Exploring resilience in nursing and midwifery students: a literature review.
The aim of this study was to explore the concepts of 'resilience' and 'hardiness' in nursing and midwifery students in educational settings and to identify educational interventions to promote resilience. Resilience in healthcare professionals has gained increasing attention globally, yet to date resilience and resilience education in nursing and midwifery students remain largely under-researched. An integrative literature review was planned, however, only quantitative evidence was identified therefore, a review of quantitative studies was undertaken using a systematic approach. A comprehensive search was undertaken using Medline, CINAHL, Embase, PsycINFO and Maternity and Infant Care databases January 1980-February 2015. Data were extracted using a specifically designed form and quality assessed using an appropriate checklist. A narrative summary of findings and statistical outcomes was undertaken. Eight quantitative studies were included. Research relating to resilience and resilience education in nursing and midwifery students is sparse. There is a weak evidence that resilience and hardiness is associated with slightly improved academic performance and decreased burnout. However, studies were heterogeneous in design and limited by poor methodological quality. No study specifically considered student midwives. A greater understanding of the theoretical underpinnings of resilience in nursing and midwifery students is essential for the development of educational resources. It is imperative that future research considers both nursing and midwifery training cohorts and should be of strong methodological quality.


Transclavicular Osseous Sutures for the Treatment of Displaced Distal Clavicular Fractures in Children.
We describe a novel surgical technique for the treatment of displaced distal clavicular fractures in children. These fractures are rare, and recommendations on treatment vary. Conservative treatment might lead to persistent deformity and limitations of function. Previous reports of surgical treatment involve fracture fixation with K-wires. This requires a routine sequential reoperation to remove the implant and has been associated with serious complications in some patients. The surgical technique described here is based on osseous sutures through the clavicular shaft and coracoclavicular ligaments and is found successful for the treatment of distal clavicular fractures in children and may also be feasible for true acromioclavicular dislocations. The main principle of the technique is a fixation of the displaced clavicle through transclavicular drill holes, against the intact inferior periosteal sleeve at the insertion of the coracoclavicular ligaments. No temporary K-wire fixation is needed. To date, we have treated 7 patients with this technique. All fractures healed uneventfully with an excellent functional result and without skeletal deformity.


An intercontinental array--a next-generation radio telescope.
It is difficult to estimate accurately the cost of constructing a large scientific instrument that involves many techniques. On the other hand, most of the component parts of the VLBA consist of antennas and electronic systems that already exist or are being fabricated. The kind of 25-m antennas being constructed for the VLA will cost about $900,000 each and will work at wavelengths as short as 1 cm. A multifrequency radiometer, hydrogen maser frequency standard, small control computer, control building, and wide-band instrumentation recorder bring the cost to about $1.5 million per element, or $15 million for a ten-element array using tape recorders. A multistation playback facility, with ten recorders and enough correlators to handle all interferometer pairs simultaneously, together with the necessary computers to control the processor and reduce the data, may add $5 million. The total cost is thus about $20 million at current prices, including an adequate supply of magnetic tape. This is comparable to the cost of existing large radio telescopes and arrays. An array that used a geostationary communication satellite to transmit the data to a real-time correlator would cost $30 million to $50 million more, but this is still within the price range of other space astronomy projects. It is thus feasible to construct at reasonable cost an intercontinental very long baseline array which has sub-milliarcsecond resolution. This would complement the Very Large Array now being constructed (4), which is much more sensitive to objects of low surface brightness. This next step would permit the study of the universe with unprecedented angular resolution.


Hypoxic tumour cell-derived exosomal miR-340-5p promotes radioresistance of oesophageal squamous cell carcinoma via KLF10.
Radiotherapy resistance is a major obstacle in the treatment of oesophageal squamous cell carcinoma (OSCC). Hypoxia is a critical cause of radioresistance. However, the communication between hypoxic cells and aerobic cells via exosomes during the transfer of radiation resistance remains unclear. Exo-miR-340-5p levels were analysed by RNA-seq and qRT-PCR. We co-cultured OSCC cells with isolated normoxic and hypoxic exosomes to study their impact on radiosensitivity. We used a specific exo-miR-340-5p mimic and knock-down retrovirus to explore the role of this miRNA in the transfer of radioresistance from hypoxic to normoxic cells. Dual-luciferase reporter and RIP assays were used to verify KLF10 as a putative target of miR-340-5p. Several in vitro assays were conducted and xenograft models were established to investigate the effect of exo-miR-340-5p on OSCC radiosensitivity. The plasma exo-miR-340-5p levels in OSCC patients were analysed to study the clinical value of this parameter. Hypoxic exosomes alleviated radiation-induced apoptosis and accelerated DNA damage repair. miR-340-5p was highly expressed in hypoxic exosomes and was transferred into normoxic cells, where it induced radioresistance. Overexpression of miR-340-5p in normoxic OSCC cells mimicked the radioresistance of cells co-cultured with hypoxic exosomes. Knockdown of miR-340-5p in hypoxic exosomes reversed the radioresistance effect, indicating that exo-miR-340-5p is critical for hypoxic EV-transferred radioresistance. KLF10 was identified as the direct target of miR-340-5p. Moreover, metformin was found to increase the expression of KLF10 and enhance the radiosensitivity of OSCC. Higher levels of miR-340-5p in the plasma exosomes from OSCC patients are related to a poorer radiotherapy response and prognosis. Hypoxic tumour cell-derived exosomal miR-340-5p confers radioresistance in OSCC by targeting KLF10/UVRAG, suggesting that miR-340-5p could be a potential biomarker and therapeutic target for the enhancement of radiosensitivity in OSCC. Metformin can increase KLF10 expression, which ameliorates the radioresistance induced by exo-miR-340-5p transfer. Therefore, metformin could be further investigated as a therapeutic option for the treatment of OSCC.


Elucidation of Cellular Responses in Non-human Primates With Chronic Schistosomiasis Followed by Praziquantel Treatment.
For decades, mass drug treatment with praziquantel (PZQ) has been utilized to treat schistosomiasis, yet reinfection and the risk of drug resistance are among the various factors precluding successful elimination of schistosomiasis. Tractable models that replicate "real world" field conditions are crucial to effectively evaluate putative schistosomiasis vaccines. Herein, we describe the cellular immune responses and cytokine expression profiles under field conditions that include prior infection with schistosomes followed by treatment with PZQ. Baboons were exposed to Schistosoma mansoni cercariae through trickle infection over 5 weeks, allowed for chronic disease to develop, and then treated with PZQ. Peripheral blood mononuclear cells (PBMCs) were monitored for cellular immune response(s) at each disease stage and PZQ therapy. After initial infection and during chronic disease, there was an increase in non-classical monocytes, NK and NKT cells while the CD4:CD8 T cell ratio inverted from a 2:1 to 1:2.5. The cytokine expressions of PBMCs after trickle infections were polarized more toward a Th2 response with a gradual increase in Th1 cytokine expression at chronic disease stage. Following PZQ treatment, with the exception of an increase in B cells, immune cell populations reverted back toward naïve levels; however, expression of almost all Th1, Th2, and Th17 cytokines was significantly increased. This preliminary study is the first to follow the cellular immune response and cytokine expression profiles in a non-human primate model simulating field conditions of schistosomiasis and PZQ therapy, providing a promising reference in predicting the immune response to future vaccines for schistosomiasis.


Role of TRPM7 in Cancer: Potential as Molecular Biomarker and Therapeutic Target.
The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed ion channel with intrinsic kinase activity. Molecular and electrophysiological analyses of the structure and activity of TRPM7 have revealed functional coupling of its channel and kinase activity. Studies have indicated the important roles of TRPM7 channel-kinase in fundamental cellular processes, physiological responses, and embryonic development. Accumulating evidence has shown that TRPM7 is aberrantly expressed and/or activated in human diseases including cancer. TRPM7 plays a variety of functional roles in cancer cells including survival, cell cycle progression, proliferation, growth, migration, invasion, and epithelial-mesenchymal transition (EMT). Data from a study using mouse xenograft of human cancer show that TRPM7 is required for tumor growth and metastasis. The aberrant expression of TRPM7 and its genetic mutations/polymorphisms have been identified in various types of carcinoma. Chemical modulators of TRPM7 channel produced inhibition of proliferation, growth, migration, invasion, invadosome formation, and markers of EMT in cancer cells. Taken together, these studies suggest the potential value of exploiting TRPM7 channel-kinase as a molecular biomarker and therapeutic target in human malignancies.


Isolation of skin permeability factors from culture filtrates of Salmonella typhimurium.
Engerotoxins isolated from Vibrio cholerae and toxigenic Escherichia coli cause permeability alterations in rabbit skin. Firm induration and erythema are observed within 18 to 24 h, and visualization of the reaction may be enhanced by intravenous injection of Pontamine sky blue dye. Two skin permeability factors (PF) have been found in culture filtrates of Salmonella typhimurium. A rapid acting factor, produced optimally in brain heart infusion broth at 37 degrees C by numerous Salmonella species, has a critical bluing time of 1 h after completion of skin testing. This rapid PF is heat stable at 100 degrees C for at least 4 h and has no associated induration. The delayed factor is heat labile, being completly destroyed within 30 min at 75 degrees C and causes marked duration of the rabbit skin within 18 h that is indistinguishable from the permeability reactions of V. cholerae and E. coli enterotoxins. Induration produced by the delayed PF is observed only after chromatography of the culture filtrate on a Sephadex G-100 column. Thus, the effects of the delayed PF appear to be masked or blocked by an inhibitor-like substance present in crude culture filtrates. Both early and delayed factors are estimated to have a molecular weight of at least 90,000. It is postulated that one or both of these factors may participate in the pathogenesis of Salmonella infections.


Notch modulates Wnt signalling by associating with Armadillo/beta-catenin and regulating its transcriptional activity.
The establishment and stability of cell fates during development depend on the integration of multiple signals, which ultimately modulate specific patterns of gene expression. While there is ample evidence for this integration at the level of gene regulatory sequences, little is known about its operation at other levels of cellular activity. Wnt and Notch signalling are important elements of the circuitry that regulates gene expression in development and disease. Genetic analysis has suggested that in addition to convergence on the transcription of specific genes, there are modulatory cross-regulatory interactions between these signalling pathways. We report that the nodal point of these interactions is an activity of Notch that regulates the activity and the amount of the active/oncogenic form of Armadillo/beta-catenin. This activity of Notch is independent of that induced upon cleavage of its intracellular domain and which mediates transcription through Su(H)/CBF1. The modulatory function of Notch described here, contributes to the establishment of a robust threshold for Wnt signalling which is likely to play important roles in both normal and pathological situations.


