Injectable hyaluronic acid gel for soft tissue augmentation. A clinical and histological study.
Several biomaterials are available for the purpose of soft tissue augmentation, but none of them has all the properties of the ideal filler material. The recent development of hyaluronic acid gels for dermal implantation give the physician new possibilities of effective treatment in this field. This study provides a clinical and histological evaluation of safety and efficacy of a cross-linked stabilized non-animal hyaluronic acid gel (Restylane, Q-Med, Uppsala, Sweden) to determine its characteristics, advantages, disadvantages, and side-effects. 158 patients were treated with facial intradermal implant of hyaluronic acid gel for augmentation therapy of wrinkles and folds, and for lip augmentation and/or recontouring. The results were evaluated in all patients by subjective judgement by the physician and the patient, and by photographic method at time 0 and after 1, 2, 4 and 8 months from the procedure. In addition, a smaller histological study was carried out in five volunteer patients for a term of 52 weeks to determine the interaction and duration of the material in human healthy skin. Clinically, both the physicians' and patients' evaluations revealed very satisfactory results, with a global 78.5% and 73.4% respectively of moderate or marked improvement after eight months, independent of the treated area. The photographic evaluation revealed even better results with a 80.4% of moderate or marked improvement after 8 months. The safety evaluation showed a 12.5% of postoperative immediate adverse events, that were localized and transient. There was no evidence of major systemic side effects. Histologically, the product was shown to be long-lasting and well tolerated as judged by histological techniques. Stabilized, non-animal, hyaluronic acid gel is well tolerated and effective in augmentation therapy of soft tissues of the face. This material presents several advantages in comparison to previously used injectable biomaterials and expands the arsenal of therapeutic tools in the field of soft tissue augmentation.


Science imitates art: the cloning of mice from olfactory sensory neurons.
The functional identity of an olfactory sensory neuron is defined by its expression of one odorant receptor from a large multigene family. The complexity of this process has led to speculation that DNA rearrangements are used to limit the expression of one receptor gene per cell. However, a recent report in Nature directly rules out irreversible DNA rearrangements as a mechanism for odorant receptor gene choice.


Role of xanthine oxidase in conduit artery endothelial dysfunction in cigarette smokers.
Xanthine oxidase contributes to oxidant stress and has been proposed as a risk factor for endothelial dysfunction. We studied the role of xanthine oxidase in conduit artery endothelial dysfunction in 12 smokers and 12 controls. Conduit artery vasodilation was impaired in smokers (4.3%) compared with controls (7.9%) (p = 0.006) and improved with xanthine oxidase inhibition in smokers (9.2%, p <0.001).


Animal biomass in a New Zealand forest compared with other parts of the world.
Data on mammalian, avian and invertebrate biomass in mixed broadleaf-podocarp forest of the Orongorongo Valley are summarised and compared with the biomass in other forests. Animal biomass totalled at least 504 kg/ha - more than twice that in several tropical forests but less than that reported from temperate deciduous forests of Europe. Earthworms (333 kg/ha) provided most animal biomass: arthropods at least 145 kg/ha, mammals (all introduced) 25 kg/ha, and birds 0.6 kg/ha. By world standards the biomass of mammals, and litter-dwelling and underground arthropods, is high and that of birds moderate. Introduced mammals have greatly altered the distribution of biomass in this forest, herbivores and predatory mammals gaining biomass at the expense of some native aboveground invertebrates and birds, several of which have been lost to this community.


