Soluble P-selectin in hyperlipidaemia with and without symptomatic vascular disease: relationship with von Willebrand factor.
Soluble P-selectin (CD62P) may arise from platelets, the endothelium, or both, and raised levels are found in those with thrombotic disease and atherosclerosis. To determine whether these increased levels in atherosclerosis are related to hypercholesterolaemia, blood samples were obtained from 86 patients (43 with symptomatic vascular disease) attending a hypercholesterolaemia clinic, and 86 age- and sex-matched controls. Parallel measurement of endothelial cell product von Willebrand factor helped define the origin of sP-selectin. Using ELISAs, soluble P-selectin was higher (median 290 ng/ml, range 80-735, P < 0.05) in patients with vascular disease than in both patients with uncomplicated hypercholesterolaemia (median 210 ng/ml, range 55-550), and controls (median 190 ng/ml, range 48-500). Von Willebrand factor was raised in both patients with uncomplicated hypercholesterolaemia (115 +/- 26 IU/dl, P < 0.05) and patients with hypercholesterolaemia and vascular disease (129 +/- 32 IU/dl, P < 0.02) compared with controls (102 +/- 30 IU/dl). Levels of soluble P-selectin did not correlate with von Willebrand factor, total low-density-lipoprotein (LDL) or high-density-lipoprotein (HDL) cholesterol or triglycerides levels, blood pressure or smoking, but von Willebrand factor correlated with LDL cholesterol (r = 0.42, P < 0.05). We conclude that plasma lipoproteins are not a major influence on levels of soluble P-selectin.


Evaluation of a novel subtilisin inhibitor gene and mutant derivatives for the expression and secretion of mouse tumor necrosis factor alpha by Streptomyces lividans.
In order to evaluate the expression and secretion signals of the highly secreted subtilisin inhibitor of Streptomyces venezuelae CBS762.70 (VSI) for the production of heterologous proteins by Streptomyces lividans, mouse tumor necrosis factor alpha (mTNF) was chosen as a model protein. The mTNF cDNA was fused to the vsi signal sequence. The analysis of secretion by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and biological activity measurements revealed an efficient translocation of mTNF. Up to 300 mg of secreted biologically active mTNF per liter could be obtained in shaken-flask cultures. By analyzing the effects of mutations in the N region of the VSI signal peptide on secretion, we found that decreasing the +3 charge of the wild-type protein to +2 resulted in a 3- to 10-fold increase in secretion.


[Gallstone ileus--is it possible to reduce the still high mortality rate? An analysis of personal cases and review of the literature].
Acute intestinal obstruction caused by gallstones: we report about our own experience with 13 patients and discuss this topic by referring to the current literature. Since there is indeed a tendency towards multimorbidity in our high-aged population, a gallstone ileus should always be included in the differential diagnosis of acute intestinal obstruction in the elderly. We put emphasis on a less traumatic operative procedure (enterolithotomy). Good results can be achieved (in terms of postoperative mortality) by operating at the early onset of symptoms.


[Functional hemisphere differences in auditory and tactile recognition in aged people].
The effects of aging on hemispheric specialization in verbal and visuo-spatial functions were examined by dichotic listening and tactile recognition tests. In the first experiment, thirty aged (65-91 year) intact subjects and university students were tested by a dichotic listening tape with pairs of two-syllable meaningful words. The results revealed an overall decline of scores in the aged subjects but there was no interaction between subject and the degree of right ear advantage. In the second experiment, subjects were asked to judged whether successively presented nonsense tactile stimuli to each hand were identical or not. Reaction times and accuracy rates of each hand of the aged subjects were inferior to those of the control subjects. However, no interaction was found between hand and subject group. Both experiments show that there is no evidence to suggest any selective deterioration or specialization of hemispheric function in the aged people, though overall performance level declines with age, which may be caused by short-term memory deficit.


Repeated cocaine treatment decreases whole-cell calcium current in rat nucleus accumbens neurons.
Dopamine D1 receptors within the nucleus accumbens (NAc) are intricately involved in the rewarding effects of cocaine and in withdrawal symptoms after cessation of repeated cocaine administration. These receptors couple to a variety of ion channels to modulate neuronal excitability. Using whole-cell recordings from dissociated adult rat NAc medium spiny neurons (MSNs), we show that, as in dorsal striatal MSNs, D1 receptor stimulation suppresses N- and P/Q-type Ca(2+) currents (I(Ca)) by activating a cAMP/protein kinase A/protein phosphatase (PP) signaling system, presumably leading to channel dephosphorylation. We also report that during withdrawal from repeated cocaine administration, basal I(Ca) density is decreased by 30%. Pharmacological isolation of specific I(Ca) components indicates that N- and R-type, but not P/Q- or L-type, currents are significantly reduced by repeated cocaine treatment. Inhibiting PP activity with okadaic acid enhances I(Ca) in cocaine withdrawn, but not control, NAc neurons, suggesting an increase in constitutive PP activity. This suggestion was supported by a significant decrease in the ability of D1 receptor stimulation and direct activation of cAMP signaling to suppress I(Ca) in cocaine-withdrawn NAc neurons. Chronic cocaine-induced reduction of I(Ca) in NAc MSNs will globally impact Ca(2+)-dependent processes, including synaptic plasticity, transmitter release, and intracellular signaling cascades that regulate membrane excitability. Along with our previously reported reduction in whole-cell Na(+) currents during cocaine withdrawal, these findings further emphasize the important role of whole-cell plasticity in reducing information processing during cocaine withdrawal.


[Fibrinolysis in right ventricular thrombus].
After fracture of his toes, a 34-year-old male patient developed deep leg vein thrombosis and subsequent pulmonary embolism. Because of progressive heart enlargement, 2D-echocardiography was performed. A floating mass measuring 4.5 cm X 3.5 cm was found in the right ventricle. On account of the deep leg vein thrombosis and the lung perfusion deficits detected by scintigraphy, the floating mass was thought to be a thrombus. Because of the severity of the patient's state and the lack of success of a heparin therapy with 32,000 IU/d, fibrinolytic treatment with streptokinase was started. After initial improvement in pulmonary gas exchange the patient died about 7 hours later from progressive cardiopulmonary insufficiency. Necropsy revealed a smaller right ventricular thrombus than that seen by echocardiography. There were typical surface erosions caused by the fibrinolytic treatment. Many younger and older emboli which in part were fragmented could be shown in the pulmonary vessels. A fragmentation of the right ventricular thrombus and subsequent lethal occlusion of pulmonary vessels had to be considered. With respect to the course of the described case and some case reports in the literature we think fibrinolysis is more dangerous than surgical thrombectomy in right ventricular thrombosis.


[Severe immunoallergic hemolytic anemia caused by a glafenine metabolite].
Three weeks after a surgical operation, a 74-year old woman was admitted to hospital for severe haemolytic anaemia. A strongly positive IgG type direct Coombs test pointed to a iatrogenic origin, but a search for anti-molecule antibodies directed against all medicines taken by the patient after surgery was negative. We extended our immunological investigations and were able to demonstrate the presence of IgG type antibodies directed against an ex vivo metabolite of glafenine.


Assessment of mastication in healthy children and children with cerebral palsy: a validity and consistency study.
The aim of this study was to develop the Mastication Observation and Evaluation instrument for observing and assessing the chewing ability of children eating solid and lumpy foods. This study describes the process of item definition and item selection and reports the content validity, reproducibility and consistency of the instrument. In the developmental phase, 15 experienced speech therapists assessed item relevance and descriptions over three Delphi rounds. Potential items were selected based on the results from a literature review. At the initial Delphi round, 17 potential items were included. After three Delphi rounds, 14 items that regarded as providing distinctive value in assessment of mastication (consensus >75%) were included in the Mastication Observation and Evaluation instrument. To test item reproducibility and consistency, two experts and five students evaluated video recordings of 20 children (10 children with cerebral palsy aged 29-65 months and 10 healthy children aged 11-42 months) eating bread and a biscuit. Reproducibility was estimated by means of the intraclass correlation coefficient (ICC). With the exception of one item concerning chewing duration, all items showed good to excellent intra-observer agreement (ICC students: 0.73-1.0). With the exception of chewing duration and number of swallows, inter-observer agreement was fair to excellent for all items (ICC experts: 0.68-1.0 and ICC students: 0.42-1.0). Results indicate that this tool is a feasible instrument and could be used in clinical practice after further research is completed on the reliability of the tool.


Emergency double balloon enteroscopy: a feasible and promising diagnostic as well as possible therapeutic option in recurrent midgut bleeding.
Gastrointestinal (GI) tract bleeding, in particular originating within the long segment of the small intestine, remains a diagnostic and therapeutic challenge. The authors describe the potential utility of emergency double balloon enteroscopy (DBE) for small bowel bleeding. An elderly woman was admitted because of a hypertensive crisis to the medical department of a regional hospital. Her medical history was significant for non-steroidal anti-inflammatory drug (NSAID) abuse. While in hospital she had massive obscure GI bleeding. Upper GI endoscopy and colonoscopy for recurrent bleeding showed only thrombotic residuals in two sigmoid diverticuli, which led to segmental resection of the sigmoid colon. However, postoperatively, bleeding recurred leading to transfer to our university hospital. Immediate angiography only revealed a vascular malformation at the upper jejunum but no ongoing bleeding. Subsequent emergency DBE detected an oozing jejunal ulcer, which was coagulated using a argon beamer. Because of recurrent falls in haemoglobin with the need for repeated transfusion, the patient underwent surgical reintervention including segmental resection of the ulcerated upper jejunum with subsequent end-to-end anastomosis. Histopathology revealed NSAID-induced ulcerous jejunopathy. Postoperatively, there was no further bleeding and the patient was discharged home in a stable condition. In conclusion, this is one of the first reports of successful emergency use of DBE in a case of recurrent and occult bleeding within the small bowel which successfully located the source of bleeding and facilitated successful superficial ulcer coagulation with an argon beamer to prevent further bleeding.