[Characterization of Pasteurella species isolated from man].
Fifty-four clinical isolates of Pasteurella are classified into different taxa. P. multocida subsp.multocida is more frequently encountered than other subspecies of P. multocida. P. canis is only identified from wounds inflicted by animals. The frequency of isolation of different species and subspecies is comparable with that observed from animal isolates. The distribution of the strains in the capsular types is different according to the origin, human or animal, of the strains.


TEFM is a potent stimulator of mitochondrial transcription elongation in vitro.
A single-subunit RNA polymerase, POLRMT, transcribes the mitochondrial genome in human cells. Recently, a factor termed as the mitochondrial transcription elongation factor, TEFM, was shown to stimulate transcription elongation in vivo, but its effect in vitro was relatively modest. In the current work, we have isolated active TEFM in recombinant form and used a reconstituted in vitro transcription system to characterize its activities. We show that TEFM strongly promotes POLRMT processivity as it dramatically stimulates the formation of longer transcripts. TEFM also abolishes premature transcription termination at conserved sequence block II, an event that has been linked to primer formation during initiation of mtDNA synthesis. We show that POLRMT pauses at a wide range of sites in a given DNA sequence. In the absence of TEFM, this leads to termination; however, the presence of TEFM abolishes this effect and aids POLRMT in continuation of transcription. Further, we show that TEFM substantially increases the POLRMT affinity to an elongation-like DNA:RNA template. In combination with previously published in vivo observations, our data establish TEFM as an essential component of the mitochondrial transcription machinery.


Correlation between c-erbB-2 amplification and risk of recurrent disease in node-negative breast cancer.
Drawing upon the comprehensive population-based Northern Alberta Breast Cancer Registry containing 704 patients with histologically negative axillary lymph nodes who have been followed for 5-16 years, we have undertaken a retrospective case-control study to evaluate the utility of genomic amplification of specific protooncogenes [c-erbB-2 (nee HER-2/neu), c-erbA, c-myc, int-2, and hst-1] as predictive indicators of clinical outcome in node-negative disease. To this end, 115 women with node-negative breast cancer who had recurred at any time up to 16 years posttreatment (cases) were matched pairwise for appropriate clinicopathological variables (size of primary tumor, menopausal state, estrogen receptor status, anniversary year of treatment, and patient age) with a second group of 115 women (controls) selected from a cohort of 502 node-negative patients who had not relapsed during long-term follow-up. Tumor DNA extracted from archival formalin-fixed, paraffin-embedded tissue blocks were analyzed for protooncogene copy number by slot-blot hybridization. Taking a gene copy number of 3 as the cutoff, 27 of the 230 tumor samples examined contained from 3- to 22-fold elevation in c-erbB-2 genomic equivalents. Twenty-one of the 27 tumors amplified for c-erbB-2 were derived from cases and 6 from controls, signifying that 18% of the node-negative patients who had relapsed harbored excessive copies of the protooncogene in their malignant tissue compared to only 5% for the patients who had remained in remission. Accordingly, the occurrence of amplification of c-erbB-2 proved to be a statistically significant predictor of poor prognosis, especially disease-free interval (P = 0.006). Moreover, this genetic alteration appeared to be independent of and to have greater predictive power than most commonly used prognostic factors. Our findings also indicated that as a clinical test, measurement of c-erbB-2 amplification suffers from low sensitivity; however, when greater than 6 gene copies are present, the test has a positive predictive value for recurrence of 70%. Concurrent analysis of tumor DNA blots with probes for the other four protooncogenes examined revealed that their amplification, which others have reported to arise often, especially in node-positive disease, was seldom found even in our high-risk case group (2-3%). In short, our data strongly suggest that amplification of c-erbB-2 may contribute to the pathogenesis of some forms of node-negative breast cancer and thus may serve as a useful genetic marker to identify a subset of high-risk patients.


Genetically encoded multimeric tags for subcellular protein localization in cryo-EM.
Cryo-electron tomography (cryo-ET) allows for label-free high-resolution imaging of macromolecular assemblies in their native cellular context. However, the localization of macromolecules of interest in tomographic volumes can be challenging. Here we present a ligand-inducible labeling strategy for intracellular proteins based on fluorescent, 25-nm-sized, genetically encoded multimeric particles (GEMs). The particles exhibit recognizable structural signatures, enabling their automated detection in cryo-ET data by convolutional neural networks. The coupling of GEMs to green fluorescent protein-tagged macromolecules of interest is triggered by addition of a small-molecule ligand, allowing for time-controlled labeling to minimize disturbance to native protein function. We demonstrate the applicability of GEMs for subcellular-level localization of endogenous and overexpressed proteins across different organelles in human cells using cryo-correlative fluorescence and cryo-ET imaging. We describe means for quantifying labeling specificity and efficiency, and for systematic optimization for rare and abundant protein targets, with emphasis on assessing the potential effects of labeling on protein function.


[Diurnal variations of central and paracentral corneal thickness and curvature].
Corneal topography and thickness has clinical importance in contact lens fitting and refractive surgery, however repeated measurement of corneal thickness and curvature is complicated by the natural phenomenon of diurnal variation. Our aim was determine diurnal variations of central and paracentral corneal thickness and curvature over a period of ten hours. Corneal thickness and curvature of 10 right eyes of 10 young healthy men were determined by Orbscan Topography System and EyeSys videokeratoscope respectively. Both parameters were determined for central and paracentral regions 1 mm and 2 mm from the centre of the cornea at 2-hour internals for ten hours. The cornea was thickest and flattest on awakening. There was a difference in corneal thickness (ANOVA, Schfféc method p< 0.05) and curvature (ANOVA, Tamhane method p< 0.05) over time for all the corneal locations studied, with greater changes observed in the peripheral corneal data. The minimum value was 10 and 8 hours after eye opening for central and paracentral zones, respectively. Change in central and paracentral corneal thickness was strongly correlated with corneal curvature, except for the 2 mm nasal and superior semi-meridians. These data indicate a shift in corneal thickness and curvature that can be of clinical relevance as individual changes vary greatly.


[Postoperative mortality in infective endocarditis: determinant factors].
The factors leading to high postoperative mortality in active infectious endocarditis (IE) are poorly defined. We studied patients operated at an University Hospital between March 1978 and April 1992. We hypothesized that the summation of potential adverse factors would strongly increase mortality after surgery. We studied 39 patients (28 men), age range 13-70 years (mean +/- SD = 32 +/- 16) operated during active IE (time from onset 52 +/- 48 days). Predisposing factor: rheumatic valvar disease in 14 cases, intravenous drug use in 5. Affected valves: aortic in 14, mitral in 10, tricuspid in 8, multiple structures in 7. In most cases, S aureus (12) or Streptococcus sp (10) was isolated in blood cultures. Surgery was indicated in most patients because of heart failure (30), multiple embolic complications (17) or treatment failure (14). The possible adverse influence of specific demographic characteristics, clinical features and surgical variables was assessed by the Student t test or the chi 2 test. Also, multiple regression analysis was performed in order to identify independent adverse factors for increased mortality. Positive correlations were further investigated with the chi 2 test to assess whether an increasing number of adverse factors could identify a special subset of patients with markedly elevated death risk. Fourteen patients (36%) died after surgery. Emergency surgery (p = 0.001), the presence of coma 6 hours after surgery (p = 0.0015) and S. aureus infection (p = 0.023) were all associated with increased mortality. The presence of neurological complications was correlated with a high mortality (54% vs. 27%). However this increase was of dubious statistical significance (p = 0.097). Multiple regression analysis confirmed S. aureus and emergency surgery as independent adverse factors for increased mortality. When put together, an increasing number of adverse factors was highly predictive of a fatal outcome, even after exclusion of that evaluated after surgery (level of consciousness). Patients with two or three adverse factors had a very high mortality rate (> 76.9%). Mortality following surgery for active IE is increased in patients operated on an emergency basis especially if the infection is caused by S. aureus. The presence of neurological complications may also be associated with worse outcome. Early consideration of surgery should reduce the high mortality in patients with active IE.


The differences in chromogranin A (CgA) concentrations measured in serum and in plasma by IRMA and ELISA methods.
Chromogranin A (CgA) is regarded as a major, nonspecific marker of neuroendocrine tumors (NET). Its estimation appears helpful for diagnostic purposes and is particularly useful for monitoring the treatment of NET. It must be kept in mind, however, that various factors, drugs, or coexisting diseases may influence the outcome of CgA measurement in blood. One such analytical factor is the sort of studied biological material, whether it is plasma or serum. The aim of our study was to compare directly the results of CgA concentrations measured in serum and in plasma by IRMA and ELISA. We analysed 122 samples of EDTA-plasma and 122 samples of serum by IRMA method, 20 samples of EDTAplasma and 20 samples of serum by IRMA and ELISA, 25 heparinised-plasma samples and 25 samples of EDTA-plasma by IRMA and ELISA methods, and 8 EDTA-plasma, heparinised-plasma, and serum samples by IRMA and ELISA. The material for comparative study was obtained during the same blood collection from the same subjects (volunteers and patients with NET). CgA was measured with the use of kits manufactured by CIS bio International (France). CgA concentrations were markedly higher in plasma than in serum. Using the IRMA method, the difference in the CgA range between 10-100 ng/mL approached 20-70% (median 61 v. 42), in the range 101-300 ng/mL--12-60% (median 147 v. 101), and in the CgA range 301-1076 ng/mL--14-40% (median 486 v. 356). The differences between results in serum and plasma using ELISA were similar but slightly smaller. There was no significant difference between CgA levels in EDTA and heparinised-plasma samples, and the results of measurements performed by IRMA and ELISA in most cases were similar. Referring each individual CgA result to the proposed reference range (or cut-off value) we must take into account whether the measurement is performed in plasma or in serum.


