reduced in rhein-treated tumours. These data demonstrate that rhein can induce β-catenin degradation and inhibit tumour growth.


Active control of locomotion facilitates nonvisual navigation.
In some navigation tasks, participants are more accurate if they view the environment beforehand. To characterize the benefits associated with visual previews, 32 blindfolded participants were guided along simple paths and asked to walk unassisted to a specified destination (e.g., the origin). Paths were completed without vision, with or without a visual preview of the environment. Previews did not necessarily improve nonvisual navigation. When previewed landmarks stood near the origin or at off-path locations, they provided little benefit; by contrast, when they specified intermediate destinations (thereby increasing the degree of active control), performance was greatly enhanced. The results suggest that the benefit of a visual preview stems from the information it supplies for actively controlled locomotion. Accuracy in reaching the final destination, however, is strongly contingent upon the destination's location during the preview.


Effects of body mass index on the outcomes of percutaneous nephrolithotomy.
To examine the the effect of body mass index (BMI) on PNL results and complications with a large number of patients. A total of 958 patients were included in the study, who underwent percutaneous nephrolithotomy in our clinic between 2008 and 2015. Patients were divided into 2 groups according to their body mass index. Patients with a BMI < 30 kg/m2 were classified as group 1 (n:676) and patients with a BMI ≥ 30 kg/m2 were classified as group 2 (n:282). Achieving stone-free status or having residual stones of ≤ 4 mm were considered as operational success. The mean age was 47.9 years for group 1 and 48.9 years for group 2 patients. At postoperative first month CT analysis, residual stone was not observed in 466 patients (69%) of group 1 and 20 (72%) patients of group 2. There was no significant difference between the groups in terms of stone-free status (p=0.348). There was no significant difference between two groups complications. Also, there was no difference between the groups for requiring additional intervention (p=0.924). No other complications were observed in the patients. BMI does not affect the outcomes of percutaneous nephrolithotomy as well as complication rate.


A Bayesian outlier criterion to detect SNPs under selection in large data sets.
The recent advent of high-throughput SNP genotyping technologies has opened new avenues of research for population genetics. In particular, a growing interest in the identification of footprints of selection, based on genome scans for adaptive differentiation, has emerged. The purpose of this study is to develop an efficient model-based approach to perform bayesian exploratory analyses for adaptive differentiation in very large SNP data sets. The basic idea is to start with a very simple model for neutral loci that is easy to implement under a bayesian framework and to identify selected loci as outliers via Posterior Predictive P-values (PPP-values). Applications of this strategy are considered using two different statistical models. The first one was initially interpreted in the context of populations evolving respectively under pure genetic drift from a common ancestral population while the second one relies on populations under migration-drift equilibrium. Robustness and power of the two resulting bayesian model-based approaches to detect SNP under selection are further evaluated through extensive simulations. An application to a cattle data set is also provided. The procedure described turns out to be much faster than former bayesian approaches and also reasonably efficient especially to detect loci under positive selection.


On the Nature of Extra-Framework Aluminum Species and Improved Catalytic Properties in Steamed Zeolites.
Steamed zeolites exhibit improved catalytic properties for hydrocarbon activation (alkane cracking and dehydrogenation). The nature of this practically important phenomenon has remained a mystery for the last six decades and was suggested to be related to the increased strength of zeolitic Bronsted acid sites after dealumination. We now utilize state-of-the-art infrared spectroscopy measurements and prove that during steaming, aluminum oxide clusters evolve (due to hydrolysis of Al out of framework positions with the following clustering) in the zeolitic micropores with properties very similar to (nano) facets of hydroxylated transition alumina surfaces. The Bronsted acidity of the zeolite does not increase and the total number of Bronsted acid sites decreases during steaming. O5Al(VI)-OH surface sites of alumina clusters dehydroxylate at elevated temperatures to form penta-coordinate Al1O5 sites that are capable of initiating alkane cracking by breaking the first C-H bond very effectively with much lower barriers (at lower temperatures) than for protolytic C-H bond activation, with the following reaction steps catalyzed by nearby zeolitic Bronsted acid sites. This explains the underlying mechanism behind the improved alkane cracking and alkane dehydrogenation activity of steamed zeolites: heterolytic C-H bond breaking occurs on Al-O sites of aluminum oxide clusters confined in zeolitic pores. Our findings explain the origin of enhanced activity of steamed zeolites at the molecular level and provide the missing understanding of the nature of extra-framework Al species formed in steamed/dealuminated zeolites.