Citrate Phosphate Dextrose Alters Coagulation Dynamics Ex Vivo.
Citrate-phosphate-dextrose (CPD) is the most common anticoagulant for blood product storage in the United States. It was developed to prolong shelf life, though there is little research regarding its impact on function following transfusion. We used flow cytometry (FC), thromboelastography (TEG), and a clot contraction assay called the zFlex platform to measure platelet activation and global clot formation in blood samples anticoagulated with either CPD or in a standard blue top citrate (BTC) tube. Samples were obtained through venipuncture of the antecubital fossa from healthy donors who had not recently taken antiplatelet medication. Samples for FC analysis were spun to obtain platelet-rich plasma, while TEG and zFlex utilized recalcified whole blood. Mean fluorescence intensity for CD62p (P-selectin, marker of platelet activation) in baseline samples was equal, while mean fluorescence intensity in samples activated with thrombin receptor activating peptide was higher in CPD than BTC (65,814 ± 4445 versus 52,483 ± 5435, P = 0.007). TEG results demonstrated similar maximum amplitude for CPD (62.7 ± 1.8 mm versus 61 ± 1 mm) (P = 0.33), though reaction time and kinetics time were significantly longer in CPD versus BTC. CPD R-time: 7.9 ± 0.4 min versus BTC: 3.8 ± 0.4 (P < 0.001). CPD K-time: 2.2 ± 0.2 min versus BTC: 1.6 ± 0.1 min (P < 0.001). Clot contraction strength was not different between the two groups on zFlex: CPD 4353 ± 6 = 517 μN versus BTC 4901 ± 390 μN (P = 0.39). Our findings suggest that CPD does not affect platelet function (minimal difference on FC and no difference in ultimate clot strength, which is ∼80% due to platelet function) but may alter clot dynamics by attenuating thrombin generation.


Increased agglutinability and haemadsorption of Marek's disease HPRS line 1 lymphoblastoic cells after concanavalin A treatment.
The HPRS line 1 lymphoblastoid cells derived from an ovarian lymphoma induced by Marek's disease virus in chickens displayed increased agglutinability and haemadsorption when incubated with Con A. The increase was proportional to the concentration of Con A used. The same Con A-untreated cells and normal chicken lymphocytes incubated with Con A exhibited no increase in agglutinability and haemadsorption, however.


Ferrocenylnaphthalene diimide-based electrochemical detection of methylated gene.
Ferrocenylnaphthalene diimide (FND)-based electrochemical hybridization assay was applied to the detection of methylated cytosine of DNA using the products obtained after treatment with bisulfite followed by polymerase chain reaction (PCR), where unmethylated cytosine is converted to thymine and methylated one to cytosine. Twenty-meric DNA probes for the methylated (cytosine) and unmethylated (thymine) types of the part of the promoter region of cyclin D-dependent protein kinase inhibitor, p16, gene (p16(Ink4a)) were used to be immobilized on the electrochemical array (ECA) chip. Using 1 microL of 10 ng/microL of methylated sample obtained from the methylation-specific PCR of methylated genome containing 10-times excess of unmethylated one, the methylated PCR sample could be detected by the identical electrochemical signals from the two DNA probes under the settled optimum hybridization conditions.


RELATIONSHIP BETWEEN PROFESSIONAL MALADAPTATION OF DOCTORS - INTERNS WITH THE MEANINGFULNESS OF LIFE.
The aim: To study relationship peculiarities between the manifestations of professional maladaptation of interns with their value and meaningful sphere of life for developing preventive measures to preserve their health and reduce the outflow of medical personnel from Ukraine. Materials and methods: The study has involved 81 male and female interns. The following methods were used: diagnostic, psychological, analysis, relation¬ships, comparison, systematization and mathematical statistics. Results: Manifestations of professional maladaptation of interns were revealed. The peculiarities of the relationship between the manifestations of professional maladaptation of interns with their meaningful sphere of life are presented. Developed, tested and implemented effective measures for preventing professional burnout and maladaptation are presented. Conclusions: The expediency of providing psychological knowledge in the program of education of interns, as well as the introduction of mandatory psycholog¬ical support in the institutions of higher medical education are proved. These measures will contribute to future doctor's deeper psychological self-knowledge, self-development, self-regulation of their own behavior and emotions, keeping a healthy lifestyle and effective work to strengthen the state.