Improved Bipolar Properties of Ester-Functionalized Discotic Diimine-Dithiolene Complexes.
A series of platinum diimine-dithiolene complexes with a 5,6-dihydro-1,4-dithiin-2,3-dithiolato (dddt2- ) dithiolene ligand and a bipyridine carrying tris-alkoxyphenyl fragments connected through an ester linker (bpyCn, n=8, 12, 16, 10(s), 20) (Scheme 1) has been developed. The mesomorphic properties of the ligands and of the platinum complexes have been investigated by a combination of DSC, POM and SAXS analyses. The platinum complexes were found to self-organize into columnar mesophases of hexagonal symmetry over large temperature range including room temperature. Their electronic properties were also characterized by a combination of electrochemistry, absorption and emission spectroscopy measurements and TD-DFT calculations. Besides being liquid crystalline, these compounds can undergo two oxidation processes and two reduction processes in a fully reversible manner, allowing the isolation of stable dicationic and dianionic species. Such a behavior is highly promising for the development of ambipolar semiconducting soft materials.


Activated neutrophils induce prolonged DNA damage in neighboring cells.
We have measured the capacity of highly-purified, paraffin oil-elicited neutrophils to induce DNA single-strand breaks in a newly established plasmacytoma cell line, RIMPC 2304, which was induced by a retrovirus containing the c-myc and V-Ha-ras oncogenes. This cell line effectively repairs DNA damage induced by gamma-irradiation. DNA damage induced by neutrophils was correlated with the oxidative burst of the neutrophils. The levels of superoxide anion, H2O2, and HOCl produced after stimulation of the neutrophils (6 X 10(5)/cm3) with the tumor promoter phorbol myristate acetate (100 nM) were 33.8 microM, 12.8 microM and 1.7 microM respectively in 15 min, and 98 microM, 20 microM and 8.7 microM respectively in 90 min. The results of alkaline elution experiments revealed that when the same concentration of neutrophils was co-incubated for 15 min in serum-free medium with an equal number of radioactively labeled RIMPC 2304 cells, the latter incurred a level of damage that approximated that caused by 300 rad equivalents of gamma-irradiation or by a 1-min treatment with 20 microM H2O2 at 37 degrees C. Damage from neutrophils was coincident with the oxidative burst; it was induced rapidly (within 5 min) but remained high for more than 90 min. The level of damage achieved was dependent upon the ratio of neutrophils: target cells and was clearly detectable at ratios as low as 0.25:1. Induction of single-strand breaks was completely inhibited by catalase and partially inhibited by superoxide dismutase, mannitol, and reduced glutathione but not by Na azide. Addition of the non-steroidal anti-inflammatory drug indomethacin either enhanced (at 50 microM) or had no effect (at 2 microM) on the damage detected. Finally, repair of strand breaks induced by neutrophils was significantly slower (half-time approximately 10 min) than that observed for repair of similar levels of damage induced by H2O2 or gamma-irradiation (half-times approximately 3 min, each). The results indicate that neutrophils cause prolonged DNA damage in neighboring cells. Moreover, they indicate that although H2O2 produced in the oxidative burst is an essential mediator of the damage observed, additional reactive oxygen intermediates including the superoxide anion are also implicated. The data are discussed in relation to the possible role of neutrophils in chronic inflammation and in pristane-induced plasmacytoma formation in mice.


[Problems in reforming health care centers].
Reformation of therapeutic and prophylactic institutions attached to various institutions and ministries is and important problem of public health at the modern stage of its development. A model developed and tried in Magnitogorsk can serve as a perspective trend of such reforms. A medical institution with mixed form of property has been created. The institution was set up by administration of the territory and a plant (Magnitogorsk metallurgical plant). Creation of a new health center as a non-commercial institution promoted its integration in the municipal public health system; the institution possesses all the potentialities of a budget organization and retains close contact with the plant. Such a solution of the problem improved the financial status of the health center and promoted its adaptation to marketing conditions. Attraction of additional finances from industry to municipal public health allowed the administration of the health center start and carry out internal restructuring aimed at priority development of outpatient care, restructuring of the bed fund, technological updating, and, in general, more rational utilization of the available resources.


Effects of abdomen undulation in energy consumption and stability for monarch butterfly.
The flight of monarch butterflies is characterized by a relatively large wing, flapping at a relatively low frequency coupled with abdomen undulation. This paper presents the dynamics of a flapping wing flyer that can be applied to the coupled motion of the wing, body, and abdomen at the monarch butterfly scale, which is formulated directly on the configuration manifold. The resulting thorax and abdomen motion as well as the resultant forces are consistent with the flight of a live monarch butterfly. Based on these, beneficial effects of the abdomen undulation in the flight of monarch butterflies are illustrated. For both hover and forward-climbing trajectories, the abdomen undulation results in a reduction of the energy and power consumption. Furthermore, the Floquet stability analysis shows that the periodic orbits associated with both flight modes are stable. In particular, the abdomen undulation improves the stability. Compared to the dynamics of hawkmoth, bumblebee, and fruitfly models, the monarch possesses superior stability properties.


A new approach to the management of epidermoid carcinoma of the anal canal.
Until recently most squamous cell carcinomas of the anal canal were treated by radical surgery. Radiation therapy was only considered for palliation in case of inoperable tumors. Important progress has been made in the knowledge of the natural history of the disease and in the field of radiotherapy. Anal canal squamous cell carcinoma should not be treated any longer by the same procedure as adenocarcinoma of the lower rectum, because both these diseases differ markedly. Multimodality therapy with radiotherapy as first approach has been considered. This series of 121 cases treated since 1971 and followed more than three years suggests that three protocols based on irradiation followed or not by surgery should be used according to the extent of the disease. Of the 72 patients with resectable tumor, the five-year survival rate was 65%. Three-quarters of the patients cured had normal anal function. The rate of death from cancer was 18%. The method requires an accurate assessment of the extent of the tumor and of its pelvic lymphatic spread. Great care must be taken in planning treatment in a close cooperation between radiotherapist and surgeon.


Eustachian Tube Function Assessment after Radiofrequency Turbinate Reduction in Atopic and Non-Atopic Patients.
(1) Background: Inferior turbinates' hypertrophy is often associated with Eustachian tube dysfunction (ETD); radiofrequency turbinate reduction (RTR) may provide a long-term improvement of nasal obstruction and ETD-related symptoms. (2) Aim: The study aimed to compare ETD in atopic and non-atopic patients before and after RTR and to investigate the correlation between tympanometry and Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7). (3) Methods: Ninety-seven patients, ranging from 33 to 68 years old, were screened by skin tests and divided into atopic (G1) and non-atopic (G2). Eustachian tube function (ETF) was evaluated through tympanometry, William's test and ETDQ-7. (4) Results: A moderate to severe subjective ETDQ-7 was found in the 35.42% of G1 and in the 22.45% of G2 patients before RTR. William's test resulted normal in 141 ears (72.68%), partially impaired in 15 (7.73%), and grossly impaired in 38 (19.59%) before surgery. A grossly ETD was evidenced in the 19.59% of cases before surgery and decreased to 6.18% after surgery with a significant difference among atopic patients (p < 0.001). (5) Conclusion: RTR may be considered a treatment option in patients suffering from ETD and inferior turbinates' hypertrophy; RTR reduced the percentage of grossly impaired ET function (p < 0.001). ETDQ-7 and William's test may represent valuable tools to assess ET function before and after surgery.


HIV preexposure prophylaxis in the United States: impact on lifetime infection risk, clinical outcomes, and cost-effectiveness.
The combination of tenofovir and emtricitabine shows promise as HIV preexposure prophylaxis (PrEP). We sought to forecast clinical, epidemiologic, and economic outcomes of PrEP, taking into account uncertainties regarding efficacy, the risks of developing drug resistance and toxicity, behavioral disinhibition, and drug costs. We adapted a computer simulation of HIV acquisition, detection, and care to model PrEP among men who have sex with men and are at high risk of HIV infection (i.e., 1.6% mean annual incidence of HIV infection) in the United States. Base-case assumptions included 50% PrEP efficacy and monthly tenofovir-emtricitabine costs of $753. We used sensitivity analyses to examine the stability of results and to identify critical input parameters. In a cohort with a mean age of 34 years, PrEP reduced lifetime HIV infection risk from 44% to 25% and increased mean life expectancy from 39.9 to 40.7 years (21.7 to 22.2 discounted quality-adjusted life-years). Discounted mean lifetime treatment costs increased from $81,100 to $232,700 per person, indicating an incremental cost-effectiveness ratio of $298,000 per quality-adjusted life-year gained. Markedly larger reductions in lifetime infection risk (from 44% to 6%) were observed with the assumption of greater (90%) PrEP efficacy. More-favorable incremental cost-effectiveness ratios were obtained by targeting younger populations with a higher incidence of infection and by improvements in the efficacy and cost of PrEP. PrEP could substantially reduce the incidence of HIV transmission in populations at high risk of HIV infection in the United States. Although it is unlikely to confer sufficient benefits to justify the current costs of tenofovir-emtricitabine, price reductions and/or increases in efficacy could make PrEP a cost-effective option in younger populations or populations at higher risk of infection. Given recent disappointments in HIV infection prevention and vaccine development, additional study of PrEP-based HIV prevention is warranted.


Discovery and optimization of 2,4-diaminoquinazoline derivatives as a new class of potent dengue virus inhibitors.
The results of a high-throughput screening assay using the DENV-2 replicon showed that the 2,4-diaminoquinazoline derivative 4a has a high dengue virus inhibitory activity (EC(50) = 0.15 μM). A series of 2,4-diaminoquinazoline derivatives based on 4a as a lead compound were synthesized and subjected to structure-antidengue activity relationship studies. Among the series of 2,4-diaminoquinazoline derivative probed, 4o was observed to display both the highest antiviral potency (EC(50) = 2.8 nM, SI > 1000) and an excellent pharmacokinetic profile.