Advanced carcinoma of the nasopharynx. A clinical study of 274 patients.
A total of 274 patients with a diagnosis of nasopharyngeal carcinoma was treated in eight Veterans Administration Hospitals over a period of 22 years. Of the 274 patients, 256 (93%) had squamous-cell carcinoma, while 18 (7%) had other tumors. Most of the squamous-cell carcinoma patients (82%) had Stage IV disease; cervical lymph node metastases were found in 193 (75%), and distant metastases were present in 22 (9%). The actuarial 5-, 10-, and 15-year survival rates for the 256 squamous-cell carcinoma patients were 15%, 10%, and 7%, while they were 49%, 42%, and 35% for the 18 patients with other tumors (p = 0.006). There was a progressive decrease in 5-year survival with the increase in the stage of tumor. The survival of the 63 patients without metastases was better than the survival of the 193 patients with cervical metastases (24% vs. 12% at 5 years, p = 0.03). The presence of T4 disease or Initial Performance Status of less than 80 on the Karnofsky Scale indicated a poor prognosis (p = 0.0001). Treatment failure occurred in 83% of the patients by 2 years after therapy and was due to the lack of tumor control at the primary site. Advanced (N3) cervical lymph node metastases indicated that systemic tumor dissemination of the nasopharynx is an uncommon malignancy.


Assessing the effectiveness of High Intensity Interval Training (HIIT) for smoking cessation in women: HIIT to quit study protocol.
Smoking and physical inactivity are major risk factors for heart disease. Linking strategies that promote improvements in fitness and assist quitting smoking has potential to address both these risk factors simultaneously. The objective of this study is to compare the effects of two exercise interventions (high intensity interval training (HIIT) and lifestyle physical activity) on smoking cessation in female smokers. This study will use a randomised controlled trial design. Women aged 18-55 years who smoke ≥ 5 cigarettes/day, and want to quit smoking. all participants will receive usual care for quitting smoking. Group 1--will complete two gym-based supervised HIIT sessions/week and one home-based HIIT session/week. At each training session participants will be asked to complete four 4-min (4 × 4 min) intervals at approximately 90% of maximum heart rate interspersed with 3- min recovery periods. Group 2--participants will receive a resource pack and pedometer, and will be asked to use the 10,000 steps log book to record steps and other physical activities. The aim will be to increase daily steps to 10,000 steps/day. Analysis will be intention to treat and measures will include smoking cessation, withdrawal and cravings, fitness, physical activity, and well-being. The study builds on previous research suggesting that exercise intensity may influence the efficacy of exercise as a smoking cessation intervention. The hypothesis is that HIIT will improve fitness and assist women to quit smoking. ACTRN12614001255673 (Registration date 02/12/2014).


Alzheimer's disease comorbidity in normal pressure hydrocephalus: prevalence and shunt response.
The clinical impact of Alzheimer's disease pathology at biopsy was investigated in 56 cognitively impaired patients undergoing shunt surgery for idiopathic normal pressure hydrocephalus (NPH). Cognition was measured by means of the global deterioration scale (GDS), the mini mental status examination (MMSE) and a battery of six psychometric tests. Gait was assessed using objective measurements of velocity and the ambulatory index (AI). The prevalence of cases exhibiting neuritic plaques (positive biopsies) increased in parallel with dementia severity from 18% for patients with GDS 3 to 75% for patients with GDS scores > or =6. Patients with positive biopsies were more cognitively impaired (higher GDS and lower MMSE scores) as well as more gait impaired (higher AI scores and slower velocities) than patients with negative biopsies. After surgery, gait velocity and AI scores improved significantly and to a comparable degree for patients with and without positive biopsies. Similar proportions of positive and negative biopsy patients also had improved gait as assessed by means of subjective video tape comparisons. There were no significant differences between the biopsy groups in the magnitude of postoperative psychometric change or in the proportion of cases exhibiting improved urinary control. Alzheimer's disease pathology is a common source of comorbidity in older patients with idiopathic NPH where it contributes to the clinical impairment associated with this disorder. For patients accurately diagnosed with NPH, concomitant Alzheimer's disease pathology does not strongly influence the clinical response to shunt surgery.