Effects of Homogeneous and Heterogeneous Crowding on Translational Diffusion of Rigid Bovine Serum Albumin and Disordered Alfa-Casein.
Intracellular environment includes proteins, sugars, and nucleic acids interacting in restricted media. In the cytoplasm, the excluded volume effect takes up to 40% of the volume available for occupation by macromolecules. In this work, we tested several approaches modeling crowded solutions for protein diffusion. We experimentally showed how the protein diffusion deviates from conventional Brownian motion in artificial conditions modeling the alteration of medium viscosity and rigid spatial obstacles. The studied tracer proteins were globular bovine serum albumin and intrinsically disordered α-casein. Using the pulsed field gradient NMR, we investigated the translational diffusion of protein probes of different structures in homogeneous (glycerol) and heterogeneous (PEG 300/PEG 6000/PEG 40,000) solutions as a function of crowder concentration. Our results showed fundamentally different effects of homogeneous and heterogeneous crowded environments on protein self-diffusion. In addition, the applied "tracer on lattice" model showed that smaller crowding obstacles (PEG 300 and PEG 6000) create a dense net of restrictions noticeably hindering diffusing protein probes, whereas the large-sized PEG 40,000 creates a "less restricted" environment for the diffusive motion of protein molecules.


Chitosan: Properties and Its Application in Agriculture in Context of Molecular Weight.
Chitosan is a naturally occurring compound that can be obtained from deacetylated chitin, which is obtained from various sources such as fungi, crustaceans, and insects. Commercially, chitosan is produced from crustaceans. Based on the range of its molecular weight, chitosan can be classified into three different types, namely, high molecular weight chitosan (HMWC, >700 kDa), medium molecular weight chitosan (MMWC, 150-700 kDa), and low molecular weight chitosan (LMWC, less than 150 kDa). Chitosan shows several properties that can be applied in horticultural crops, such as plant root growth enhancer, antimicrobial, antifungal, and antiviral activities. Nevertheless, these properties depend on its molecular weight (MW) and acetylation degree (DD). Therefore, this article seeks to extensively review the properties of chitosan applied in the agricultural sector, classifying them in relation to chitosan's MW, and its use as a material for sustainable agriculture.


Inverse problems in geographical economics: parameter identification in the spatial Solow model.
The identification of production functions from data is an important task in the modelling of economic growth. In this paper, we consider a non-parametric approach to this identification problem in the context of the spatial Solow model which allows for rather general production functions, in particular convex-concave ones that have recently been proposed as reasonable shapes. We formulate the inverse problem and apply Tikhonov regularization. The inverse problem is discretized by finite elements and solved iteratively via a preconditioned gradient descent approach. Numerical results for the reconstruction of the production function are given and analysed at the end of this paper.


Interactional complexity and communication.
This paper draws attention to an oversimplification that we believe has been frequently made in the analysis of interpersonal communication. This happens when one uses interpersonal communication models that do not match the interactional complexity of the system under observation. The aim of the paper is to present some conceptual parameters (Territoriality, Temporality, Duality) of an N-adic model of communication in the effort to match the interactional complexity of the N-person games. In other words, if we accept the so-called "systems" approach, we need communication models that allow us to observe different levels of interactional complexity. The observer (the therapist) may decide on which level to take up his or her stance with reference to the particular case at hand and the goals in studying it.


[Alcoholic and nonalcoholic steatohepatitis: the same disease! II. Management].
Both alcoholic and non-alcoholic steatohepatitis share common histological findings and the risk of developing cirrhosis. Liver biopsy is required for the diagnosis, and the aim of treatment is to prevent cirrhosis. In alcoholic steatohepatitis, abstinence from alcohol is associated to prednisone in a severe form, as defined by a Maddrey's score > 32. Due to common pathogenic mechanisms, we recommend that coexisting metabolic alterations that are commonly observed in non-alcoholic steatohepatitis should also be treated in alcoholics. Thus, weight reduction, physical exercise, improvement of insulin sensitivity and reduction of oxidative stress, all may be beneficial both in alcoholic and non-alcoholic steatohepatitis.


[Prognostic factors of vulvar cancer].
While vulvar cancer is rare in Japan, the management of this disease has changed dramatically over the past 20 years. The radical vulvectomy that was previously believed to be the only effective treatment for vulvar cancer has now been replaced by more individualized treatments, from the standpoint of QOL. Because the lesion diameter and groin node status (laterality and number positive) are the most important prognostic factors of vulvar cancer, numerous refinements have been made in the management. The refinements include conservative surgery for patients with isolated lesions, omission of groin lymph node dissection in T 1 A tumors with stromal invasion <1 mm, and omission of contralateral groin lymph node dissection in T 1 tumor with negative ipsilateral node metastasis. In addition to these changes, elimination of groin dissection using sentinel lymph node procedure and preoperative chemoradiation for patients with advanced disease are currently under investigation. In this review, we discuss these issues along with the evidence upon which these therapies are based.


1-(3,5-Dimethyl-phenyl)-2-(4-fluoro-phenyl)-4,5-dimethyl-1H-imidazole.
In the title compound, C(19)H(19)FN(2), the imidazole ring is essentially planar [maximum deviation of 0.0015 (9) Å] and makes dihedral angles of 77.61 (9) and 26.93 (10)° with the benzene rings attached to nitro-gen and carbon, respectively. The dihedral angle between the two benzene rings is 78.84 (8)°. A C-H⋯π inter-action is found in the crystal structure.


Cognitive development from infancy to young adulthood in common marmosets (Callithrix jacchus): Effect of age, sex, and hormones on learning and affective state.
Studies looking at individual variability in cognition have increased in recent years. We followed 43 marmosets (21 males, 22 females) from infancy to young adulthood. At 3-months old, marmosets were trained to touch a rewarded stimulus. At 9-, 15-, and 21-months old, they were given visual discrimination and cognitive bias tests, and urine samples were collected to examine hormone levels. Marmosets were significantly more successful learners at 15 months than 9 months. Individuals who were more successful learners at 9 months were also more successful at 15 months, with more male learners than expected at 15 months. At 9 months, learning success was associated with higher cortisol levels. At 15 months, males with higher estradiol levels were more successful learners, whereas at 21 months, females with higher estradiol and cortisol levels tended to be less successful learners and more pessimistic. Nine months, therefore, appears to be an important developmental timepoint for acquiring cognitive control, which has developed by 15 months. Steroids may have differential effects on each sex, with complex interactions between gonadal and adrenal hormones having an influence on cognitive function over the lifespan. This longitudinal study offers new insight into cognition, including its development and biological underpinnings.


A Systematic Approach to Restoring Full Arch Length with Maxillary Fixed Implant Reconstruction: The PATZi Protocol.
The traditional configuration of four maxillary implants to restore full-arch maxillary fixed implant prostheses is not without pitfalls. Intraoperative variability, such as bone quality and quantity, may lead to unexpected intraoperative challenges that may not allow for execution of the original treatment plan. Additionally, extensive maxillary sinus pneumatization may inhibit posterior spread and lead to a shortened dental arch or excessive cantilever forces. The PATZi protocol is a systematized algorithm for maxillary full-arch implant treatment planning that addresses such intraoperative surprises and achieves full arch length in the planned prosthesis. PATZi also assigns a numbering classification to each implant configuration, which leads to uniform communication and grading of surgical difficulty, as well as predictable planning for developing future salvage plans. By using the PATZi protocol as a guideline, the surgeon may improve composite torque value and anteroposterior (AP) spread, eliminate distal cantilever forces, and ultimately improve the predictability of the prosthetic treatment plan.


Dissolved PCBs, PAHs, and HCB in pore waters and overlying waters of contaminated harbor sediments.
Aqueous concentrations of polychlorinated biphenyls (PCBs), polyaromatic hydrocarbons (PAHs), pentachlorobenzene, and hexachlorobenzene (HCB) were determined by exposing low-density polyethylene (LDPE) strips to the pore waters and the overlying water in two contaminated harbors. LDPE strips were also exposed in the laboratory to sediment slurries and to stagnant sediments collected at the same locations. Surprisingly short equilibration time scales (1-60 days for log K(ow) < 7) were observed for the exposures to sediment slurries. This was a result of a profound decrease in transport resistance, due to the presence of particles in the aqueous boundary layer. Concentrations in the pore water were calculated from the initial uptake rates and the dissipation rates of performance reference compounds. Good correspondence existed with concentrations estimated from the equilibrium amounts in the strips and LDPE-water partition coefficients. Sediment-water partition coefficients for PAHs were higher than for PCBs and chlorobenzenes by approximately 1 order of magnitude. A one-dimensional diffusion model was used to describe contaminant uptake by LDPE strips from stagnant sediments. The results indicated that 95% of the PAHs and 50% of the PCBs were immobile on a time scale of two months. A comparison of concentrations in pore waters and water columns indicated that a fair degree of equilibrium existed for PCBs and that one sediment was a potential source of PAHs. Concentrations of HCB near a former discharge site were higher by a factor of 6 compared to reference locations.


Efficiency and performance tests of the sorptive building materials that reduce indoor formaldehyde concentrations.
The adsorption of volatile organic compounds by building materials reduces the pollutant concentrations in indoor air. We collected three interior building materials with adsorption potentials-latex paint, micro-carbonized plywood, and moisture-buffering siding-used the sorptive building materials test (SBMT) to determine how much they reduced indoor formaldehyde (HCHO) concentrations, and then assessed the consequent reduction in human cancer risk from HCHO inhalation. Adsorption of HCHO by building materials significantly improved the effective ventilation efficiency. For example, the equivalent ventilation rate for Celite siding-used for humidity control-was 1.44 m3/(m2·h) at 25°C, 50% relative humidity (RH); the loading factor (L) was 0.4 m2/m3, and the HCHO concentration was 0.2 ppm; this effect is equivalent to a higher ventilation rate of approximately 0.6 air changes per hour in a typical Taiwanese dwelling. There was also a substantial reduction of risk in Case MCP-2 (Cin,te: 245 μg/m3, 30°C, 50% RH): males: down 5.73 × 10-4; females: down 4.84 × 10-4). The selection of adsorptive building materials for interior surfaces, therefore, significantly reduces human inhalation of HCHO. Our findings should encourage developing and using innovative building materials that help improve indoor air quality and thus provide building occupants with healthier working and living environments.