Telomere biology disorders may manifest as common variable immunodeficiency (CVID).
Telomere biology disorders (TBD) are caused by germline pathogenic variants in genes related to telomere maintenance and are characterized by critically short telomeres. In contrast to classical dyskeratosis congenita (DC), which is typically diagnosed in infancy, adult or late onset TBD frequently lack the typical DC triad and rather show variable organ manifestations and a cryptic disease course, thus complicating its diagnosis. Common variable immunodeficiency (CVID), on the other hand, is a primary antibody deficiency (PAD) syndrome. PADs are a heterogenous group of diseases characterized by hypogammaglobulinemia which occurs due to dysfunctional B lymphocytes and additional autoimmune and autoinflammatory complications. Genetic screening reveals a monogenic cause in a subset of CVID patients (15-35%). In our study, we screened the exomes of 491 CVID patients for the occurrence of TBD-related variants in 13 genes encoding for telomere/telomerase-associated proteins, which had previously been linked to the disease. We found 110/491 patients (22%) carrying 91 rare candidate variants in these 13 genes. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we classified two variants as benign, two as likely benign, 64 as variants of uncertain significance (VUS), four as likely pathogenic, and one heterozygous variant in an autosomal recessive disease gene as pathogenic. We performed telomere length measurement in 42 of the 110 patients with candidate variants and CVID. Two of these 42 patients showed significantly shorter telomeres compared to controls in both lymphocytes and granulocytes. Following the evaluation of the published literature and the patient's manifestations, we re-classified two VUS as likely pathogenic variants. Thus, 0.5-1% of all CVID patients in our study carry possibly pathogenic variants in telomere/telomerase-associated genes. Our data adds CVID to the broad clinical spectrum of cryptic adult-onset TBD. As the molecular diagnosis greatly impacts patient management and treatment strategies, we advise inclusion of all TBD-associated genes-despite their low prevalence-into the molecular screening of patients with antibody deficiencies.


Doing Violence, Making Race: Southern Lynching and White Racial Group Formation.
This article presents a theoretical framework of how intergroup violence may figure into the activation and maintenance of group categories, boundaries, and identities, as well as the mediating role played by organizations in such processes. The framework's analytical advantages are demonstrated in an application to southern lynchings. Findings from event- and community-level analyses suggest that "public" lynchings, carried out by larger mobs with ceremonial violence, but not "private" ones, perpetrated by smaller bands without public or ceremonial violence, fed off and into the racial group boundaries, categories, and identities promoted by the southern Democratic Party at the turn of the 20th century and on which the emerging Jim Crow system rested. Highlighting that racialized inequalities cannot be properly understood apart from collective processes of racial group boundary and identity making, the article offers clues to the mechanisms by which past racial domination influences contemporary race relations.


Crystal structures of oxidized and reduced forms of NADH peroxidase.
X-ray structural characterization of cysteine-sulfenic acid-containing proteins is one of the most defining approaches to characterizing this rapidly growing class of protein functional groups. Although outside the scope of this chapter, these structural analyses can lead to kinetic measurements in the crystal that allow intermediate states to be trapped, visualized, and studied. An understanding of the biochemistry of these reactive groups can be more fully gained by studying the localized protein environment in which these groups function. Increased perception of how elements of a protein can stabilize and contribute to modulation of function in these systems will allow novel means of enhancing or inhibiting function in important classes of protein molecules, including transcription factors and redox-regulated enzymes.


Teaching-learning mechanisms in consumer health education.
A study of a special school program on cigarette smoking and health was undertaken in Niagara County, N.Y., to determine whether it produced effects on knowledge, attitudes, and behavior among teachers and parents as well as students and, if so, how these effects were accomplished. Data for parents, the subject of this report, were collected by questionnaire and interview before and after the program from selected parents of students in 36 junior high school classes assigned equally to experimental and control groups. The parents failed to show statistically significant modifications of either knowledge or attitudes after the program. They did, however, show a consistent and significant downward shift in numbers of reported tobacco users. This finding was true for both experimental and control groups, but the change was distinctly greater in the experimental group. Additionally, the changes were greater for urban than for rural parents and for parents with incomes of $10,000 or more than for those with lower incomes. The results for parents differed from those for students and teachers concerning knowledge and attitudes, but they were similar to those for teachers and unlike those for students concerning smoking behavior. The study findings suggest that teaching-learning mechanisms beyond the traditional superordinate-subordinate model may be operative, with pupils, parents, and teachers in roles quite different from what they are generally thought to be. Specifically, the students may serve as mediators of value change and behavior modification for both teachers and parents.


Catestatin: A Master Regulator of Cardiovascular Functions.
Cardiovascular disease (CVD), the most common cause of death globally, accounts for ~30% of all deaths worldwide. Hypertension is a common contributor to morbidity and mortality from CVD. The plasma concentration of chromogranin A (CgA) is elevated in patients with CVD as well as patients with established human essential hypertension and heart failure (HF). In contrast, the plasma level of the CgA-derived peptide catestatin (CST) is diminished in human essential hypertension. Low conversion of CgA-to-CST has been associated with increased mortality in patients hospitalized with acute HF. Consistent with human findings, the lack of CST in CgA knockout (Chga-KO) mice eventuates in the development of hypertension and supplementation of CST to Chga-KO mice restores blood pressure, implicating CST as a key player in regulating hypertension. In the peripheral system, CST decreases blood pressure by stimulating histamine release, inhibiting catecholamine secretion, or causing vasodilation. Centrally, CST improves baroreflex sensitivity (BRS) and heart rate variability (HRV) by exciting GABAergic neurons in the caudal ventrolateral medulla (CVLM) and pyramidal neurons of the central amygdala; CST also decreases BRS by exciting glutamatergic rostral ventrolateral medulla (RVLM) neurons. In addition, CST provides cardioprotection by inhibiting inotropy and lusitropy; activating mitochondrial KATP channels, and stimulating reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways and consequent inhibition of mitochondrial permeability transition pore (mPTP). CST modulates cardiomyocyte Ca2+ levels by direct inhibition of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) activity and consequent reduction in phosphorylation of phospholamban and ryanodine receptor 2, thereby providing support for a direct functional role of CST in the failing myocardium. These multitude of effects establish CST as a master regulator of cardiovascular functions.


Conjectures concerning cross-sex hormone treatment of aging transsexual persons.
Guidelines for cross-sex hormone treatment of transsexual people are now in place. However, little attention has been paid to the issue of treatment suitability for older people. Does existing treatment need to be adapted as subjects age, and does it make a difference if treatment is only started when the subject is already older? To assess the necessity of adapting cross-sex hormone administration for elderly transsexual people. Risks/benefits of continued use of cross-sex hormones with regard to bone health, cardiovascular risks, and malignancies. Due to lack of data on the subject population, sex hormone treatment of other conditions in older non-transsexual people has been taken as the best available analogy to determine the extent to which these might be applicable to comparable transsexual persons. Findings in transsexual people receiving cross-sex hormone treatment sometimes modified the above approach of applying guidelines for the elderly to the aging transsexual population. Testosterone administration to female-to-male transsexual persons (FtoM) carries little risk with regard to cardiovascular disease and cancer. For those with high hematocrit or cardiac insufficiency the dose can be reduced. Administration of estrogens to male-to-female transsexual persons (MtoF), particularly when combined with progestins, does significantly increase the risk of developing cardiovascular disease (almost a twofold incidence compared with the general population). This may require dose adjustment or changing from oral to safer transdermal estrogens. Tumors of the breasts, prostate and pituitary may occur. In FtoM, breast cancer can occur even after breast ablation. Older subjects can commence cross-sex hormone treatment without disproportionate risks. Cross-sex hormones may be continued into old age but monitoring for cardiovascular disease and malignancies, both of the old and new sex, is recommended. MtoF will have more health complications in old age than FtoM requiring adaptations of treatment.


Evaluation of ¹¹¹in-labelled exendin-4 derivatives containing different meprin β-specific cleavable linkers.
Cleavable linkers, which are specifically cleaved by defined conditions or enzymes, are powerful tools that can be used for various purposes. Amongst other things, they have been successfully used to deliver toxic payloads as prodrugs into target tissues. In this work novel linker sequences targeting meprin β, a metalloprotease expressed in the kidney brush-border membrane, were designed and included in the sequence of three radiolabelled exendin-4 derivatives. As radiolabelled exendin-4 derivatives strongly accumulate in the kidneys, we hypothesised that specific cleavage of the radiolabelled moiety at the kidney brush-border membrane would allow easier excretion of the activity into the urine and therefore improve the pharmacological properties of the peptide. The insertion of a cleavable linker did not negatively influence the in vitro properties of the peptides. They showed a good affinity to the GLP-1 receptor expressed in CHL cells, a high internalisation and sufficiently high stability in fresh human blood plasma. In vitro digestion with recombinant meprin β rapidly metabolised the corresponding linker sequences. After 60 min the majority of the corresponding peptides were digested and at the same time the anticipated fragments were formed. The peptides were also quickly metabolised in CD1 nu/nu mouse kidney homogenates. Immunofluorescence staining of meprin β in kidney sections confirmed the expression of the protease in the kidney brush-border membrane. Biodistribution in GLP-1 receptor positive tumour-xenograft bearing mice revealed high specific uptake of the 111In-labelled tracers in receptor positive tissue. Accumulation in the kidneys, however, was still high and comparable to the lead compound 111In-Ex4NOD40. In conclusion, we show that the concept of cleavable linkers specific for meprin β is feasible, as the peptides are rapidly cleaved by the enzyme while retaining their biological properties.


New iron chelators in anthracycline-induced cardiotoxicity.
The use of anthracycline anticancer drugs is limited by a cumulative, dose-dependent cardiac toxicity. Iron chelation has long been considered as a promising strategy to limit this unfavorable side effect, either by restoring the disturbed cellular iron homeostasis or by removing redox-active iron, which may promote anthracycline-induced oxidative stress. Aroylhydrazone lipophilic iron chelators have shown promising results in the rabbit model of daunorubicin-induced cardiomyopathy as well as in cellular models. The lack of interference with the antiproliferative effects of the anthracyclines also favors their use in clinical settings. The dose, however, should be carefully titrated to prevent iron depletion, which apparently also applies for other strong iron chelators. We have shown that a mere ability of a compound to chelate iron is not the sole determinant of a good cardioprotector and the protective potential does not directly correlate with the ability of the chelators to prevent hydroxyl radical formation. These findings, however, do not weaken the role of iron in doxorubicin cardiotoxicity as such, they rather appeal for further investigations into the molecular mechanisms how anthracyclines interact with iron and how iron chelation may interfere with these processes.