A noval pulmonary function evaluation method based on ResNet50 + SVR model and cough.
Traditionally, the clinical evaluation of respiratory diseases was pulmonary function testing, which can be used for the detection of severity and prognosis through pulmonary function parameters. However, this method is limited by the complex process, which is impossible for patients to monitor daily. In order to evaluate pulmonary function parameters conveniently with less time and location restrictions, cough sound is the substitute parameter. In this paper, 371 cough sounds segments from 150 individuals were separated into 309 and 62 as the training and test samples. Short-time Fourier transform (STFT) was applied to transform cough sound into spectrogram, and ResNet50 model was used to extract 2048-dimensional features. Through support vector regression (SVR) model with biological attributes, the data were regressed with pulmonary function parameters, FEV1, FEV1%, FEV1/FVC, FVC, FVC%, and the performance of this models was evaluated with fivefold cross-validation. Combines with deep learning and machine learning technologies, the better results in the case of small samples were achieved. Using the coefficient of determination (R2), the ResNet50 + SVR model shows best performance in five basic pulmonary function parameters evaluation as FEV1(0.94), FEV1%(0.84), FEV1/FVC(0.68), FVC(0.92), and FVC%(0.72). This ResNet50 + SVR hybrid model shows excellent evaluation of pulmonary function parameters during coughing, making it possible to realize a simple and rapid evaluation for pneumonia patients. The technology implemented in this paper is beneficial in judge the patient's condition, realize early screening of respiratory diseases, evaluate postoperative disease changes and detect respiratory infectious diseases without time and location restrictions.


Perturbed and spontaneous regional cerebral blood flow responses to changes in blood pressure after high-level spinal cord injury: the effect of midodrine.
Individuals with spinal cord injury (SCI) above the T6 spinal segment suffer from orthostatic intolerance. How cerebral blood flow (CBF) responds to orthostatic challenges in SCI is poorly understood. Furthermore, it is unclear how interventions meant to improve orthostatic tolerance in SCI influence CBF. This study aimed to examine 1) the acute regional CBF responses to rapid changes in blood pressure (BP) during orthostatic stress in individuals with SCI and able-bodied (AB) individuals; and 2) the effect of midodrine (alpha1-agonist) on orthostatic tolerance and CBF regulation in SCI. Ten individuals with SCI >T6, and 10 age- and sex-matched AB controls had beat-by-beat BP and middle and posterior cerebral artery blood velocity (MCAv, PCAv, respectively) recorded during a progressive tilt-test to quantify the acute CBF response and orthostatic tolerance. Dynamic MCAv and PCAv to BP relationships were evaluated continuously in the time domain and frequency domain (via transfer function analysis). The SCI group was tested again after administration of 10 mg midodrine to elevate BP. Coherence (i.e., linearity) was elevated in SCI between BP-MCAv and BP-PCAv by 35% and 22%, respectively, compared with AB, whereas SCI BP-PCAv gain (i.e., magnitudinal relationship) was reduced 30% compared with AB (all P < 0.05). The acute (i.e., 0-30 s after tilt) MCAv and PCAv responses were similar between groups. In individuals with SCI, midodrine led to improved PCAv responses 30-60 s following tilt (10 ± 3% vs. 4 ± 2% decline; P < 0.05), and a 59% improvement in orthostatic tolerance (P < 0.01). The vertebrobasilar region may be particularly susceptible to hypoperfusion in SCI, leading to increased orthostatic intolerance.


Synthesis and in Vivo Evaluation of [123I]Melanin-Targeted Agents.
This study reports the synthesis, [(123)I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [(131)I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60-90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [(123)I]4 (ICF01012). The most favorable compounds ([(123)I]20, [(123)I]23, [(123)I]41, and [(123)I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [(123)I]20 and [(123)I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [(123)I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [(123)I]41 and [(123)I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [(123)I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [(131)I] therapeutic evaluation.


DNA-attacking ability of carcinogenic mycotoxins in recombination-deficient mutant cells of Bacillus subtilis.
Thirty mycotoxins and 5 chemically modified toxins were tested for DNA-attacking ability in the rec assay using the recombination-deficient mutant of Bacillus subtilis M45 (rec-) and the parent strain H17 (rec+). Six Penicillium toxins (citrinin, penicillic acid, patulin, (-)-luteoskyrin, (+)-rugulosin, and PR-toxin), 5 Aspergillus toxins (aflatoxins B1 and G1, sterigmatocystin, O-acetylsterigmatocystin, and O-acetyldihydrosterigmatocystin), and 2 Fusarium toxins (zearalenone and zearalenol-b) were positive. Among these 13 compounds, the following 8 mycotoxins have been reported to be carcinogenic in animals: citrinin, penicillic acid, patulin, (-)-luteoskyrin, (+)-rugulosin, aflatoxins B1, and G1, sterigmatocystin. Correlation between the rec effect and in vivo carcinogenicity of mycotoxins is discussed.