Linear association between maternal age and need of medical interventions at delivery in primiparae: a cohort of 21,235 singleton births.
We sought to investigate the potential association between maternal age and the need for active obstetrical intervention intrapartum in primiparas. Observational study over 14 years (2001-2014) of all consecutive primiparous singleton births having delivered at the Centre Hospitalier Universitaire Hospitalier Sud Reunion's maternity (French overseas department, Indian Ocean). Of the 21,235 singleton primiparous births, there were three significant linear associations between maternal age from 12 years of age to 42 + (all χ2 for linear trend, p < .0001) (a) vaginal deliveries without any medical intervention, (b) rate of cesarean sections, and (c) rate of operative vaginal procedures. These three linear associations persisted when controlling for maternal obesity (±30 kg/m2), "heavy babies" (>3.5 kg), and ethnicity. Using maternal age remained significantly an independent risk factor (p < .0001), after controlling for the major confounders: maternal BMI, maternal height, birthweight ≥3500 g, p < .0001. Increasing maternal age has a linear association with vaginal deliveries without any medical intervention, rate of cesarean sections, and rate of operative vaginal procedures. These associations are independent of maternal BMI and maternal height. We currently do not have a specific explanation why younger women appear to be protected from requiring intrapartum obstetric intervention. Nevertheless, these strong facts deserve acknowledgement and further research.


You don't always get what you want, and you don't always want what you get: An examination of control-desire for control congruence in transactional relationships.
In this research we develop a framework to examine the drivers of customers' desire for control over the sales relationship, and consequences of fit between perceived and desired control. Data collected in a lagged field study of 144 retailer manager (customer)-salesperson dyads were modeled using hierarchical linear modeling and response surface modeling techniques. Results from our analysis reveal that salesperson expertise drives retailers' desire for control in these relationships. In addition, while incongruence in perceived-desired control was negatively associated with both satisfaction and objective sales, retailer satisfaction was higher when both desired and perceived control were high. Further, as desired and perceived control over the sales relationship both increase, product sales initially decrease, and then increase, exhibiting a "U-shaped" effect. Implications for both theory and practice are discussed. These include adaptive sales training to identify misalignment between desired and perceived control, optimization of cocreation strategies, incorporation of interorganizational relational constructs, exploration of triadic social network configurations, examination of unmet expectations, and the implications of assimilation-contrast theory.


Pseudoaneurysm of the aortic arch after aortosubclavian bypass treated with endoluminal stent grafting--a case report.
This paper describes a case of aortic arch pseudoaneurysm treated with stent graft 2 years after aortosubclavian bypass repair of a subclavian artery aneurysm. An 84-year-old man presented with back pain. Two years before, he had had a left subclavian artery aneurysm repaired with aortosubclavian bypass. Upon examination by computed tomography (CT) scan and angiography he was found to have a bovine arch configuration, a 7-centimeter pseudoaneurysm arising from the stump f the native subclavian artery, a patent aortosubclavian bypass, and a left hemothorax. A 37 mm by 10 mm Gore Excluder thoracic graft was introduced into the right femoral artery cutdown and deployed across the arch, excluding the pseudoaneurysm and preserving the brachiocephalic vessels. Follow up CT scan at 1 year shows exclusion of the pseudoaneurysm. The patient continues to do well 1 year after implantation without evidence of endoleak. In the presence of unusual anatomical characteristics, endoluminal stent graft repair can be successfully performed across the aortic arch.


FLUCTUATING ASYMMETRY IN A SALIX HYBRID SYSTEM: THE IMPORTANCE OF GENETIC VERSUS ENVIRONMENTAL CAUSES.
To examine the effects of hybridization and environmental stress on developmental instability, we examined fluctuating asymmetry (FA), the variance in random deviations from perfect symmetry in bilaterally symmetrical traits, for leaf symmetry in a Salix hybrid system. An abiotic environmental stress (water stress), an interspecific biotic stress (pathogen attack), and an intraspecific biotic stress (competition) were examined to determine which factors increase developmental instability. None of these three environmental stressors significantly increased FA. However, genetic stress through hybridization was detected; hybrid plants showed significantly higher levels of FA than parental species. In contrast to hybridization providing greater developmental stability through heterozygosity, these results suggest that complex, nonadditive interactions provided developmental stability and that developmental instability increased when coadapted gene complexes were disrupted through hybridization. In addition, plant biomass was significantly, negatively correlated with FA, suggesting that those individuals that were more able to buffer themselves against the disruptive effects of environmental stress may have a selective advantage over those that are less able to buffer themselves against these disruptive effects.


Interferon level in human normal sera.
Interferon (IFN) level in the sera of normal humans was determined by their protective effect on a KB cell culture against the cytopathic effect (CPE) induced by vesicular stomatitis virus. The technique revealed all the three known types of IFN. In the investigated population 15 of 37 sera (40%) were found to protect against the CPE at 1/10 dilution, 11 of 37 (30%) still protect at 1/20 dilution, and 7 of 37 sera (19%) still protect at a dilution of 1/40. No serum was found to have detectable IFN levels at 1/80 dilution. We can thus consider that the normal serum level ranges up to a 1/20 dilution i.e., up to 20 IU/ml. The above titers are slightly higher than the normal IFN level reported by other investigators in other human populations, although no clear reasons can be given to account for the differences.


A retrospective analysis of 7 cases of familial mediterranean fever.
Familial mediterranean fever (FMF) is a single inherited autoinflammatory disease characterized by periodic fever with relatively short duration of 1 to 3 days and sterile serositis. Although the prevalence rate is highest in the Mediterranean coastal area, a large number of cases have been reported recently by genetic analysis by identification of MEFV (Mediterranean fever) which is responsible gene in Japan too. In outpatient department of rheumatology, diagnosis and treatment of FMF is performed in cases where fever and abdominal pain attack are repeated for a short period of time. We examined cases in which symptoms considered periodic seizures were repeated, excluding autoimmune diseases, infectious diseases, and malignant tumors. In both cases, genetic analysis is performed as auxiliary diagnosis. Seven cases satisfied the Tel-Hashomer criteria criteria and MEFV gene mutation was detected. Everyone was a female, and half had seizure symptoms at menstruation. Even though there is a difference in the amount of colchicine to be used, either one is effective. In cases of periodic symptoms or cases called periodic fever, exclusion diagnosis is carried out, there is a need to suspect FMF, determine the effect of colchicine, and perform genetic analysis.


Counseling the pregnant vegetarian.
Underlying any successful counseling effort must be an understanding of the acceptable and unacceptable foods of the particular person being counseled, with the recognition that nutrient needs may be met in many ways. This knowledge base necessary for successful counseling along with an understanding of other lifestyle practices that may have an impact on health will be difficult to develop unless rapport is established. Nonjudgmental, accepting attitudes on the part of the health professional are essential to the development of relationships with those individuals who may be suspicious of traditional medical and health-care practices. Strategies for counseling with particular attention to the vegetarian are noted.


Thermal diffusivity of composite restorative materials.
The substantial increases in the filler volume fraction of the current generation of composite resins, and the incorporation of radiopacifying heavy elements in many of these fillers, constitute significant changes which may affect thermal transport properties. Thermal diffusivity has been determined for 21 of these composite materials recommended for anterior and posterior applications. For radiopaque hybrid and for microfine composites, there was, however, only a gradual trend to increased thermal diffusivity with increasing volume fraction of inorganic filler. The diffusivity values were not greatly in excess of the level observed for dentin. Nevertheless, a small group of materials, incorporating substantial amounts of quartz or silicon nitride filler particles, exhibited high rates of thermal diffusion, up to three times the level exhibited by dentin.


Inferior alveolar neurosensory deficiency associated with placement of dental implants.
This study reports and analyzes a large series of patients with neurosensory deficiency related to the placement of dental implants (DIs) and resulting in liability claims (LCs). From 1998 to 2009, there were 92 LCs related to persistent altered sensation post DI placements in Israel. Patients' demographics, year and source of LCs, interval between the procedure that resulted in a neurosensory deficiency and the LC, qualifications of the surgeon, preoperative imaging modality, DI length, available alveolar bone for DI placement, placement site, timing of DI placement (immediately after tooth extraction or after socket healing), and treatment after the diagnosis of neurosensory deficiency were recorded and analyzed. There were 21 cases during the first 5 years of the study (mean 4.2/year) and 63 cases (mean 12.6/year) over the following 5 years. Thirty LCs were issued during the second postoperative year and 15 LCs after >5 years. Most LCs (76%) involved procedures that were planned and performed according to radiographs and 24% after computed tomography. Sixty-five percent of the LCs were performed by general dental practitioners and 35% by specialists. More than one DI was performed during the surgical procedure that resulted in a neurosensory deficiency in 73 LCs (79.3%), and the DI was >10 mm in 55 (59.8%) cases. LCs for DIs that result in a neurosensory deficiency pose a legal risk to the practitioner long after the injury has occurred.


Variables associated with mouth breathing diagnosis in children based on a multidisciplinary assessment.
: This study was conducted to identify variables associated with mouth breathing diagnosis in children, based on multidisciplinary domains. 119 children, six to 12 years old, underwent anamnesis, speech therapy (orofacial structures and stomatognathic functions), otorhinolaryngologic (OTRL) with clinical and endoscopic examinations, dental (occlusion) and physiotherapy (body posture and nasal patency) assessments. Nasal patency was evaluated using Peak Nasal Inspiratory Flow (PNIF) and the Nasal Obstruction Symptom Evaluation (NOSE) scale. A multiple logistic regression was performed considering breathing mode as the dependent variable and the co-variables from each multidisciplinary assessment as associated variables. Association with MB diagnosis was found in each professional domain with: nasal obstruction report (Odds ratio - OR=5.55), time of pacifier use (OR=1.25), convex facial type (OR=3.78), obtuse nasal angle (OR=4.30), half-open or open lip posture (OR=4.13), tongue position on the mouth floor (OR=5.88), reduced hard palate width (OR=2.99), unexpected contraction during mastication (OR=2.97), obstructive pharyngeal tonsils (OR=8.37), Angle Class II malocclusion (OR=10.85) and regular gingival maintenance (OR=2.89). We concluded that a multidisciplinary diagnosis is important, given that each evaluation domain, including OTRL, dental and speech therapy, presented variables associated with MB diagnosis. Body posture and nasal patency variables were not associated with MB.