Expanding the phenotypic spectrum of TRIM2-associated Charcot-Marie-Tooth disease.
Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of distal symmetric polyneuropathies due to progressive and length-dependent degeneration of peripheral nerves. Cranial nerve involvement has been described in association with various CMT-genes mutations, such as GDAP1, TRPV4, MFN2, MTMR2 and EGR2. Compound heterozygous mutations in the TRIM2 gene, encoding an E3 ubiquitin ligase, were previously identified in two patients with early-onset axonal CMT (CMT2). One of them also had bilateral vocal cord paralysis. The aim of this study is to further delineate the phenotypic and molecular genetic features of TRIM2-related CMT. We studied clinical, genetic and neurophysiological aspects of two unrelated CMT2 patients. Genetic analysis was performed by next generation sequencing of a multigene CMT panel. Patients presented with congenital hypotonia and bilateral clubfoot, delayed motor milestones, and severely progressive axonal neuropathy. Interestingly, along with vocal cord paralysis, they exhibited clinical features secondary to the involvement of several other cranial nerves, such as facial weakness, dysphagia, dyspnoea and acoustic impairment. Genetic analysis revealed two novel TRIM2 mutations in each patient. Our results expand the genotypic and phenotypic spectrum of TRIM2 deficiency showing that cranial nerves involvement is a core feature in this CMT2-subtype. Its finding should prompt physicians to suspect TRIM2 neuropathy. Conversely, patients carrying TRIM2 variants should be carefully evaluated for the presence of cranial nerve dysfunction in order to prevent and manage its impact on auditory and respiratory function and nutrition.


Sphingosine-1-phosphate and lysophosphatidic acid stimulate endothelial cell migration.
Endothelial cell migration is necessary for the formation of new blood vessels. We investigated the effects of 2 lysophospholipid mediators, sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA), on endothelial cell migration. S1P and LPA stimulated migration of fetal bovine heart endothelial cells (FBHEs) in a 3D-modified Boyden chamber assay with concentrations as low as 15 nmol/L stimulating a 2-fold change and concentrations in the 1- to 2-micromol/L range stimulating 14- to 20-fold changes. S1P specifically stimulated the migration of several endothelial cell strains but did not stimulate the migration of tumor cells or smooth muscle cells. LPA stimulated some endothelial and nonendothelial cell types to migrate. For FBHEs, S1P and LPA were mostly chemokinetic in checkerboard assays. S1P and LPA stimulated extracellular signal-regulated kinase 1/2 phosphorylation and enhanced paxillin localization to focal contacts, with no discernible change in the actin cytoskeleton in FBHEs. To characterize responsible receptor-dependent signaling pathways, we investigated the involvement of G(i), Rho, and phosphoinositide 3-OH kinase in S1P- and LPA-stimulated migration. Although perturbation of all 3 signaling molecules resulted in decreased migration, the mechanisms underlying the decreased migration were different. Pertussis toxin treatment, to target G(i), caused endothelial cells to develop dense bundles of F-actin and distribute paxillin staining to the cell periphery in response to S1P or LPA. Modification of Rho with C3 toxin disrupted the actin cytoskeleton. Inhibition of phosphoinositide 3-OH kinase decreased S1P- or LPA-induced endothelial cell migration with only minor disruption of the actin cytoskeleton. Inhibition of extracellular signal-regulated kinase kinase with PD98059 caused a loss of phosphorylation of extracellular signal-regulated kinase 1/2, similar to pertussis toxin, but only a minimal decrease in migration. These results indicate that S1P and, for some cells, LPA stimulate migration of endothelial cells through a mechanism that likely requires a balance between G(i) and Rho signaling to achieve the cytoskeletal remodeling necessary for cell migration.


Metal concentrations in the edible claw and body muscle of a popular recreational crab species (Scylla serrata).
In crabs, metal concentrations differ among tissues, but may also differ in edible white meat (muscle) in different parts of the body. This case study compared metal contaminants in the claw and body muscle for a popular crab species (Giant Mud Crab, Scylla serrata). For lead and nickel, body muscle concentrations were generally lower than claw concentrations, while the converse was true for arsenic, cadmium and mercury. When body and appendage meat proportions were used to weight body and claw metal concentrations the estimated concentration in total edible muscle closely reflected the claw muscle for zinc, but remained elevated relative to claw muscle (to varying degrees) for arsenic, cadmium and mercury. Linear models for these relationships allowed the total edible muscle concentration to be estimated from measured claw muscle concentrations. The relationships reported are useful for modelling exposure risk, and in crab ecotoxicology more broadly.


Safety and Feasibility of Intradiscal Administration of Matrilin-3-Primed Adipose-Derived Mesenchymal Stromal Cell Spheroids for Chronic Discogenic Low Back Pain: Phase 1 Clinical Trial.
Functionally enhanced mesenchymal stromal cells participate in the repair of intervertebral disc. This study aimed to assess the safety and tolerability of intradiscal administration of matrilin-3-primed adipose-derived stromal cell (ASC) spheroids with hyaluronic acid (HA) in patients with chronic discogenic low back pain (LBP). In this single-arm, open-label phase I clinical trial, eight patients with chronic discogenic LBP were observed over 6 months. Each patient underwent a one-time intradiscal injection of 1 mL of 6.0 × 106 cells/disc combined with HA under real-time fluoroscopic guidance. Safety and feasibility were gauged using Visual Analogue Scale (VAS) pain and Oswestry Disability Index (ODI) scores and magnetic resonance imaging. All participants remained in the trial, with no reported adverse events linked to the procedure or stem cells. A successful outcome-marked by a minimum 2-point improvement in the VAS pain score and a 10-point improvement in ODI score from the start were observed in six participants. Although the modified Pfirrmann grade remained consistent across all participants, radiological improvements were evident in four patients. Specifically, two patients exhibited reduced high-intensity zones while another two demonstrated decreased disc protrusion. In conclusion, the intradiscal application of matrilin-3-primed ASC spheroids with HA is a safe and feasible treatment option for chronic discogenic LBP.


Thyroid Dysfunction in Heart Failure and Cardiovascular Outcomes.
The effects of thyroid dysfunction in patients with preexisting heart failure have not been adequately studied. We examined the prevalence of thyroid dysfunction and associations with cardiovascular outcomes in a large, prospective cohort of outpatients with preexisting heart failure. We examined associations between thyroid dysfunction and New York Heart Association class, atrial fibrillation, and a composite end point of ventricular assist device placement, heart transplantation, or death in 1365 participants with heart failure enrolled in the Penn Heart Failure Study. Mean age was 57 years, 35% were women, and the majority had New York Heart Association class II (45%) or III (32%) symptoms. More severe heart failure was associated with higher thyroid-stimulating hormone (TSH), higher free thyroxine (FT4), and lower total triiodothyronine (TT3) concentrations ( P<0.001 all models). Atrial fibrillation was positively associated with higher levels of FT4 alone ( P≤0.01 all models). There were 462 composite end points over a median 4.2 years of follow-up. In adjusted models, compared with euthyroidism, subclinical hypothyroidism (TSH 4.51-19.99 mIU/L with normal FT4) was associated with an increased risk of the composite end point overall (hazard ratio, 1.82; 95% CI, 1.27-2.61; P=0.001) and in the subgroup with TSH ≥7.00 mIU/L (hazard ratio, 3.25; 95% CI, 1.96-5.39; P<0.001), but not in the subgroup with TSH 4.51-6.99 mIU/L (hazard ratio, 1.26; 95% CI, 0.78-2.06; P=0.34). Isolated low T3 was also associated with the composite end point (hazard ratio, 2.12; 95% CI, 1.65-2.72; P<0.001). In patients with preexisting heart failure, subclinical hypothyroidism with TSH ≥7 mIU/L and isolated low T3 levels are associated with poor prognosis. Clinical trials are needed to explore therapeutic effects of T4 and T3 administration in heart failure.


Analysis of volume and costs of dental care provided in outpatient settings.
A conducted analysis of volume and cost of dental care provided in outpatient settings proves the need for harmonization of Russian Ministry of Health's documentation regulating dental checks in adults and children, and the Programme of state guarantees.


Risk assessment of dimethylfumarate residues in dwellings following contamination by treated furniture.
Recently, numerous cases of dermatitis induced by dimethylfumarate (DMFu) have been reported in Europe. DMFu has been used to prevent mold development in various items, although it is not registered as a biocide. In France, from October 2008 to December 2009, more than 100 cases were reported. Despite a ban on articles containing DMFu and the removal of potentially contaminated products, some people were still suffering from dermatitis or other health problems. The French Agency for Food, Environmental and Occupational Health & Safety was mandated to assess whether the existence in the past of DMFu-contaminated items in dwellings could continue to pose a threat to the health of inhabitants. A risk assessment was performed based on the classical risk analysis approach for environmental contaminants. Hazard assessment of DMFu with regard to its sensitizing properties was performed, based on human case reports collected in France between January 2009 and February 2010. For around half of the 132 individual cases reported, the causal link to DMFu was considered at least probable. An Organisation for Economic Co-Operation and Development (OECD) local lymph node assay performed in a study on mice showed strong sensitizing potential for DMFu. Exposure was assessed by measuring DMFu in items sampled in preselected dwellings. These investigations demonstrated that DMFu exposure can persist after removal of the primary contaminated items. We therefore concluded that there was clearly a risk of skin reactions in patients previously sensitized to DMFu. Furthermore, the available data do not support the existence of significant health effects through the respiratory route.