The release of endogenous dopamine from rat striatum during incubation in vitro.
In this study the conditions for quantitative estimation of the spontaneous and KCl-stimulated release of endogenous dopamine from rat striatum during in vitro incubation have been investigated. KCl concentrations of 15-35 mM produced increasing stimulation of dopamine release during 20 min of incubation in vitro, while KCl concentrations of 45 and 60 mM produced no further significant increase in release. In the presence of 4.7 or 20 mM KCl, dopamine release was linear throughout a 20 min period of incubation; in the presence of 25 or 60 mM KCl, however, dopamine release was not linear, reaching a maximum within 8 min of incubation. Three structurally unrelated inhibitors of monoamine uptake were shown to enhance the net spontaneous release of endogenous dopamine at low concentrations, but to inhibit release at high concentrations. The ethanol-induced enhancement of striatal dopamine release was used to demonstrate the importance of an appropriate concentration of an amine uptake inhibitor in the incubation media. It is concluded that the incubation of rat striatal tissues in vitro, coupled with amine analysis by high performance liquid chromatography with electrochemical detection, constitutes an effective technique for the quantitative estimation of endogenous dopamine release, providing appropriate concentrations of a reuptake inhibitor and a monoamine oxidase inhibitor are included in the incubation media. Where rates of KCl-stimulated amine release with time are to be determined, however, a low concentration of KCl must be used, or the tissues must be subjected to incubation for short periods of time.


Immortalized embryonic mouse fibroblasts lacking the RelA subunit of transcription factor NF-kappaB have a malignantly transformed phenotype.
The RelA transcription factor is part of dimeric complexes, most commonly either p50-RelA (NF-kappaB) heterodimers or RelA homodimers, that control a variety of cellular processes. Immortalized embryonic fibroblasts established from rela knockout mice have previously been shown to be more sensitive to apoptosis induced by tumor necrosis factor (TNF) than are control fibroblasts. In this report, we show that one line of rela-/- fibroblasts has additional phenotypes that distinguish them from control mouse fibroblasts. As compared to normal 3T3 cells, RelA-deficient fibroblasts have a spindled morphology, are less adherent to culture dishes, grow to a higher saturation density, and can form colonies in soft agar. These properties are consistent with a weakly transformed phenotype for rela-/- cells. Furthermore, RelA-deficient fibroblasts can form tumors in immunodeficient mice, but these tumors regress, probably because of the sensitivity of these cells to TNF. The ability of rela-/- fibroblasts to form colonies in soft agar can be reverted by re-expression of wild-type mouse RelA, but not by expression of RelA mutants that cannot form homodimers. There is no clear correlation between the absence of RelA and the levels of expression of other Rel/NF-kappaB family members or adhesion proteins (ICAM-1 and VCAM-1) whose genes have upstream kappaB sites. Taken together, these results suggest that RelA has tumor suppressing activity under some circumstances and that RelA complexes are involved in the control of a variety of cellular properties associated with oncogenesis.


Breath acidification in adolescent runners exposed to atmospheric pollution: a prospective, repeated measures observational study.
Vigorous outdoors exercise during an episode of air pollution might cause airway inflammation. The purpose of this study was to examine the effects of vigorous outdoor exercise during peak smog season on breath pH, a biomarker of airway inflammation, in adolescent athletes. We measured breath pH both pre- and post-exercise on ten days during peak smog season in 16 high school athletes engaged in daily long-distance running in a downwind suburb of Atlanta. The association of post-exercise breath pH with ambient ozone and particulate matter concentrations was tested with linear regression. We collected 144 pre-exercise and 146 post-exercise breath samples from 16 runners (mean age 14.9 years, 56% male). Median pre-exercise breath pH was 7.58 (interquartile range: 6.90 to 7.86) and did not change significantly after exercise. We observed no significant association between ambient ozone or particulate matter and post-exercise breath pH. However both pre- and post-exercise breath pH were strikingly low in these athletes when compared to a control sample of 14 relatively sedentary healthy adults and to published values of breath pH in healthy subjects. Although we did not observe an acute effect of air pollution exposure during exercise on breath pH, breath pH was surprisingly low in this sample of otherwise healthy long-distance runners. We speculate that repetitive vigorous exercise may induce airway acidification.