Chemotaxis towards hyaluronan is dependent on CD44 expression and modulated by cell type variation in CD44-hyaluronan binding.
The accumulation of the extracellular matrix glycosaminoglycan hyaluronan by tumours and tumour-associated stroma promotes cancer cell invasion and metastasis. Using the Dunn chamber chemotaxis assay, we demonstrate for the first time that high molecular mass hyaluronan acts as a soluble chemoattractant promoting the directional migration of MDA-MB-468 and MDA-MB-231 breast cancer cells. Moreover, chemotaxis towards hyaluronan, but not foetal bovine serum, can be abrogated following treatment of the cells with siRNA oligonucleotides to downregulate CD44 expression. These data indicate that CD44 is the principal receptor mediating this response and that CD44 expression is not a general requirement for cell migration and gradient sensing, rather it elicits a ligand-specific response. However, expression of CD44 alone is not sufficient to drive chemotaxis towards hyaluronan, as NIH-3T3 fibroblasts were unable to respond to a hyaluronan gradient even when transfected with high levels of human CD44. For NIH-3T3 cells to bind exogenous hyaluronan, it was necessary to both increase the level of receptor expression and remove a hyaluronan pericellular matrix. Together, these studies reveal a direct mechanism for promoting cell invasion into the hyaluronan-rich matrix and predict that in the complex multicellular environment in vivo, multiple mechanisms exist to regulate the ability of a cell to respond to a chemotactic hyaluronan gradient.


A review of the use of routine data on CHD in general practice research in Scotland.
The primary aim of the Platform Project is to maximise the use of routine data for primary care research in Scotland. To assess the extent to which routine data is available and has been used in studies on CHD in General Practice research in Scotland. To assess the advantages and limitations of using routine data in this setting. Literature review using a variety of databases catalogues and websites, bibliographies of articles retrieved and searching through journals by hand not available electronically. This review has found that the use of routine data in CHD studies in General Practice research in Scotland remains small. There has been little work undertaken which has combined the use of routine data with other research methods. Limitations with routine data exist particularly with regard to risk factors and ethnicity. However, despite such limitations there exists an increasingly extensive range of data, which exists to help explain tends in CHD, which so far has been largely underused.


New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis.
Multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis, are neuroinflammatory diseases driven by autoreactive pathogenic TH cells that elicit demyelination and axonal damage. How TH cells acquire pathogenicity and communicate with myeloid cells and cells of the CNS remain unclear. IL-1β is recognized to play an important role in experimental autoimmune encephalomyelitis (EAE) and perhaps MS. Clinical EAE is significantly attenuated in IL-1R-deficient and IL-1β-deficient mice, and IL-1β is found in the blood, cerebrospinal fluid, and CNS lesions of MS patients. In this article, we focus on new reports that elucidate the cellular sources of IL-1β and its actions during EAE, in both lymphoid tissues and within the CNS. Several immune cell types serve as critical producers of IL-1β during EAE, with this cytokine inducing response in both hematopoietic and nonhematopoietic cells. These findings from the EAE model should inspire efforts toward investigating the therapeutic potential of IL-1 blockade in MS.


Induction of the SOS response and mutations by reactive oxygen-generating compounds in various Escherichia coli mutants defective in the mutM, mutY or soxRS loci.
Derivatives of E. coli WP2s (uvrA trpE) defective in 7,8-dihydro-8-oxoguanine (8-OG) DNA glycosylase activity (mutM), MutY glycosylase activity on an A:8-OG mispair (mutY), and/or an adaptive response to oxidative stress by superoxide (soxRS) were constructed to compare the mutability to various reactive oxygen-generating compounds. Induction of Trp+ reversion was assayed both in the presence and absence of plasmid pKM101. Phenazine methosulfate and phenazine ethosulfate showed mutagenic activity at a relatively low dose in soxRS mutants. In comparison to the parent strain WP2s, however, the introduction of mutM, mutY, or soxRS mutations, in any combination, did not make the strain hypersensitive in terms of mutability (i.e. mutation induction at relatively low doses) to hydrogen peroxide, cumene hydroperoxide, t-butyl hydroperoxide, or phenylhydrazine. Mutagenicity of formaldehyde was detected only in the pKM101-carrying strains. On the other hand, bleomycin, menadione, plumbagin, paraquat, and diquat were not mutagenic to any strain, with or without pKM101. The SOS-response inducing activity was measured by monitoring the expression of a umu'-'lacZ fusion gene, carried on the plasmid pSK1002. The induction of the SOS response by hydrogen peroxide, cumene hydroperoxide, t-butyl hydroperoxide, formaldehyde, phenylhydrazine, and bleomycin was of almost the same magnitude between the parent strain and a mutM or soxRS mutant. Phenazine methosulfate and phenazine ethosulfate induced the SOS response only in the soxRS derivatives. No induction was detected by treatment with redox-cycling compounds, such as menadione, plumbagin, paraquat, or diquat.


A morphospace for reef fishes: elongation is the dominant axis of body shape evolution.
Tropical reef fishes are widely regarded as being perhaps the most morphologically diverse vertebrate assemblage on earth, yet much remains to be discovered about the scope and patterns of this diversity. We created a morphospace of 2,939 species spanning 56 families of tropical Indo-Pacific reef fishes and established the primary axes of body shape variation, the phylogenetic consistency of these patterns, and whether dominant patterns of shape change can be accomplished by diverse underlying changes. Principal component analysis showed a major axis of shape variation that contrasts deep-bodied species with slender, elongate forms. Furthermore, using custom methods to compare the elongation vector (axis that maximizes elongation deformation) and the main vector of shape variation (first principal component) for each family in the morphospace, we showed that two thirds of the families diversify along an axis of body elongation. Finally, a comparative analysis using a principal coordinate analysis based on the angles among first principal component vectors of each family shape showed that families accomplish changes in elongation with a wide range of underlying modifications. Some groups such as Pomacentridae and Lethrinidae undergo decreases in body depth with proportional increases in all body regions, while other families show disproportionate changes in the length of the head (e.g., Labridae), the trunk or caudal region in all combinations (e.g., Pempheridae and Pinguipedidae). In conclusion, we found that evolutionary changes in body shape along an axis of elongation dominates diversification in reef fishes. Changes in shape on this axis are thought to have immediate implications for swimming performance, defense from gape limited predators, suction feeding performance and access to some highly specialized habitats. The morphological modifications that underlie changes in elongation are highly diverse, suggesting a role for a range of developmental processes and functional consequences.


Metabolic Obesity Phenotypes and Risk of Cellulitis: A Cohort Study.
No cohort studies have evaluated the effect of obesity on the risk of cellulitis according to metabolic health status. We investigated an association of BMI and metabolic health status with the development of cellulitis. We conducted a cohort study of 171,322 Korean adults who underwent a health checkup examination and were followed from 2011 to 2016 for cellulitis and hospital admission related to cellulitis, which were ascertained through the linkage to the Health Insurance and Review Agency database. Being metabolically healthy was defined as not having any metabolic syndrome component and having a homeostasis model assessment of insulin resistance <2.5. During 638,240.4 person-years of follow-up, 14,672 cases of incident cellulitis were identified with 225 cases of cellulitis-related admission. After adjustment for possible confounders, the multivariable-adjusted hazard ratios (95% CI) for incident cellulitis comparing BMIs 23-24.9, 25-29.9, and ≥30 with a BMI of 18.5-22.9 kg/m2 as the reference were 1.07 (1.02-1.11), 1.09 (1.04-1.13), and 1.19 (1.08-1.31), respectively, whereas the corresponding multivariable-adjusted hazard ratios (95% CI) for cellulitis-related admission were 1.55 (1.05-2.3), 2.47 (1.73-3.53), and 4.8 (2.86-8.05), respectively. These associations were consistently observed in both metabolically healthy and unhealthy individuals with no significant interaction. In a large cohort of apparently healthy adults, increased BMI was associated with an increased risk of cellulitis and hospitalization for cellulitis in both metabolically healthy and unhealthy individuals. Obesity appears to be an independent risk factor for cellulitis regardless of metabolic phenotype.


Poly(T) variation in heteroderid nematode mitochondrial genomes is predominantly an artefact of amplification.
We assessed the rate of in vitro polymerase errors at polythymidine [poly(T)] tracts in the mitochondrial DNA (mtDNA) of a heteroderid nematode (Heterodera cajani). The mtDNA of these nematodes contain unusually high numbers of poly(T) tracts, and have previously been suggested to contain biological poly(T) length variation. However, using a cloned molecule, we observed that poly(T) variation was generated in vitro at regions containing more than six consecutive Ts. This artefactual error rate was estimated at 7.3 × 10(-5) indels/poly(T) tract >6 Ts/cycle. This rate was then compared to the rate of poly(T) variation detected after the amplification of a biological sample, in order to estimate the 'biological + artefactual' rate of poly(T) variation. There was no significant difference between the artefactual and the artefactual + biological rates, suggesting that the majority of poly(T) variation in the biological sample was artefactual. We then examined the generation of poly(T) variation in a range of templates with tracts up to 16 Ts long, utilizing a range of Heteroderidae species. We observed that T deletions occurred five times more frequently than insertions, and a trend towards increasing error rates with increasing poly(T) tract length. These findings have significant implications for studies involving genomes with many homopolymer tracts.


Aberration-free holographic microscope for simultaneous imaging and stimulation of neuronal populations.
A technical challenge in neuroscience is to record and specifically manipulate the activity of neurons in living animals. This can be achieved in some preparations with two-photon calcium imaging and photostimulation. These methods can be extended to three dimensions by holographic light sculpting with spatial light modulators (SLMs). At the same time, performing simultaneous holographic imaging and photostimulation is still cumbersome, requiring two light paths with separate SLMs. Here we present an integrated optical design using a single SLM for simultaneous imaging and photostimulation. Furthermore, we applied axially dependent adaptive optics to make the system aberration-free, and developed software for calibrations and closed-loop neuroscience experiments. Finally, we demonstrate the performance of the system with simultaneous calcium imaging and optogenetics in mouse primary auditory cortex in vivo. Our integrated holographic system could facilitate the systematic investigation of neural circuit function in awake behaving animals.