Prediction Models for the 5- and 10-Year Incidence of Home Morning Hypertension: The Ohasama Study.
We aimed to develop risk prediction models for new-onset home morning hypertension. We followed up 978 participants without home hypertension in the general population of Ohasama, Japan (men: 30.1%, age: 53.3 years). The participants were divided into derivation (n = 489) and validation (n = 489) cohorts by their residential area. The C-statistics and calibration plots were assessed after the 5- or 10-year follow-up. In the derivation cohort, sex, age, body mass index, smoking, office systolic blood pressure (SBP), and home SBP at baseline were selected as significant risk factors for new-onset home hypertension (≥135/85 mm Hg or the initiation of antihypertensive treatment) using the Cox model. In the validation cohort, Harrell's C-statistic for the 5-/10-year home hypertension was 0.7637 (0.7195-0.8100)/0.7308 (0.6932-0.7677), when we used the full model, which included the significant risk factors in the derivation cohort. The calibration test revealed good concordance between the observed and predicted 5-/10-year home hypertension probabilities (P ≥ 0.19); the regression slope of the observed probability on the predicted probability was 1.10/1.02, and the intercept was -0.04/0.06, respectively. A model without home SBP was also developed; for the 10-year home hypertension risk, the calibration test revealed a good concordance (P = 0.19) but Harrell's C-statistic was 0.6689 (0.6266-0.7067). The full model revealed good ability to predict the 5- and 10-year home morning hypertension risk. Although the model without home SBP is acceptable, the low C-statistic implies that home BP should be measured to predict home morning hypertension precisely.


Isolation and functional analysis of a chk2 homologue from Entamoeba histolytica.
Mammalian Chk2 is a Ser/Thr kinase required for cell-division arrest induced by DNA damage. We found six new kinase genes of Entamoeba histolytica by analysis in silico. One of the kinase genes was a homologue of human chk2 gene. The chk2 homologue gene (Eh chk2) was expected to encode 398 amino acids and showed nearly 50% homology to human Chk2 in amino acid sequence. Eh chk2 had a catalytic domain of Ser/Thr kinase and a fork head-associated (FHA) domain that is highly conserved among Chk2 homologues in vertebrates. To examine the biological functions of Eh chk2, we synthesized Eh chk2 mRNA in vitro and injected it into immature frog eggs (Xenopus laevis oocytes) as a model system of cell division. Eh chk2 markedly delayed the cell division of frog eggs by disrupting transition of G2 phase to M phase. Eh chk2 also inhibited the activation of p42 MAPK and Cdc2 kinase which are representative events induced by cell division. These results suggest that Eh chk2 gene should be a cell-division regulator in E. histolytica.


Factors that influence elastomeric coating performance: the effect of coating thickness on basal plate morphology, growth and critical removal stress of the barnacle Balanus amphitrite.
Silicone coatings are currently the most effective non-toxic fouling release surfaces. Understanding the mechanisms that contribute to the performance of silicone coatings is necessary to further improve their design. The objective of this study was to examine the effect of coating thickness on basal plate morphology, growth, and critical removal stress of the barnacle Balanus amphitrite. Barnacles were grown on silicone coatings of three thicknesses (0.2, 0.5 and 2 mm). Atypical ("cupped") basal plate morphology was observed on all surfaces, although there was no relationship between coating thickness and i) the proportion of individuals with the atypical morphology, or ii) the growth rate of individuals. Critical removal stress was inversely proportional to coating thickness. Furthermore, individuals with atypical basal plate morphology had a significantly lower critical removal stress than individuals with the typical ("flat") morphology. The data demonstrate that coating thickness is a fundamental factor governing removal of barnacles from silicone coatings.


Recovery and characterization of a minute virus of canines.
Four antigenically related transmissible agents were recovered from canine fecal specimens. The agents produced cytopathic effects in a continuous dog cell line developed in this laboratory. Increased antibody titers were demonstrated in three of the four dogs which provided the isolates. The virus did not produce cytopathic effects in primary canine kidney or thymus cell cultures, or in cell cultures of human, simian, porcine, bovine, feline, and murine origin. The agent is resistant to ether, chloroform, and heat treatment, and the growth of the virus is inhibited by 5-iodo-2-deoxyuridine. After acridine orange staining, green fluorescent intranuclear inclusions are seen in infected cell cultures. By electron microscopy, the virions measure approximately 20 to 21 nm in overall diameter and are present in the nuclei of infected cells. These properties are consistent with membership in the parvovirus or picodnavirus group. The agent hemagglutinates rhesus red blood cells at 5 C and by hemagglutination-inhibition tests could be readily distinguished from H-1, rat virus, and the minute virus of mice. Canine gamma globulin contains high titers of neutralizing antibody and neutralizing antibody was found in a high percentage of military dogs and in beagles of a breeding colony.


Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies.
Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are major causes of blindness. They result from mutations in many genes which has long hampered comprehensive genetic analysis. Recently, targeted next-generation sequencing (NGS) has proven useful to overcome this limitation. To uncover "hidden mutations" such as copy number variations (CNVs) and mutations in non-coding regions, we extended the use of NGS data by quantitative readout for the exons of 55 RP and LCA genes in 126 patients, and by including non-coding 5' exons. We detected several causative CNVs which were key to the diagnosis in hitherto unsolved constellations, e.g. hemizygous point mutations in consanguineous families, and CNVs complemented apparently monoallelic recessive alleles. Mutations of non-coding exon 1 of EYS revealed its contribution to disease. In view of the high carrier frequency for retinal disease gene mutations in the general population, we considered the overall variant load in each patient to assess if a mutation was causative or reflected accidental carriership in patients with mutations in several genes or with single recessive alleles. For example, truncating mutations in RP1, a gene implicated in both recessive and dominant RP, were causative in biallelic constellations, unrelated to disease when heterozygous on a biallelic mutation background of another gene, or even non-pathogenic if close to the C-terminus. Patients with mutations in several loci were common, but without evidence for di- or oligogenic inheritance. Although the number of targeted genes was low compared to previous studies, the mutation detection rate was highest (70%) which likely results from completeness and depth of coverage, and quantitative data analysis. CNV analysis should routinely be applied in targeted NGS, and mutations in non-coding exons give reason to systematically include 5'-UTRs in disease gene or exome panels. Consideration of all variants is indispensable because even truncating mutations may be misleading.


The Problems Experienced by Employees with Chronic Disease during the COVID-19 Pandemic.
Chronic diseases served as a silent global epidemic before the pandemic, and individuals living with chronic disease now form one of the groups most affected by COVID-19. This study aims to determine the problems that employees with chronic disease face during the COVID-19 pandemic. As part of the study, data were collected from 952 individuals who live with chronic disease in Turkey. Of these, 76.6% of respondents worked for the public sector, a large majority of whom (67.7%) have worked full time during the COVID-19 pandemic. It was found that the COVID-19 fear level of employees living with chronic disease was higher than moderate (21.061 ± 7.607). When the variables affecting the COVID-19 fear level are listed in order of relative significance, eating problems, residing in the Mediterranean region, having asthma, and working as a female employee made the greatest impact, respectively. Necessary conditions of work should be provided to those living with chronic disease who could adapt themselves to working flexibly or working from home, so that they would not feel isolated from business life. This group should be provided with essential protective equipment, their working conditions must be reviewed and vaccination priority could be given to them.


Neuroimaging-based pain biomarkers: definitions, clinical and research applications, and evaluation frameworks to achieve personalized pain medicine.
One of the key ambitions of neuroimaging-based pain biomarker research is to augment patient and clinician reporting of clinically relevant phenomena with neural measures for prediction, prognosis, and detection of pain. Despite years of productive research on the neuroimaging of pain, such applications have seen little advancement. However, recent developments in identifying brain-based biomarkers of pain through advances in technology and multivariate pattern analysis provide some optimism. Here, we (1) define and review the different types of potential neuroimaging-based biomarkers, their clinical and research applications, and their limitations and (2) describe frameworks for evaluation of pain biomarkers used in other fields (eg, genetics, cancer, cardiovascular disease, immune system disorders, and rare diseases) to achieve broad clinical and research utility and minimize the risks of misapplication of this emerging technology. To conclude, we discuss future directions for neuroimaging-based biomarker research to achieve the goal of personalized pain medicine.


Imaging of hypoxia-inducible factor 1α and septin 9 interaction by bimolecular fluorescence complementation in live cancer cells.
Hypoxia-inducible factor 1 (HIF-1) is a major mediator of the hypoxic response involved in tumor progression. We had earlier described the interaction between septin 9 isoform 1 (SEPT9_i1) protein and the oxygen-regulated subunit, HIF-1α. SEPT9_i1 is a member of the conserved family of GTP-binding cytoskeleton septins. SEPT9_i1 stabilizes HIF-1α and facilitates its cytoplasmic-nuclear translocation. We utilized split yellow fluorescent protein (YFP) bimolecular fluorescence complementation (BiFC) methodology to monitor the interaction between HIF-1α and SEPT9_i1 in live cells. N-terminal (YN) and C-terminal (YC) split YFP chimeras with HIF-1α and SEPT9_i1 on both their amino and carboxyl termini were generated. HIF-1α and SEPT9_i1 chimeras were expressed in cancer cells and screened for functional complementation. SEPT9_i1-YN and YC-HIF-1α formed a long-lived highly stable complex upon interaction. The BiFC signal was increased in the presence of hypoxia-mimicking agents. In contrast, YC-ΔHLH-HIF-1α chimera, which lacked the helix-loop-helix domain that is essential for the interaction with SEPT9_i1 as well as the expression of SEPT9_i1 252-379 amino acids fragment required for the interaction with HIF-1α, significantly reduced the BiFC signal. The signal was also reduced when cells were treated with 17-N-allylamino-17-demethoxygeldanamycin, an HSP90 inhibitor that inhibits HIF-1α. It was increased with fourchlorfenuron, a small molecule that increases the interaction between HIF-1α and SEPT9_i1. These results reconfirmed the interaction between HIF-1α and SEPT9_i1 that was imaged in live cells. This BiFC system represents a novel approach for studying the real-time interaction between these two proteins and will allow high-throughput drug screening to identity compounds that disrupt this interaction.


The crystal structure of a new high-calcium form of annexin V.
Annexin V was crystallized in the presence of a high concentration of calcium and the structure refined at 1.9 A resolution. The crystals are triclinic (P1) with three molecules per asymmetric unit and pseudo-R3 symmetry, reflecting a tendency of annexin to form trimers. The overall structure of the protein is similar to that seen in other crystal forms. There are, however, significant changes in domain III, where a new calcium site is formed. The whole region surrounding this site is reorganized in our structure, rendering annexin V more symmetrical and more alike annexin I. The formation of the new calcium site causes the displacement of Trp187 from a buried to an exposed conformation, a change that has recently been demonstrated by fluorescence measurements. The affinity of the different potential calcium sites is modulated: there is no calcium bound in domains II and IV, while up to two secondary calcium ions sites (in domains I and III) can substitute, depending on the calcium concentration present. We suggest that annexin can act as a calcium buffer, binding or releasing calcium depending on its local concentration. Our results also show that annexin displays inherent mobility which, together with its capacity to modulate the calcium affinity of its sites, can be of importance for its function on the membrane surface.