Food arousal in the pond snail, Lymnaea stagnalis.
Factors affecting food arousal were examined in a behavioral study of the freshwater, browsing pulmonate, Lymnaea stagnalis. Presentation of a food stimulus (sucrose) leads to a progressive decrease in interbite interval over the first four subsequent bites. This is thought to represent an increase in food-induced arousal. The latency to first bite is correlated with total number of bites in the first 5 min following application of food. Latency to bite is significantly reduced for up to 15 min following a brief food stimulus. Previous levels of food consumption do not significantly affect latency to bite (i.e., food responsiveness). However, hunger does lead to an increase in spontaneous biting activity in the absence of food (i.e., food search activity). Latency to bite is negatively correlated with a more general measure of behavioral arousal, the Behavioral State Score. These results are discussed in relation to previous work on other gastropod species. It is concluded that mechanisms of food arousal are adapted to the animal's habitat and life-style.


[A comparative study of diurnal patterns of activity and diurnal changes of body weight in caged and free-living warblers (sylvia)].
1. In Sylvia atricapilla und S. borin the pattern of locomotor activity in caged birds and the temporal distribution of capture of free-living birds are concurrent, as are also the body-weight curves of the two groups. 2. This agreement leads to the conclusion that the diurnal distribution of captures accurately reflects the diurnal pattern of activity of the typical individual bird, and that the averaged curve of body weight represents the diel cycle of body weight of a typical individual. 3. Our results show that it is possible to extrapolate accurately from the diurnal pattern of activity and from the diurnal cycle of body weight of caged birds to the patterns and cycles of free-living birds and vice versa.


Spiral breast computed tomography with a photon-counting detector (SBCT): The future of breast imaging?
Dedicated breast computed tomography (BCT) is an emerging breast imaging modality. The latest development has been the introduction of a spiral breast computed tomography scanner equipped with a photon-counting detector (SBCT). SBCT promises multiple advantages: Unlike conventional mammography, contrast enhanced spectral mammography (CESM: both 2D), and digital breast tomosynthesis (DBT: pseudo 3D), SBCT enables 3D breast imaging without tissue overlap. SBCT achieves high isotropic spatial resolution of breast tissue enabling the assessment of both soft tissue and microcalcifications. Similar to CESM and MRI, SBCT supports contrast-enhanced imaging, enabling the assessment of breast neovascularization. Unlike mammography and its derived methods (CESM, DBT), SBCT does not require compression of the breast. Accordingly, women consistently report significantly increased patient comfort compared to mammography in a previous investigation. Radiation safety is crucial in breast imaging. Studies showed different results in terms of dose, with some staying within the limits of two-view FFDM defined by the ACR and others exceeding the limit by up to 21%. Therefore, a higher radiation dose compared to state-of-the-art mammography and DBT systems has to be acknowledged. SBCT is currently under scientific investigation in multiple trials. Three major indications are currently explored: Whereas our colleagues in Zurich/Switzerland investigate the role of SBCT for opportunistic screening, in our department SBCT is mainly indicated for the work-up of equivocal lesions, and for preoperative staging. In this narrative review, we summarize the concepts of SBCT and potential implications for patient care. We report on our initial clinical experience with the technology and outline future developments of SBCT.


The Influence of Education and Specialty Certification on Nurses' Intent to Support Breastfeeding Post-Birth.
Breastfeeding is something that many new mothers aspire to do, but also something that many struggle with in the days following birth. Nursing support in the hospital can make a huge difference in the success of this endeavor for many patients. It is important for nurse educators that work with the obstetric population, and the nurses that care for them, to understand what drives nurses to be supportive of patients who have recently given birth in their breastfeeding efforts. This will allow for appropriate interventions to be implemented to increase the level of support. This study seeks to determine if a relationship exists between nurses' level of education and specialty certification, and their intent to provide support to new mothers in their efforts to breastfeed their babies.