Severity of obstetric complications and risk of adult schizophrenia in male patients: a case-control study.
Obstetric complications may be an etiologically important factor in the development of schizophrenia. The aim of this study was to evaluate whether the risk for developing schizophrenia in adult life is increased in individuals with more severe obstetric complications at birth. To this end, mothers were interviewed to gather data about obstetric complications. The 'midwife protocol' of Parnas and colleagues was used to quantify the presence and entity of obstetric complications. We studied the frequency distribution and the severity of obstetric complications in 64 male DSM IV schizophrenic patients. The genetic load was reduced by using 81 brothers who were not psychiatric patients as controls. Odds ratios for the effects of obstetric complications, maternal age, birth order and birth weight were calculated using conditional logistic regression. The only factor found to have a significant effect on the risk of schizophrenia was the overall measure of obstetric complications at birth. The history of obstetric complications was higher in schizophrenic patients than in their siblings. The results seem to confirm the hypothesis that obstetric complications may contribute to increased vulnerability to the disease, in addition to genetic risk factors.


Development of highly sensitive fluorescent probes for detection of intracellular copper(I) in living systems.
We describe here the new copper-selective fluorescent probes FluTPA1 and FluTPA2, in which the tetradentate ligand tris[(2-pyridyl)methyl]amine (TPA) is connected to a reduced form of a fluorescein platform through a benzyl ether linkage. These probes selectively react with copper ions in the presence of submillimolar glutathione and emit intense green fluorescence from the reaction product, O-methylfluorescein. Confocal images of live cells further show that FluTPA2 is membrane-permeable and allows visualization of Cu(I) present in living cells.


[Future perspectives on tumor-specific immunotherapy using hapten-reactive T cell activity].
Recent studies concerning cellular and molecular mechanisms of T cell-mediated immunity have revealed the involvement of various types of lymphokines. Irrespective of which types of lymphokines and cell-cell interactions among various T cell subsets are involved in the implementation of host immune responses against tumor, the feasible and practical approach is to use both molecular and cellular mechanisms for the augmented induction of effector T cell activity against tumor-resistant antigens (TRA). We have demonstrated previously that the in vivo effector T cells comprise 2 subsets of TRA-specific non-cytolytic CD4- and CD8-positive helper T cells, both of which release lymphokines and activate macrophages as an ultimate anti-tumor cytocidal effector. We have also defined conditions under which enhanced anti-tumor immunity can be obtained by pre-inducing potent helper T cell activity reactive to a certain antigenic determinant such as trinitrophenyl (TNP) residue of muramyl dipeptide (MDP)-derivatives as hapten, and immunized with tumor cells coupled with the corresponding haptenic determinant. This system induced most efficient and physiological cellular and molecular mechanisms responsible for the generation of tumor-specific effector T cell activity in vivo by virtue of the close linkage of hapten-reactive helper T cells and TRA-specific effector-precursor T cells in the microenvironment of hapten-coupled tumor cells. We have subsequently demonstrated that this protocol resulted in enhanced in vivo tumor protective immunity but also was applicable to the immunotherapy whereby a growing solid tumor as well as disseminated leukemia cells could be effectively eradicated in mice. Thus, these results emphasize the role of hapten-reactive helper T cell in augmenting tumor-specific immunity, and this protocol provides an effective maneuver for tumor-specific immunotherapy in human in future.


Cholinergic-adrenergic antagonism in the induction of tachyarrhythmia by electrical stimulation in isolated rat atria.
Atrial tachyarrhythmias (AT) are the most common cardiac rhythm disturbance. In the present study, we analyzed the cholinergic-adrenergic interaction in the in vitro induction of cholinergic-dependent tachyarrhythmia by high-frequency electric stimulation. Tachyarrhythmia was evoked in isolated rat right atria by trains of electric stimuli. Atrial response was expressed as the tachyarrhythmia induction index (ATI, i.e. the fraction of applied trains that resulted in arrhythmia induction). ATI was reversibly increased by 0.6 microM carbachol (CCh), which also decreased atrial spontaneous rate (ASR). In contrast, 10 nM isoproterenol (ISO), 100 microM tyramine and the phosphodiesterase inhibitor isobutyl-methylxanthine (IBMX, 100 microM) increased ASR and decreased ATI. Amiodarone (AMI, 10 microM) reduced ATI in the presence and absence of CCh. Further CCh addition restored ATI in atria treated with either IBMX or AMI, but not when both compounds were present. Increase in ATI by CCh in atria pretreated with IBMX plus ISO was significantly attenuated by 3 mM NaF. The antagonism between cholinergic muscarinic and beta-adrenergic receptor stimulation (the former facilitating and the latter inhibiting tachyarrhythmia installation) possibly involves regulation of the phosphorylation status of adenosine cyclic 3'-5'-monophosphate (cAMP)-dependent protein kinase substrates. Additionally, cAMP-independent, AMI-sensitive mechanism stimulated by CCh (possibly muscarinic-dependent K(+) current activation) seems to contribute to AT facilitation.


Improvements of complex-valued Hopfield associative memory by using generalized projection rules.
In this letter, new design methods for the complex-valued multistate Hopfield associative memories (CVHAMs) are presented. We show that the well-known projection rule proposed by Personnaz et al. can be generalized to complex domain such that the weight matrix of the CVHAM can be designed by using a simple and effective method. The stability of the proposed CVHAM is analyzed by using energy function approach which shows that in synchronous update mode the proposed model is guaranteed to converge to a fixed point from any given initial state. Moreover, the projection geometry of the generalized projection rule (GPR) is discussed. In order to enhance the recall capability, a strategy of eliminating the spurious memories is also reported. The validity and the performance of the proposed methods are investigated by computer simulation.


Neuronal and behavioral plasticity: the role of serotonin and BDNF systems tandem.
Serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) are known as principal players in different kinds of plasticity. The 5-HT-BDNF interaction in early ontogeny and in adult brain is an intriguing problem. Area covered: This paper concentrates on the interaction between 5-HT and BDNF systems and its implication in different plasticity levels, from neurons to behavior. This review describes (1) different 5-HT functioning in the embryonic (as neurotrophin) and adult brain (as a neurotransmitter); (2) BDNF as a modulator of 5-HT system and vice versa; (3) the prolonged positive effect of BDNF on genetically and epigenetically defined central nervous system disorders; (4) The 5-HT-BDNF interplay contribution to aggressive behavior, depression, drug addiction, suicide, and stress response; and (5) the role of common second messengers for 5-HT and BDNF signaling in the 5-HT-BDNF interaction. Expert opinion: Dysregulation in 5-HT-BDNF interaction may be responsible for development of neuropsychiatric and behavioral abnormalities. 5-HT-BDNF cross-talk is a potential target for the treatment of various neurological diseases. Understanding the function of the members of BDNF system in response to challenges of the environment and the interaction with different 5-HT receptors in health and disease will one day lead to new classes of drugs.


Barbara Grier and the world she built.
Mentored in the art of lesbian literary detection by Jeannette Howard Foster, Barbara Grier became part of a vibrant print-based network of lesbians through her involvement with The Ladder. Building on that foundation, she developed Naiad Press into a successful lesbian business, one that opened doors for lesbian writers and preserved lesbian classics for new generations of readers. Shaped by her class and the times in which she came of age, Grier understood the power of print to change women's lives. Some challenged her commitment to lesbian feminism, but few questioned her dedication to building Naiad into a press that heightened lesbian visibility, fostered self-understanding, and contributed to the creation of community.


Subtle familial translocation t(11;22)(q24.2;q13.33) resulting in Jacobsen syndrome and distal trisomy 22q13.3: further details of genotype-phenotype maps.
We report on 3 kindred patients with terminal 11q monosomy and distal 22q trisomy involving the SHANK3 gene, resulting from a subtle familial translocation t(11;22)(q24.2;q13.33). The patients presented with the characteristic symptoms of Jacobsen syndrome (JBS), including: mental retardation, short stature, and craniofacial dysmorphism in all 3 cases; cardiac defects in 2 cases; and thrombocytopenia, brain abnormality, eye coloboma, recurrent infections, cryptorchidism and toe anomalies in single cases. The oldest patient also had Hashimoto disease and diabetes mellitus type 2. So far, these 2 conditions have not been reported in adult patients with JBS. Features typical for distal 22q trisomy in our patients include muscular hypotonia and prenatal failure to thrive, seen in 2 and 1 cases, respectively. We also present a family member with 11q24.2-qter trisomy and 22q13.33-qter monosomy, whose clinical phenotype is partially overlapping with several dysmorphic features of JBS. In addition, multiple pregnancy losses and infantile deaths occurred in this family, suggesting that these chromosomal imbalances may produce a lethal phenotype. FISH with a panel of BAC probes determined the accurate sizes of the deletion 11q (9.9 Mb) and trisomy 22q (0.8 Mb). To date, only 5 cases of submicroscopic 22q13.3-qter trisomy have been reported. A detailed clinical description of our patients, along with a precise cytogenetic designation of chromosomal breakpoints, allow further refinement of genotype-phenotype correlation for distal imbalances in 11q and 22q.


DNA-Based MXFs to Enhance Radiotherapy and Stimulate Robust Antitumor Immune Responses.
Metal "X" Frameworks (MXFs) constructed from metal ions and biomacromolecules ("X components") via coordination interactions show crystalline structures and diverse functionalities. Here, a series of MXFs composed of various metal ions (e.g., Zn2+, Hf4+, Ca2+) and DNA oligodeoxynucleotides were reported. With MXF consisting of Hf4+ and CpG oligodeoxynucleotides as the example, we show that such Hf-CpG MXF can achieve high-Z elements-enhanced photon radiotherapy and further trigger robust tumor-specific immune responses, thus showing efficient tumor suppression ability. In vivo experiments showed that external beam radiotherapy applied on tumors locally injected with Hf-CpG MXF result in the thorough elimination of primary tumors, complete inhibition of tumor metastasis, and protection against tumor rechallenge by triggering robust antitumor immune responses. Our findings provide a blueprint for fabricating a variety of rationally designed MXFs with desired functions and present the strategy of stimulating whole-body systemic immune responses by only local treatment of radiotherapy.


A statistical model for improved membrane protein expression using sequence-derived features.
The heterologous expression of integral membrane proteins (IMPs) remains a major bottleneck in the characterization of this important protein class. IMP expression levels are currently unpredictable, which renders the pursuit of IMPs for structural and biophysical characterization challenging and inefficient. Experimental evidence demonstrates that changes within the nucleotide or amino acid sequence for a given IMP can dramatically affect expression levels, yet these observations have not resulted in generalizable approaches to improve expression levels. Here, we develop a data-driven statistical predictor named IMProve that, using only sequence information, increases the likelihood of selecting an IMP that expresses in Escherichia coli The IMProve model, trained on experimental data, combines a set of sequence-derived features resulting in an IMProve score, where higher values have a higher probability of success. The model is rigorously validated against a variety of independent data sets that contain a wide range of experimental outcomes from various IMP expression trials. The results demonstrate that use of the model can more than double the number of successfully expressed targets at any experimental scale. IMProve can immediately be used to identify favorable targets for characterization. Most notably, IMProve demonstrates for the first time that IMP expression levels can be predicted directly from sequence.