Validity of a Serological Diagnostic Kit for SARS-CoV-2 Available in Iran.
The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic broke out in December 2019 and is now characterized as a pandemic. Effective control of this infectious disease requires access to diagnostic techniques, for both case finding and epidemic size estimation. The molecular technique is routinely used worldwide. Although it is the "standard" case detection and management method, it has its own shortcomings. Thus, some easy-to-use rapid serological tests have been developed. One hundred and fourteen positive RT-PCR-diagnosed patients were tested by VivaDiag Kit, a brand of rapid serological kits available in hospitals affiliated to Tehran University of Medical Sciences (TUMS), Tehran, Iran. Frozen serum specimens taken from healthy people in summer and fall 2019 were also tested as negative controls. Test sensitivity was 47.9% (95% confidence interval [CI]: 38.8-56.9) for IgM and 47.0% (95% CI: 38.0-56.0) for IgG. There was no difference between IgG and IgM seropositivity except in one case. Specificity was calculated as 99.0% (95% CI: 96.4-99.9) for IgM and of 100.0% (95% CI: 0.98.2-100.0) for IgG. Sensitivity was higher in men and older participants. This test can be used for epidemiological investigations, especially for the estimation of the level of infection in the community, after it is properly corrected for sensitivity and specificity. The low sensitivity could be attributed to the technical limitations of the kit or low levels of antibodies after infection. The different sensitivity in age and sex groups supports the hypothesis that different people show different immune responses to this virus.


The biochemical properties of the ATPase activity of a 70-kDa heat shock protein (Hsp70) are governed by the C-terminal domains.
The cytosolic 70-kDa heat shock proteins (Hsp70s), Ssa and Ssb, of Saccharomyces cerevisiae are functionally distinct. Here we report that the ATPase activities of these two classes of Hsp70s exhibit different kinetic properties. The Ssa ATPase has properties similar to those of other Hsp70s studied, such as DnaK and Hsc70. Ssb, however, has an unusually low steady-state affinity for ATP but a higher maximal velocity. In addition, the ATPase activity of Hsp70s, like that of Ssa1, depends on the addition of K+ whereas Ssb activity does not. Suprisingly, the isolated 44-kDa ATPase domain of Ssb has a Km and Vmax for ATP hydrolysis similar to those of Ssa, rather than those of full length Ssb. Analysis of Ssa/Ssb fusion proteins demonstrates that the Ssb peptide-binding domain fused to the Ssa ATPase domain generates an ATPase of relatively high activity and low steady-state affinity for ATP similar to that of native Ssb. Therefore, at least some of the biochemical differences between the ATPases of these two classes of Hsp70s are not intrinsic to the ATPase domain itself. The differential influence of the peptide-binding domain on the ATPase domain may, in part, explain the functional uniqueness of these two classes of Hsp70s.


Effects of cyclic AMP on contact formation and differentiation in Dictyostelium discoideum.
It has been shown previously that Dictyostelium discoideum NC4 cells dissociated at the early aggregation stage form cell clumps and differentiate into prespore cells in a shaking culture containing glucose, albumin, EDTA and cyclic AMP. In this culture system, we found that the cells neither differentiate nor form cell clumps in the absence of cyclic AMP. Wheat-germ agglutinin (WGA) completely inhibited the cyclic AMP-induced formation of cell contact and the inhibition was nullified by the addition of N-acetyl-D-glucosamine. When the cells were prevented from forming contact by either rapid shaking or the addition of WGA, they were unable to differentiate even in the presence of cyclic AMP, indicating that contact formation is a prerequisite for prespore differentiation. Cells dissociated from migrating slugs formed cell clumps in shaking culture, with or without cyclic AMP, and the cell contact was sensitive to WGA. In the absence of cyclic AMP, prespore cells lost their differentiated state, even though the cells were in contact. This indicates that cyclic AMP has a second effect, that of pomoting differentiation, in addition to the effect of inducing contact formation. Both effects were required for prespore differentiation of strain NC4 cells.


The Supportive Care Needs of Primary Caregivers of Lung Transplant Candidates.
Caring for people with advanced illness has an impact on caregivers' physical, psychological, and emotional health. Patients being evaluated for lung transplantation or those on the transplant waitlist are required to have identified social support. However, little is known about the caregivers' specific supportive care needs. The aim of this study was to determine the supportive care needs of informal caregivers of patients who are being evaluated for or awaiting lung transplantation. A cross sectional survey of the caregivers of lung transplant candidates using the Carers' Support Needs Assessment Tool (CSNAT) was conducted. The sample (n = 78) included caregivers from a single-center academic institution in the United States. Participants were predominantly Caucasian and female, mean age 58 years (SD:13). Most were the patient's spouse or partner and over half reported needs in the following areas: what to expect in the future; who to call with healthcare concerns; financial, legal and work issues; and caregivers' feelings and worries. When asked if they need more support in these areas, up to one-third indicated they needed "quite a bit more" or "very much more," with substantial needs regarding what to expect in the future, who to call with healthcare concerns, and financial, legal, or work issues. A substantial portion of lung transplant caregivers express need for more support. Future research should focus on testing strategies to promote regular assessment of these needs and examining the effectiveness of interdisciplinary interventions to address them.


Alternate Healthy Eating Index 2010 and risk of chronic obstructive pulmonary disease among US women and men: prospective study.
To investigate the association between the Alternate Healthy Eating Index 2010 (AHEI-2010)--a measure of diet quality--and the risk of chronic obstructive pulmonary disease (COPD). Prospective cohort study. Participants in the Nurses' Health Study and the Health Professionals Follow-up Study, United States. 73,228 female nurses from 1984 to 2000 and 47,026 men from 1986 to 1998, who completed biennial questionnaires. The primary outcome was the self report of newly diagnosed COPD. Multivariable Cox proportional hazards models were adjusted for age, physical activity, body mass index, total energy intake, smoking, second hand tobacco exposure (only in the Nurses' Health Study), race/ethnicity, physician visits, US region, spouse's highest educational attainment (only in the Nurses' Health Study), and menopausal status (only in the Nurses' Health Study). Over the study period, 723 cases of newly diagnosed COPD occurred in women and 167 in men. In the pooled analysis, a significant negative association was seen between the risk of newly diagnosed COPD and fifths of the AHEI-2010: hazard ratios were 0.81 (95% confidence interval 0.51 to 1.29) for the second fifth, 0.98 (0.80 to 1.18) for the third fifth, 0.74 (0.59 to 0.92) for the fourth fifth, and 0.67 (0.53 to 0.85) for participants who ate the healthiest diet according to the AHEI-2010 (that is, were in the highest fifth), compared with those who ate the less healthy diet (participants in the lowest fifth). Similar findings were observed among ex-smokers and current smokers. A higher AHEI-2010 diet score (reflecting high intakes of whole grains, polyunsaturated fatty acids, nuts, and long chain omega-3 fats and low intakes of red/processed meats, refined grains, and sugar sweetened drinks) was associated with a lower risk of COPD in both women and men. These findings support the importance of a healthy diet in multi-interventional programs to prevent COPD.


Serous and mesothelial proliferations of the extraovarian peritoneum and pelvic lymph nodes.
With rare exceptions, serous proliferations of the peritoneum are limited to women, whereas proliferations of mesothelial differentiation arise predominantly in men. The authors focus on the various types of serous and mesothelial proliferations of the peritoneum and pelvic lymph nodes. Discussion of each type focuses on clinical and morphologic features, histogenesis, differential diagnosis, and clinical outcome.


The thoracic muscular system and its innervation in third instar Calliphora vicina Larvae. II. Projection patterns of the nerves associated with the pro- and mesothorax and the pharyngeal complex.
We describe the anatomy of the nerves that project from the central nervous system (CNS) to the pro- and mesothoracic segments and the cephalopharyngeal skeleton (CPS) for third instar Calliphora larvae. Due to the complex branching pattern we introduce a nomenclature that labels side branches of first and second order. Two fine nerves that were not yet described are briefly introduced. One paired nerve projects to the ventral arms (VAs) of the CPS. The second, an unpaired nerve, projects to the ventral surface of the cibarial part of the esophagus (ES). Both nerves were tentatively labeled after the structures they innervate. The antennal nerve (AN) innervates the olfactory dorsal organ (DO). It contains motor pathways that project through the frontal connectives (FC) to the frontal nerve (FN) and innervate the cibarial dilator muscles (CDM) which mediate food ingestion. The maxillary nerve (MN) innervates the sensory terminal organ (TO), ventral organ (VO), and labial organ (LO) and comprises the motor pathways to the mouth hook (MH) elevator, MH depressor, and the labial retractor (LR) which opens the mouth cavity. An anastomosis of unknown function exists between the AN and MN. The prothoracic accessory nerve (PaN) innervates a dorsal protractor muscle of the CPS and sends side branches to the aorta and the bolwig organ (BO) (stemmata). In its further course, this nerve merges with the prothoracic nerve (PN). The architecture of the PN is extremely complex. It innervates a set of accessory pharyngeal muscles attached to the CPS and the body wall musculature of the prothorax. Several anastomoses exist between side branches of this nerve which were shown to contain motor pathways. The mesothoracic nerve (MeN) innervates a MH accessor and the longitudinal and transversal body wall muscles of the second segment.