The role of pH in the regulation of carbon fixation in the chloroplast stroma. Studies on CO2 fixation in the light and dark.
1. The pH in the stroma and in the thylakoid space has been measured in a number of chloroplast preparations in the dark and in the light at 20 degrees C. Illumination causes a decrease of the pH in the thylakoid space by 1.5 and an increase of the pH in the stroma by almost 1 pH unit. 2. CO2 fixation is shown to be strongly dependent on the pH in the stroma. The pH optimum was 8.1, with almost zero activity below pH 7.3.Phosphoglycerate reduction, which is a partial reaction of CO2 fixation, shows very little pH dependency. 3. Low concentrations of the uncoupler m-chlorocarbonylcyanide phenylhydrazone (CCCP) inhibit CO2 fixation without affecting phosphoglycerate reduction. This inhibition of CO2 fixation appears to be caused by reversal of light induced alkalisation in the stroma by CCCP. 4. Methylamine has a very different effect compared to CCCP. Increasing concentrations of methylamine inhibit CO2 fixation and phosphoglycerate reduction to the same extent. The light induced alkalisation of the stroma appears not to be significantly inhibited by methylamine, but the protons in the thylakoid space are neutralized. The inhibition of CO2 fixation by higher concentrations of methylamine is explained by an inhibition of photophosphorylation. It appears that methylamine does not abolish proton transport. 5. It is shown that intact chloroplasts are able to fix CO2 in the dark, yielding 3-phosphoglycerate. This requires the addition of dihydroxyacetone phosphate as precursor of ribulosemonophosphate and also to supply ATP, and the addition of oxaloacetate for reoxidation of the NADPH in the stroma. 6. Dark CO2 fixation in the presence of dihydroxyacetone phosphate and oxaloacetate has the same pH dependency as CO2 fixation in the light. This demonstrates that CO2 fixation in the dark is not possible, unless the pH in the medium is artificially raised to pH 8.8.


The second chemiluminescence emission of luminol-periodate-menadione sodium bisulfite system and its analytical application.
In this paper, a new chemiluminescence phenomenon described as the second chemiluminescence emission was observed when menadione sodium bisulfite was injected into a reaction mixture of luminol and potassium periodate, in which luminol was oxidized by excess amount of potassium periodate for about 24h. The mechanism of the second chemiluminescence emission was proposed based a series of experiments. Moreover, our experiment discovered that the second chemiluminescence intensity was a linear function of the concentration of menadione sodium bisulfite in the range of 2 x 10(-9) to 4 x 10(-5) g L(-1). Based on this phenomenon, a new flow-injection method for the determination of menadione sodium bisulfite has been established.


Functional activation for imitation of seen and heard speech.
This study examined fMRI activation when perceivers either passively observed or observed and imitated matched or mismatched audiovisual ("McGurk") speech stimuli. Greater activation was observed in the inferior frontal gyrus (IFG) overall for imitation than for perception of audiovisual speech and for imitation of the McGurk-type mismatched stimuli than matched audiovisual stimuli. This unique activation in the IFG during imitation of incongruent audiovisual speech may reflect activation associated with direct matching of incongruent auditory and visual stimuli or conflict between category responses. This study provides novel data about the underlying neurobiology of imitation and integration of AV speech.


Factors affecting the outcome of the suction blisters using two different harvesting techniques in vitiligo patients.
Suction blister grafting (SBG) technique has been used for long to treat various skin conditions. Different suction methods have been used such as syringes, Chinese cups, and suction device. There are some limitations of its use as time consumption, failure of induction or incomplete blister formation and pain. The aim of this work was to evaluate the outcome of using two different suction techniques, namely the syringes and the Chinese cups in induction of suction blisters. The effect of the device diameter and preheating of the donor area on the suction blister induction time (SBIT) was studied. The effect of saline injection in the blister formation and its completion was also evaluated. The study was a left-right comparative study that included 50 patients with stable nonsegmental vitiligo. They were classified into four groups: Group 1 included 15 patients where different diameters of syringes (1.3, 1.7, and 2 cm) were compared against each other, group 2 included 15 patients where different diameters of cups (2, 3.5, and 5 cm) were compared against each other, group 3 included 20 patients subdivided into two groups; 10 patients each, where the effect of preheating the skin on blister induction was tested with use of cups (3a) and syringes (3b). Lastly, group 4 included randomly chosen 40 incomplete or multilocular blisters where the effect of saline injection on blister completion and coalescence of multilobulation was examined. SBIT was calculated in all patients. The use of the small diameter syringes or cups gave shorter SBIT; however, the difference, which was significant between all sizes of cups, was significant between the 1.3- and 2-cm-diameter syringes only. Preheating of the donor area shorten SBIT significantly. No complications were reported at the donor site except for transient postinflammatory hyperpigmentation in all patients. The small diameter syringes or cups and preheating of the donor area shorten the SBIT, while intra-blister saline injection increased the blister size and turns the multilocular blisters to unilocular ones.