Histopathological features of peripheral nerve and muscle in mitochondrial disease.
Despite enormous strides in the molecular diagnosis of mitochondrial disease, this approach is currently applicable to only a minority of patients who are affected with these disorders. The phenotypic spectrum in this category of disease is large and, in the absence of genotypic confirmation, a pattern recognition paradigm is probably the most sensitive means to reinforce the suspicion of mitochondrial disease. Along with clinical, biochemical, radiographic, and electrophysiological markers, histopathological features from nerve and muscle biopsy are useful indices to factor into a complex equation permitting a presumptive diagnosis or to justify more elaborate diagnostic undertakings. The combination of electrophysiological evidence of demyelinating neuropathy on nerve conduction studies and mild myopathic features on electromyography is one such constellation that should instigate a high index of suspicion for mitochondrial disease. The histopathological hallmarks of mitochondrial cytopathies on muscle biopsy are the "ragged-red fiber" on light level evaluation and paracrystalline inclusions at the electron microscopic level. Neither of these is exclusive to mitochondrial disease and both may be identified among other nonspecific changes seen in biopsy specimens. Histopathological evaluation of muscle and nerve can provide information to reinforce the likelihood of mitochondrial disease or to indicate an alternative diagnosis as the more probable cause of a patient's symptoms.


Conversational model psychotherapy.
To briefly outline historical development, theoretical orientation, evidence and areas of application for Conversational Model Psychotherapy. Conversational Model Therapy remains an important evidence-based option in fostering recovery and growth for many patients with traumatic disruptions and restrictions of self. It is one of an emerging group of relational psychotherapies, broadly reflecting a change from a one person to a two person (intersubjective) psychological paradigm in psychotherapy.


Comparative Proteome Analysis of Shewanella putrefaciens WS13 Mature Biofilm Under Cold Stress.
Worldwide, Shewanella putrefaciens is the predominant seafood spoilage microorganism during cold storage. This bacterium can attach to biotic/abiotic surfaces to form biofilms which contribute to seafood quality degradation and shelf-life reduction. The mechanism of S. putrefaciens biofilm formation is not yet described. Crystal violet staining in combination with confocal laser scanning microscopy (CLSM) was used to study the sequence of events leading to the establishment of a mature biofilm at 4, 15, and 30°C. In addition, the main chemical constituents of the mature biofilm were determined by Raman spectroscopy (RM), whereas, comparative proteomic analysis was used to quantify changes in metabolic pathways and to find out underlying protein determinants. The physical dimensions of the mature biofilm, i.e., biomass, biovolume, and mean thickness, were higher at 4°C when compared to 15 and 30°C. The variations of proteins measured by RM confirmed the importance of proteins during the formation of a mature biofilm. Comparative proteomic analysis showed that siderophore and iron chelate transport proteins were down-regulated during mature biofilm formation. The down-regulated aforementioned proteins are involved in promoting iron storage in response to a higher demand for metabolic energy, whereas, the upregulated proteins of the sulfur relay system, pyrimidine metabolism, and purine metabolism are related to bacterial adaptability. Synthesis of proteins related to cold stress was increased and proteins involved in aminoacyl-tRNA biosynthesis were up-regulated, whereas, proteins involved in aminopeptidase activity were down-regulated. Proteolysis to scavenge energy was reduced as proteins involved in pyrophosphatase activity were up-regulated. Also extracellular eDNA was found which may play an important role in maintaining the stability of mature S. putrefaciens biofilm structures under cold stress. This work provides a better understanding of the role of proteins in mature biofilms. In addition, the biofilm formation mechanism of a psychrotrophic spoilage bacterial species at low temperature is explored, which may contribute to generating biofilm controlling strategies during seafood preservation and processing.


[History of incompability among medicinals of "Glycyrrhiza antagonistic to Sargassum, Euphorbia Pekinensis, Kansui, and Genkwa" and its modern recognition].
The allegation of "Glycyrrhiza antagonistic to Sargassum, Euphorbia Pekinensis, Kansui, and Genkwa", being one of the hypotheses of "18 antagonisms" in TCM pharmacology, is referring to the antagonistic action among the Radix et Rhizoma Glycyrrhiza and Radix Euphorbiae Kansui, Radix Euphorbiae Pekinensis, Flos Genkwa, and Sargassum when compounded together in a single recipe. By reviewing its history concerted with modern knowledge, it can be found that the theory of "seven emotions" was originated from Shennong's Classic of Materia Medica; while the Variorum of the Classic of Materia Medica firstly and definitely records that Radix et Rhizoma Glycyrrhizae is forbidden to be used with Radix Kansui, Flos Genkwa, Radix Euphorbiae Pekinensis, Sargassum together in a single formula. It was summarized into a Chinese poetic sentence as above-mentioned later. In the works of later ages, including Chinese Pharmacopoeia, A Great Dictionary of Chinese Materia Medica, and China's Herbology, etc., all enhance the understanding of the prohibited combination of Radix et Rhizoma Glycyrrhizae and its incompatible herbs. Nevertheless, there are discrepancies between the results of modern experimental and clinical studies on this problem, which, needless to say, should be resolved by further investigations.


METHOD OF PERCUTANEOUS ENDOTRACHEAL CATHETERIZATION.
The accumulation of tracheal secretions is frequently due to the reluctance of a postoperative patient in severe pain to aggravate the pain by coughing. The intermittent instillation of a saponifying agent through an indwelling catheter inserted percutaneously has proved to be effective in clearing pulmonary secretions by producing a strong reflex cough. Complications with this technique were few. It is not painful and can be done quickly and easily. The Bardic Deseret Intracath unit, although devised for intravenous infusion therapy, is admirably suited to this technique.


Interferon production by Shigella flexneri-infected fibroblasts depends upon intracellular bacterial metabolism.
The role of bacterial invasion and subsequent intracellular metabolism or replication, or both, in the induction of interferon (IFN) production in primary cultures of murine embryo fibroblasts (MEFs) was examined. IFN production appeared to be dependent upon bacterial invasion. MEFs that were challenged with Shigella flexneri cultured at 30 degrees C to inhibit the temperature-dependent virulence gene expression that is essential for invasion failed to produce IFN. Furthermore, inhibition of S. flexneri invasion by pretreatment of MEFs with cytochalasin B resulted in a reduction in IFN production. Intracellular bacterial residence alone, however, was not sufficient for the induction of IFN production since an avirulent isogenic variant of S. flexneri which invades but fails to grow intracellularly did not induce IFN production. In fact, the blocking of bacterial RNA synthesis immediately after cellular uptake of S. flexneri by rifampin inhibited IFN production by MEFs. Transfer of the invasion-encoding plasmid to a noninvasive Escherichia coli strain conferred upon the bacteria the ability to invade MEFs and induce IFN production. These results suggest that the induction of IFN production in S. flexneri-infected fibroblasts requires bacterial invasion and intracellular bacterial metabolism or replication, or both.


A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury.
Traumatic brain injury (TBI) affects 1.6 million Americans annually. The injury severity impacts the overall outcome and likelihood for survival. Current treatment of acute TBI includes surgical intervention and supportive care therapies. Treatment of elevated intracranial pressure and optimizing cerebral perfusion are cornerstones of current therapy. These approaches do not directly address the secondary neurological sequelae that lead to continued brain injury after TBI. Depending on injury severity, a complex cascade of processes are activated and generate continued endogenous changes affecting cellular systems and overall outcome from the initial insult to the brain. Homeostatic cellular processes governing calcium influx, mitochondrial function, membrane stability, redox balance, blood flow and cytoskeletal structure often become dysfunctional after TBI. Interruption of this cascade has been the target of numerous pharmacotherapeutic agents investigated over the last two decades. Many agents such as selfotel, pegorgotein (PEG-SOD), magnesium, deltibant and dexanabinol were ineffective in clinical trials. While progesterone and ciclosporin have shown promise in phase II studies, success in larger phase III, randomized, multicentre, clinical trials is pending. Consequently, no neuroprotective treatment options currently exist that improve neurological outcome after TBI. Investigations to date have extended understanding of the injury mechanisms and sites for intervention. Examination of novel strategies addressing both pathological and pharmacological factors affecting outcome, employing novel trial design methods and utilizing biomarkers validated to be reflective of the prognosis for TBI will facilitate progress in overcoming the obstacles identified from previous clinical trials.


Unsuppressible Repetition Suppression and exemplar-specific Expectation Suppression in the Fusiform Face Area.
Recent work casts Repetition Suppression (RS), i.e. the reduced neural response to repeated stimuli, as the consequence of reduced surprise for repeated inputs. This research, along with other studies documenting Expectation Suppression, i.e. reduced responses to expected stimuli, emphasizes the role of expectations and predictive codes in perception. Here, we use fMRI to further characterize the nature of predictive signals in the human brain. Prior to scanning, participants were implicitly exposed to associations within face pairs. Critically, we found that this resulted in exemplar-specific Expectation Suppression in the fusiform face-sensitive area (FFA): individual faces that could be predicted from the associations elicited reduced FFA responses, as compared to unpredictable faces. Thus, predictive signals in the FFA are specific to face exemplars, and not only generic to the category of face stimuli. In addition, we show that under such circumstances, the occurrence of surprising repetitions did not trigger enhanced brain responses, as had been recently hypothesized, but still suppressed responses, suggesting that repetition suppression might be partly 'unsuppressible'. Repetition effects cannot be fully modulated by expectations, which supports the recent view that expectation and repetition effects rest on partially independent mechanisms. Altogether, our study sheds light on the nature of expectation signals along the perceptual system.