β2-adrenoreceptor medications and risk of Parkinson disease.
A recent study observed a 2-fold greater risk of Parkinson disease (PD) in relation to the β2-adrenoreceptor antagonist propranolol and a markedly lower risk of PD for the β2-adrenoreceptor agonist salbutamol. We examined whether confounding by clinical indication for these medications, that is, tremor and smoking-related pulmonary conditions, explained these associations. In a large, population-based case-control study of United States Medicare beneficiaries in 2009 with diagnosis codes, procedure codes, and prescription data (48,295 incident PD cases, 52,324 controls), we examined the risk of PD in relation to use of selected β antagonists (propranolol, carvedilol, metoprolol), the β2 agonist salbutamol, and other medications used for the same clinical indications (primidone, inhaled corticosteroids). We adjusted for demographics, smoking, and overall use of medical care. We then examined the effect of also adjusting for clinical indication and applying medication exposure lagging. Propranolol appeared to increase PD risk (odds ratio [OR] = 3.62, 95% confidence interval [CI] = 3.31-3.96). When we adjusted for tremor or abnormal involuntary movement prior to the PD diagnosis/reference date and lagged propranolol exposure, the association was 0.97 (95% CI = 0.80-1.18). Primidone, also used for tremor, was similarly sensitive to this adjustment and lagging. β Antagonists not indicated for tremor appeared to reduce PD risk (carvedilol: OR = 0.77, 95% CI = 0.73-0.81; metoprolol: OR = 0.94, 95% CI = 0.91-0.97) and were insensitive to adjustment for indications and lagging. Neither salbutamol nor inhaled corticosteroids were consistently associated with PD risk. β2-adrenoreceptor agonists and antagonists do not appear to alter PD risk. Ann Neurol 2018;84:691-701.


Ulcerative lichen planus. Follow-up of surgical excision and grafting.
Four patients with ulcerative lichen planus of the feet underwent total excision and split-thickness skin grafting of the affected areas. One patient underwent grafting in 1951, and remained free of recurrent ulcers for 26 years. Another, who had an 18-year follow-up after grafting, required an additional procedure. The possibility of squamous cell carcinoma in ulcerative lichen planus is considerable, lending further support to the concept that excision with grafting is the treatment of choice for these lesions.


Bile duct apoptosis and cholestasis resembling acute graft-versus-host disease after autologous hematopoietic cell transplantation.
Acute graft-versus-host disease (GVHD) of the liver is a frequent complication of allogeneic hematopoietic cell transplantation. This report describes hepatic GVHD following autologous transplantation. We reviewed 116 consecutive autologous transplant recipients. A diagnosis of GVHD was based on histology (segmental to subtotal destruction of bile ductal epithelial cells with apoptosis and lymphocytic infiltrates), clinical criteria (elevated serum alkaline phosphatase), a response to immunosuppressive therapy, and finding no other cause for cholestatic liver disease. Two patients developed cholestatic liver disease (alkaline phosphatase levels over five times the normal upper limit) and had liver biopsies showing apoptotic and dysmorphic ductular epithelial cells typical of GVHD. Three additional patients developed cholestasis and intestinal symptoms but had gastric biopsies only, showing apoptotic crypt epithelial cells and crypt cell drop-out typical of GVHD. Two recipients of autologous hematopoietic cells developed histologic abnormalities of small bile ducts and cholestatic liver disease resembling GVHD of the liver after allogeneic transplant. The mechanisms of bile duct damage in this setting may involve immune dysregulation related to reconstitution of immunity with peripheral blood stem cells.


Calculating transition dipole moments of phosphorescent emitters for efficient organic light-emitting diodes.
The out-coupling of light from an organic light-emitting diode, and thus its efficiency, strongly depends on the orientation of the transition dipole moment (TDM) of the emitting molecules with respect to the substrate surface. Despite the importance of this quantity, theoretical investigations of the direction of the TDM of phosphorescent emitters based on iridium(iii) complexes remain limited. One challenge is to find an appropriate level of theory able to accurately predict the direction of the TDM. Here, we report relativistic time-dependent density functional theory (TDDFT) calculations of the TDM, emission energies and lifetimes for both the ground-state (S0) and triplet (T1) excited-state geometries of fac-tris(2-phenylpyridyl)iridium(iii) (Ir(ppy)3), using the two-component zero-order regular approximation (ZORA) or including spin-orbit coupling (SOC) perturbatively using the simpler one-component (scalar) formulation. We show that the one- and two-component approaches give similar emission energies and overall radiative lifetimes for each individual geometry. Use of the S0 geometry leads to two of the excited triplet substates being degenerate, with the degeneracy lifted for the T1 geometry, with the latter matching experiment. Two-component calculations using the T1 geometry give results for the direction of the TDM more consistent with experiment than calculations using the S0 geometry. Finally, we show that adding a dielectric medium does not affect the direction of TDM significantly, but leads to better agreement with the experimentally measured radiative lifetime.


[A complete clinical trial register is already a reality in the paediatric field].
Clinical trials have a fundamental role in promoting an evidence based use of drugs in adults and in children. However, it is often difficult to identify the few paediatric studies carried out and to thus implement knowledge derived from them. Furthermore, studies that are stopped prematurely or that have insignificant or negative results often remain unpublished, leading to duplication of effort by researchers, waste of resources and concealment of potentially toxic risks. The European Community decided to support the development of a European register of clinical trials in children as part of the Fifth Framework Thematic Programme "Quality of Life" in 2002. The project DEC-net is coordinated by the Laboratory of Mother and Child Health of the Mario Negri Institute for Pharmaceutical Research in Milan and currently involves members of four countries; France, Italy, Spain and the United Kingdom. It is unique in that it is the first population oriented clinical trial register. Such a register represents a useful source for planning new studies, promoting communications and collaborations between researchers, facilitating patient access and recruitment into trials, preventing trial duplication and inappropriate funding and identifying the therapeutic needs of children that remain neglected. It will also allow for active monitoring of new or evolved knowledge of drug therapies.


Pseudomonas pseudomallei pneumonia with septicemia--case report.
A case of Pseudomonas pseudomallei pneumonia with septicemia is described. The onset was insidious with paucity of systemic symptoms except fever. Diabetes mellitus and alcoholism were associated problems. Initially blood cultures were negative but subsequently P. pseudomallei was isolated. The outcome was fatal. Unless diagnosed early and treated appropriately, patients often succumb to septicemic shock.


Predation risk causes oxidative damage in prey.
While there is increasing interest in non-consumptive effects of predators on prey, physiological effects are understudied. While physiological stress responses play a crucial role in preparing escape responses, the increased metabolic rates and shunting of energy away from other body functions, including antioxidant defence, may generate costs in terms of increased oxidative stress. Here, we test whether predation risk increases oxidative damage in Enallagma cyathigerum damselfly larvae. Under predation risk, larvae showed higher lipid peroxidation, which was associated with lower levels of superoxide dismutase, a major antioxidant enzyme in insects, and higher superoxide anion concentrations, a potent reactive oxygen species. The mechanisms underlying oxidative damage are likely to be due to the shunting of energy away from antioxidant defence and to an increased metabolic rate, suggesting that the observed increased oxidative damage under predation risk may be widespread. Given the potentially severe fitness consequences of oxidative damage, this largely overlooked non-consumptive effect of predators may be contributing significantly to prey population dynamics.


Gender differences in cardiovascular disease risk: Adolescence to young adulthood.
Gender differences in cardiovascular disease (CVD) have been well documented but rarely for young adults and the extent to which gender related lifestyle differences may contribute to gender differences in CVD risk experienced by young adults have not been reported. Data are from a long-running cohort study, the Mater-University of Queensland Study of Pregnancy (MUSP). We track gender differences in CVD related behaviours at 21 and 30 years (consumption of a Western Diet/Health-Oriented Diet, cigarette smoking, vigorous physical exercise, heavy alcohol consumption). At 30 years we compare males and females for CVD risk, and the extent to which lifestyle behaviours at 21 and 30 years contribute to CVD risk. At both 21 and 30 years of age, males more frequently consume a Western Diet and less often a Health Oriented Diet. By contrast, males are also much more likely to report engaging in vigorous physical activity. On most CVD markers, males exhibit much higher levels of risk than do females at both 21 and 30 years. At 30 years of age males have about five times the odds of being at high risk of CVD. Some lifestyle behaviours contribute to this additional risk. Young adult males much more frequently engage in most CVD related risk behaviours and males have a higher level of CVD risk. Gender differences in CVD risk remain high even after adjustment for CVD lifestyles, though dietary factors independently contribute to CVD risk at 30 years.


Playing Brains: The Ethical Challenges Posed by Silicon Sentience and Hybrid Intelligence in DishBrain.
The convergence of human and artificial intelligence is currently receiving considerable scholarly attention. Much debate about the resulting Hybrid Minds focuses on the integration of artificial intelligence into the human brain through intelligent brain-computer interfaces as they enter clinical use. In this contribution we discuss a complementary development: the integration of a functional in vitro network of human neurons into an in silico computing environment.To do so, we draw on a recent experiment reporting the creation of silico-biological intelligence as a case study (Kagan et al., 2022b). In this experiment, multielectrode arrays were plated with stem cell-derived human neurons, creating a system which the authors call DishBrain. By embedding the system into a virtual game-world, neural clusters were able to receive electrical input signals from the game-world and to respond appropriately with output signals from pre-assigned motor regions. Using this design, the authors demonstrate how the DishBrain self-organises and successfully learns to play the computer game 'Pong', exhibiting 'sentient' and intelligent behaviour in its virtual environment.The creation of such hybrid, silico-biological intelligence raises numerous ethical challenges. Following the neuroscientific framework embraced by the authors themselves, we discuss the arising ethical challenges in the context of Karl Friston's Free Energy Principle, focusing on the risk of creating synthetic phenomenology. Following the DishBrain's creator's neuroscientific assumptions, we highlight how DishBrain's design may risk bringing about artificial suffering and argue for a congruently cautious approach to such synthetic biological intelligence.


Severe reactive ischemic posterior segment inflammation in Acanthamoeba keratitis: Case report of a patient with Sjögren's syndrome.
We report on a case of Acanthamoeba keratitis (AK)-related reactive ischemic posterior segment inflammation following intraocular surgery in a patient with primary Sjögren's syndrome (PSS). A 48-year-old female patient with severe protracted AK underwent uneventful cataract surgery upon development of a corneal scar. Four weeks postoperatively, she experienced a rapid loss of vision to no light perception. Central retinal artery occlusion and ischemic optic neuropathy could be excluded, and a diagnosis of PSS was made. The condition remained unresponsive to systemic steroid treatment and ultimately led to enucleation of the globe. Histologic work-up revealed ischemic posterior segment inflammation and Acanthamoeba cysts in the corneal stroma. Autoimmune disease may be a risk factor for AK-related severe reactive ischemic posterior segment inflammation, and intraocular surgery can be a trigger to its manifestation.