A Collaboration Between Game Developers and Rehabilitation Researchers to Develop a Web-Based App for Persons With Physical Disabilities: Case Study.
Individuals with a disability and their partners, who often provide care, are both at risk for depression and lower quality of life. Mobile health (mHealth) interventions are promising to address barriers to mental health care. Rehabilitation researchers and software development researchers must collaborate effectively with each other and with clinical and patient stakeholders to ensure successful mHealth development. This study aimed to aid researchers interested in mHealth software development by describing the collaborative process between a team of rehabilitation researchers, software development researchers, and stakeholders. Thus, we provide a framework (conceptual model) for other teams to replicate to build a Web-based mHealth app for individuals with physical disability. Rehabilitation researchers, software development researchers, and stakeholders (people with physical disabilities and clinicians) are involved in an iterative software development process. The overall process of developing an mHealth intervention includes initial development meetings and a co-design method called design box, in which the needs and key elements of the app are discussed. On the basis of the objectives outlined, a prototype is developed and goes through scoping iterations with feedback from stakeholders and end users. The prototype is then tested by users to identify technical errors and gather feedback on usability and accessibility. Illustrating the overall development process, we present a case study based on our experience developing an app (SupportGroove) for couples coping with spinal cord injury. Examples of how we addressed specific challenges are also included. For example, feedback from stakeholders resulted in development of app features for individuals with limited functional ability. Initial designs lacked accessibility design principles made visible by end users. Solutions included large text, single click, and minimal scrolling to facilitate menu navigation for individuals using eye gaze technology. Prototype testing allowed further refinement and demonstrated high usability and engagement with activities in the app. Qualitative feedback indicated high levels of satisfaction, accessibility, and confidence in potential utility. We also present key lessons learned about working in a collaborative interdisciplinary team. mHealth promises to help overcome barriers to mental health intervention access. However, the development of these interventions can be challenging because of the disparate and often siloed expertise required. By describing the mHealth software development process and illustrating it with a successful case study of rehabilitation researchers, software development researchers, and stakeholders collaborating effectively, our goal is to help other teams avoid challenges we faced and benefit from our lessons learned. Ultimately, good interdisciplinary collaboration will benefit individuals with disabilities and their families.


[Fast electron beams in radiotherapy. Physico-dosimetric basis].
The author starting from the electron beams production describes their interaction with matter in terms of stopping and diffusion. The "dose" and its spatial distribution is considered the physical parameter more suitable to describe the electron beams characteristics. Particularly, it is outlined that the experimental depth penetration curve of dose in water, can provide the parameter evaluation useful to characterize the electron beams both qualitatively and quantitatively, i.e.: beam dimensions at the entrance surface; mean energy Eo; maximum dose (Dmax) depth, R100; surface dose, Ds (% Dmax); depth of 50% of Dmax, R50; practical range, Rp; therapeutic range, R85. The operative steps are described as referred to the National Protocol of Standardization (basic dosimetry).


Immunohistochemical evaluation of estrogen and progesterone receptor content in 183 patients with endometrial carcinoma. Part II: Correlation between biochemical and immunohistochemical methods and survival.
One hundred eighty-three patients with endometrial carcinoma had both immunohistochemical and biochemical analysis of estrogen receptor (ER) and progesterone receptor (PR) content of the tumor. Biochemical analysis was done on a homogenate of uterine curettings; immunohistochemical stainings were done on formalin-fixed, paraffin-embedded sections. The biochemical method was scored quantitatively and the immunohistochemical, in a semiquantitative way. There was a significant correlation between the immunohistochemical categories of the malignant component of the tumor and the biochemical levels of receptor content (P = 0.0001). The sensitivity of the immunohistochemical method for the ER content was 78.5% and the specificity was 58.2%. The sensitivity for the PR was 52.5% and the specificity was 92.8%. Changing cut-off levels for positivity of the biochemical analysis changed the sensitivity and specificity. Survival was predicted by the immunohistochemical status of the ER (P = 0.001) and PR (P = 0.01). Similarly, it was predicted by the biochemical receptor status. Multivariate analysis of the immunohistochemical receptor status and the biochemical receptor status showed that the immunohistochemically determined estrogen status was the most significant predictor of survival (P = 0.001). The immunohistochemical analysis of sex steroid receptor status on formalin-fixed, paraffin-embedded tissue is not only possible and practical, but also predicts survival.