Non-invasive ventilation in amyotrophic lateral sclerosis.
Non-invasive ventilation (NIV) has become an important cornerstone of symptomatic treatment in amyotrophic lateral sclerosis (ALS), improving survival and quality of life. In this review, we summarize the most important recent developments and insights, including evidence of efficacy, indication criteria and time of initiation, ventilation parameters and adaptation strategies, treatment of complicating factors, transition from NIV to invasive ventilation, termination of NIV and end-of-life management. Recent publications have questioned former conventions and guideline recommendations, especially with regard to timing and prognostic factors; therefore, a fresh look and re-evaluation of current evidence is needed.


A three-dimensional finite element model of the transibial residual limb and prosthetic socket to predict skin temperatures.
Amputees who wear prosthetic limbs often experience discomfort from blisters and sores due to mechanical insult; these skin conditions are exacerbated by elevated skin temperatures and excessive perspiration within the prosthetic socket. The goal of this study was to create a tool for developing new prostheses that accommodate varying thermal loads arising from everyday activities. A three-dimensional thermal model of a transtibial residual limb and prosthesis was constructed using the finite element (FE) method. Transverse computerized tomography (CT) scans were used to specify the geometry of the residual limb and socket. Thermal properties from the literature were assigned to both biological tissue and prosthetic socket elements. The purpose of this work was to create a model that would aid in testing the effect of new prosthesis designs on skin temperature. To validate its output, the model was used to predict the skin temperature distribution in a common prosthetic socket system (silicone liner, wool sock, and carbon fiber socket) at rest with no mechanical loading. Skin temperatures were generally elevated near muscle and decreased anteriorly and at the distal end. Experimental temperature measurements taken at the skin-prosthesis interface of five human subjects were used to validate the model. Data extracted from the thermal model at anterior, posterior, lateral, and medial locations were typically within one standard deviation of experimental results; the mean temperatures were within 0.3 degree C for each section and were within 0.1 degree C overall.


Core body temperature as adjunct to endpoint determination in murine median lethal dose testing of rattlesnake venom.
Median lethal dose (LD50) testing in mice is the 'gold standard' for evaluating the lethality of snake venoms and the effectiveness of interventions. As part of a study to determine the murine LD50 of the venom of 3 species of rattlesnake, temperature data were collected in an attempt to more precisely define humane endpoints. We used an 'up-and-down' methodology of estimating the LD50 that involved serial intraperitoneal injection of predetermined concentrations of venom. By using a rectal thermistor probe, body temperature was taken once before administration and at various times after venom exposure. All but one mouse showed a marked, immediate, dose-dependent drop in temperature of approximately 2 to 6°C at 15 to 45 min after administration. The lowest temperature sustained by any surviving mouse was 33.2°C. Surviving mice generally returned to near-baseline temperatures within 2 h after venom administration, whereas mice that did not survive continued to show a gradual decline in temperature until death or euthanasia. Logistic regression modeling controlling for the effects of baseline core body temperature and venom type showed that core body temperature was a significant predictor of survival. Linear regression of the interaction of time and survival was used to estimate temperatures predictive of death at the earliest time point and demonstrated that venom type had a significant influence on temperature values. Overall, our data suggest that core body temperature is a useful adjunct to monitoring for endpoints in LD50 studies and may be a valuable predictor of survival in venom studies.


Transcriptomic analyses reveal biosynthetic genes related to rosmarinic acid in Dracocephalum tanguticum.
Dracocephalum tanguticum Maxim, a Lamiaceae species endemic to the Qinghai-Tibetan Plateau and adjacent regions, is an important ornamental, medicinal and aromatic herb. In this study, a comprehensive transcriptome of 18 libraries from six organs namely, roots, stems, leaves, sepals, flowers and seeds of D. tanguticum were generated. More than 100 Gb of sequence data were obtained and assembled de novo into 187,447 transcripts, including 151,463 unigenes, among which the six organs shared 17.7% (26,841). In addition, all unigenes were assigned to 362 pathways, in which 'biosynthesis of secondary metabolites' is the second enriched pathway. Furthermore, rosmarinic acid (RA) is one of the multifunctional phenolic bioactive compounds produced in some Lamiaceae species. The six organs of D. tanguticum were confirmed to produce RA. A total of 22 predicted biosynthetic genes related to RA from the transcriptome were further isolated. Two of these genes were identified as candidates by evaluating the correlation coefficient between the RA contents and the expression of the predicted biosynthetic genes in the six organs. The new sequence information will improve the knowledge of D. tanguticum, as well as provide a reference tool for future studies of biosynthetic genes related to RA in this species.


Reactive hemophagocytic syndrome associated with thrombotic thrombocytopenic purpura during therapeutic plasma exchange.
Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever, cytopenia, splenomegaly, and lymphohistiocytic proliferation with hemophagocytosis. Sporadic, familial, and reactive HLH varieties exist. The latter, also termed the reactive hemophagocytic syndrome (RHS), has been associated with a variety of infectious and noninfectious etiologies. Activation of monocytes in RHS is due to stimulation by high levels of activating cytokines. RHS has not been associated previously with thrombotic thrombocytopenic purpura (TTP). TTP is a multisystem disorder characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal impairment, and fever. We report on a 33 year old male patient with a classic picture of TTP who initially responded to therapeutic plasma exchange but then became refractory to treatment and developed RHS. It is likely that a specific pathophysiology involving the activation of neutrophils during TPE is present for the development of cytokine-induced hemophagocytosis during TTP treatment. The consequent development of RHS possibly caused early TTP relapse.


Local immune defence in relation to gastritis in Billroth-II-resected stomachs.
Biopsy specimens from Billroth-II-resected stomachs obtained endoscopically 28-32 years after the operation were subjected to an immunohistochemical study by two-colour immunofluorescence staining. The epithelial distribution of immunoglobulin A (IgA), secretory component (SC), lysozyme (Ly), and lactoferrin (Lf) was evaluated, and IgA-, IgM-, and IgG-producing cells were quantified in the lamina propria. Gastric body mucosa excised from resected stomachs obtained from patients with duodenal ulcer was used as control and showed considerably less extensive gastritis than the stump mucosa. Both specimen categories showed enhanced expression of epithelial IgA, SC, Ly, and Lf associated with severe gastritis, except for areas with intestinal metaplasia, which lacked Ly and Lf. The number of IgA-, IgM-, and IgG-producing cells was significantly increased with increasing degree of gastritis, particularly so for IgG cells on a relative basis. After partial gastrectomy, therefore, the stump mucosa generally responds with activation of local immune mechanisms; this response is principally similar to that seen in simple gastritis of comparable severity.


Recent advances in carbon quantum dots for virus detection, as well as inhibition and treatment of viral infection.
In the last decade, carbon quantum dots (CQDs), as a novel class of carbon-based nanomaterials, have received increasing attention due to their distinct properties. CQDs are ultimately small nanoparticles with an average size below 10 nm, possessing high water solubility, alluring photoluminescence, photostability, excellent biocompatibility, low/none toxicity, environmental friendliness, and high sustainability, etc. In history, there are intermittent threats from viruses to humans, animals and plants worldwide, resulting in enormous crises and impacts on our life, environment, economy and society. Some recent studies have unveiled that certain types of CQDs exhibited high and potent antiviral activities against various viruses such as human coronavirus, arterivirus, norovirus and herpesvirus. Moreover, they have been successfully explored and developed for different virus detections including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This article exclusively overviews and discusses the recent progress of designing, synthesizing, modifying/functionalizing and developing CQDs towards effective virus detection as well as the inhibition and treatment of viral infection. Their mechanisms and applications against various pathogenic viruses are addressed. The latest outcomes for combating the coronavirus disease 2019 (COVID-19) utilizing CQDs are also highlighted. It can be envisaged that CQDs could further benefit the development of virus detectors and antiviral agents with added broad-spectrum activity and cost-effective production.


Algal antifouling and fouling-release properties of metal surfaces coated with a polymer inspired by marine mussels.
The marine antifouling and fouling-release performance of titanium surfaces coated with a bio-inspired polymer was investigated. The polymer consisted of methoxy-terminated poly(ethylene glycol) (mPEG) conjugated to the adhesive amino acid l-3,4-dihydroxyphenylalanine (DOPA) and was chosen based on its successful resistance to protein and mammalian cell fouling. Biofouling assays for the settlement and release of the diatom Navicula perminuta and settlement, growth and release of zoospores and sporelings (young plants) of the green alga Ulva linza were carried out. Results were compared to glass, a poly(dimethylsiloxane) elastomer (Silastic T2) and uncoated Ti. The mPEG-DOPA3 modified Ti surfaces exhibited a substantial decrease in attachment of both cells of N. perminuta and zoospores of U. linza as well as the highest detachment of attached cells under flow compared to control surfaces. The superior performance of this polymer over a standard silicone fouling-release coating in diatom assays and approximately equivalent performance in zoospore assays suggests that this bio-inspired polymer may be effective in marine antifouling and fouling-release applications.


Asymmetric dimethyloarginin (ADMA) concentration in the aqueous humor of patients with exfoliation syndrome or exfoliative glaucoma.
Asymmetric dimethyloarginin or dimethylarginin (ADMA) is a marker and maker of oxidative stress. It is elevated in several pathological conditions, such as hyperhomocysteinemia and endothelial dysfunction, which have also been reported in patients with exfoliation syndrome (XFS), or exfoliative glaucoma (XFG). We evaluated ADMA levels in the aqueous humor of XFS and XFG patients. This study included 48 aqueous samples; 16 from cataract patients with XFS, 16 from cataract patients with XFG and 16 from age-matched cataract control patients. ADMA levels were determined employing a commercial ELISA kit. ADMA concentration was significantly greater in XFG patients (0.398 ± 0.026 μM) compared to either XFS (0.168 ± 0.028 μM; p < 0.0001) or normal cataract controls (0.245 ± 0.025 μM; p = 0.0002). In contrast, no significant difference was detected for ADMA levels in the aqueous of XFS patients as compared to normal controls (p = 0.0477). Aqueous humor ADMA concentration is significantly elevated in XFG patients supporting the view that oxidative stress plays a key role in XFG pathobiology. The lower level of this marker in XFS suggests that the development of XFG is a prerequisite for ADMA elevation.


MicroRNA-194 promotes the growth, migration, and invasion of ovarian carcinoma cells by targeting protein tyrosine phosphatase nonreceptor type 12.
Ovarian carcinoma is the most lethal gynecologic malignancy among women. Ovarian cancer metastasis is the main reason for poor prognosis. MicroRNAs (miRNAs) have been shown to play an important role in tumorigenesis and metastasis in various cancers by affecting the expression of their targets. In this study, we explored the role of miR-194 in ovarian cancer. Real-time polymerase chain reaction assays showed that miR-194 was significantly upregulated in ovarian cancer tissues. Overexpression of miR-194 in ovarian cancer cells promotes cell proliferation, migration, and invasion; in contrast, inhibition of the expression of miR-194 has the opposite effects. Meanwhile, bioinformatics tools were used to identify protein tyrosine phosphatase nonreceptor type 12 (PTPN12) as a potential target of miR-194. The luciferase assay showed that miR-194 directly binds to the 3'-untranslated region of PTPN12. Western blot analysis and quantitative real-time polymerase chain reaction assay revealed that PTPN12 expression was negatively associated with miR-194 expression in both ovarian cancer tissues and cells. Thus, we conclude that miR-194 targets PTPN12 and functions as an oncogene in ovarian cancer cells. This novel pathway may provide a new insight to explain ovarian cancer development and metastasis.


Case vignette: child abuse or acceptable cultural norms -- child psychiatrist's response; ethical issues in culturally relevant interventions; cultural contexts.
Three families from the nation of the Gambia have become socially acquainted in the greater Metropolis area where they have relocated from their native country. All three families have preadolescent daughters. None of the girls has as yet undergone the ritual "female circumcision" commonly practiced in their native country. Five of the six parents think it would be a good idea to hold such a ritual ceremony in Metropolis next month. The sixth parent is uneasy about the procedure and wonders if it is appropriate anyway. The parent comes to talk with you, a physician or mental health professional, about this. The parent describes concerns about the procedure and the practice in general, but notes that some groups in the United States do "similar things," referring to the ritual circumcision of Jewish boys at 8 days of age. The parent adds that if the procedure is not possible in the United States, it could be done in the Gambia when the family returns there on holiday. Discussants were asked for their opinions regarding advice to the parent's ethical obligations (especially in the case of mandated reporting of suspected child abuse).


Treatment of Recurrent Clostridium difficile Diarrhea.
Treatment of recurrent Clostridium difficile-associated diarrhea can be challenging. Once patients develop recurrent disease, further episodes are common and can continue for months or even a year or more. Treatment begins with a repeat standard 10-day course of antibiotics, followed by tapering and/or pulsing of the antibiotic dose. Probiotics can also be useful, particularly the nonpathogenic yeast Saccharomyces boulardii. Stool reconstitution via fecal enemas, colonoscopy, and nasogastric tubes have been performed to restore normal colonic flora. Additional approaches under investigation, such as vaccination against C. difficile, show encouraging preliminary results.


Majocchi granuloma on a child's face.
Majocchi granuloma (MG) is a rare dermal and subcutaneous fungal infection. We report a rare case of MG on the face of a six-year-old child caused by Trichophyton mentagrophytes after long term use of topical corticosteroids and other inadequate topical medications. He was treated with griseofulvin 25 mg/kg/day for 35 days unsuccessfully and successful treatment was obtained with terbinafine.


Th17 cells and CD4(+) multifunctional T cells in patients with systemic lupus erythematosus.
Recent evidence suggests that abnormalities involving Th17 lymphocytes are associated with the pathophysiology of systemic lupus erythematosus (SLE). In addition, multifunctional T cells (MFT), i.e., those producing multiple cytokines simultaneously, are present in the inflammatory milieu and may be implicated in the autoimmune process observed in SLE. In the present study, we aimed to characterize the functional status of CD4(+) T cells in SLE by simultaneously determining the concentration of IL-2, IFN-γ and IL-17 in lymphocyte cultures under exogenous and self-antigenic stimuli. Eighteen patients with active disease, 18 with inactive disease, and 14 healthy controls had functional status of CD4(+) T cells analyzed. We found that SLE patients presented a decreased number of total CD4(+) cells, an increased number of activated T cells, and an increased frequency of Th17 cells compared to healthy controls (HC). MFT cells had increased frequency in SLE patients and there was an increased frequency of tri-functional MFT in patients with active SLE compared with those with inactive SLE. Interestingly, MTF cells produced larger amounts of IFNγ than mono-functional T cells in patients and controls. Taken together these data indicate the participation of recently activated Th17 cells and MTF cells in the SLE pathophysiology.


Prevalence and characterization of cerebral small vessel disease in young adults with intracerebral hemorrhage.
Cerebral small vessel disease (CSVD) is the main cause of intracerebral hemorrhage (ICH) in older individuals but has not been systematically studied in younger people. We aimed to evaluate the prevalence and characteristics of CSVD in young adults with symptomatic ICH. We conducted a cohort study of consecutive adults aged 18-50 years with non-traumatic ICH. All patients were evaluated with brain and vascular imaging. Using validated imaging markers (cerebral microbleeds (CMBs), white matter hyperintensities and/or lacunes), patients were categorized as having CSVD-related ICH or non-CSVD-related ICH. Factors associated with CSVD were evaluated using multivariable analyses. CSVD subtypes were characterized using pre-specified criteria. Of 146 young adults with ICH (mean age = 37.7), CSVD was present in 41 patients (28.1%; 95% confidence interval (CI) = 21.0-36.1). In multivariable analysis, older age, male sex, and hypertension were independently associated with the presence of CSVD. Deep perforator arteriopathy (48.8%) and mixed CSVD (31.7%) were the most common CSVD subtypes. Our results suggest that CSVD is a frequent cause of ICH in young adults and provide new insights into the characterization of the disease. These findings may have important implications since the treatment and management differ from other causes of ICH.


The influence of femoral offset on health-related quality of life after total hip replacement.
Several factors have been implicated in unsatisfactory results after total hip replacement (THR). We examined whether femoral offset, as measured on digitised post-operative radiographs, was associated with pain after THR. The routine post-operative radiographs of 362 patients (230 women and 132 men, mean age 70.0 years (35.2 to 90.5)) who received primary unilateral THRs of varying designs were measured after calibration. The femoral offset was calculated using the known dimensions of the implants to control for femoral rotation. Femoral offset was categorised into three groups: normal offset (within 5 mm of the height-adjusted femoral offset), low offset and high offset. We determined the associations to the absolute final score and the improvement in the mean Western Ontario and McMaster Universities osteoarthritis index (WOMAC) pain subscale scores at three, six, 12 and 24 months, adjusting for confounding variables. The amount of femoral offset was associated with the mean WOMAC pain subscale score at all points of follow-up, with the low-offset group reporting less WOMAC pain than the normal or high-offset groups (six months: 7.01 (sd 11.69) vs 12.26 (sd 15.10) vs 13.10 (sd 16.20), p = 0.006; 12 months: 6.55 (sd 11.09) vs 9.73 (sd 13.76) vs 13.46 (sd 18.39), p = 0.010; 24 months: 5.84 (sd 10.23) vs 9.60 (sd 14.43) vs 13.12 (sd 17.43), p = 0.004). When adjusting for confounding variables, including age and gender, the greatest improvement was seen in the low-offset group, with the normal-offset group demonstrating more improvement than the high-offset group.


An interspecific comparison between morphology and swimming performance in cyprinids.
Flow regimes are believed to be of major evolutionary significance in fish. The flow regimes inhabited by cyprinids vary extensively from still flow regimes to riptide flow regimes. To test (i) whether flow-driven swimming performance and relevant morphological differentiation are present among fish species and (ii) whether evolutionary shifts between high-flow and low-flow habitats in cyprinids are associated with evolutionary trade-offs in locomotor performance, we obtained data on both steady and unsteady swimming performance and external body shape for 19 species of cyprinids that typically occur in different flow regimes (still, intermediate and riptide). We also measured the routine energy expenditure (RMR) and maximum metabolic rate (MMR) and calculated the optimal swimming speed. Our results showed that fish species from riptide groups tend to have a higher critical swimming speed (Ucrit ), maximum linear velocity (Vmax ) and fineness ratio (FR) than fish from the other two groups. However, there was no correlation between the reconstructed changes in the steady and unsteady swimming performance of the 19 species. According to the phylogenetically independent contrast (PIC) method, the Ucrit was actively correlated with the MMR. These results indicated that selection will favour both higher steady and unsteady swimming performance and a more streamlined body shape in environments with high water velocities. The results suggested that steady swimming performance was more sensitive to the flow regime and that for this reason, changes in body shape resulted more from selective pressure on steady swimming performance than on unsteady swimming performance. No evolutionary trade-off was observed between steady and unsteady swimming performance, although Ucrit and MMR were found to have coevolved. However, a further analysis within each typically occurring habitat group suggested that the trade-off that may exist between steady and unsteady swimming performance may be concealed by the effect of habitat.


VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors.
Von Willebrand factor (VWF) is a chaperone molecule for procoagulant factor VIII (FVIII). Its role in the reduction of the immunogenicity of therapeutic FVIII in patients with hemophilia A has been evoked but lacks clear cellular and molecular rationale. Here, we demonstrate that VWF protects FVIII from being endocytosed by human dendritic cells (DCs) and subsequently presented to FVIII-specific T cells. The immunoprotective effect of VWF requires a physical interaction with FVIII because the endocytosis of FVIII was significantly restored on hindering the formation of the VWF-FVIII complex. Interestingly, VWF had no direct inhibitory effect either on the ability of DCs to present antigenic peptides or on the activation potency of CD4+ T cells. We thus propose that VWF may reduce the immunogenicity of FVIII by preventing, upstream from the activation of immune effectors, the entry of FVIII in professional antigen-presenting cells.


BDNF and NT-3 rescue sensory but not motoneurones following axotomy in the neonate.
Following axotomy of the sciatic nerve in the neonatal rat, there is loss of almost half of the sensory neurones of the lumbar dorsal root ganglia (DRG) and a similar number of spinal motoneurones. Consistent with effects in vitro, the neurotrophins BDNF and NT-3 have previously been shown to afford partial rescue of motoneurones at 1 week following axotomy. Using stereological quantitative methods we show here that at the longer time point of 3 weeks, local application of BDNF or NT-3 to the proximal stump of a lesioned sciatic nerve failed to rescue motoneurones (44% and 51% loss, respectively), but provided almost complete rescue of the loss of 41% of DRG neurones seen in L4 and L5 of vehicle-treated control animals.