Alternative synthesis and antibacterial evaluation of 1,5-dideoxy-1,5-imino-L-rhamnitol.
A convenient synthesis is described of 5-azido-5-deoxy-2,3-O-isopropylidene-L-rhamnofuranose from L-rhamnose in seven steps and 17% overall yield. A key feature of the synthesis is the selective oxidation of the secondary alcohol in 2,3-O-isopropylidene-L-rhamnofuranose in the presence of the hemiacetal to give the corresponding ketone in good yield using the Parikh-Doering reagent. 5-Azido-5-deoxy-2,3-O-isopropylidene-l-rhamnofuranose is then converted by a literature protocol to 1,5-dideoxy-1,5-imino-L-rhamnitol, which was found to have no significant antimicrobial activity against Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and Escherichia coli.


3D simulation of pelvic system numerical simulation for a better understanding of the contribution of the uterine ligaments.
Genital prolapse remains a complex pathological condition. Physiopathology remains poorly understood, aetiology is multi-factorial, surgery is not always satisfying, as the rate of relapse cannot be overlooked. More over a good anatomical result will not always guarantee functional satisfaction. The aim of our study is to have a better understanding of the involvement of uterine ligaments in pelvic statics via 3D simulation. Simulation of pelvic mobility is performed with a validated numerical model in a normal situation (standing up to lying down) or induced pathological ones where parts of the constitutive elements of the model are virtually "cut" independently. Displacements are then discussed. Numerical results have been compared with dynamic MRI for two volunteers. Dynamic sequences had 90 images, and 180 simulations have been validated. Results are coherent with clinical data and the literature, thus validating our mechanical approach. Uterine ligaments are involved in pelvic statics, but their lesions are not sufficient to generate a genital prolapse. Round ligaments play a part in uterine orientation; the utero-sacral ligaments support the uterus when standing up. Pelvic normal and pathological mobility study via modelling and 3D simulation is a new strategy in understanding the complex multifactorial physiopathology of genital prolapse. This approach must be validated in a larger series of patients. Nevertheless, pelvic ligaments seem to play an important role in statics, especially, in agreement with a literature survey, utero-sacral ligaments in a standing position.


Medical adrenalectomy with aminoglutethimide: clinical studies in postmenopausal patients with metastatic breast carcinoma.
The use of adrenalectomy and hypophysectomy in the management of postmenopausal patients with metastatic breast carcinoma is reserved for highly selected patients. As an alternate approach, a pharmacologic method of inhibiting adrenal cortical secretion was developed which consisted of the daily administration of 1000 mg of aminoglutethimide to block steroidogensis and either dexamethasone (2.0-3.0 mg/day) or hydrocortisone (40-60 mg/day) as replacement glucocorticoid. This regimen markedly suppressed plasma levels of DHA-S, androstenedione, estrone, and estradiol, and urinary levels of aldosterone. Of 50 patients treated, 19 (38%) demonstrated either a complete (8/19) or a partial (11/19) objective disease remission which lasted for 18.05 +/- 3.1 months (mean +/- SEM). In 10 (20%) patients, there was stabilization of disease (7.8 +/- 1.2 months), accompanied by symptomatic relief of bone pain in six (12%). There was disease progression in 20 (40%) patients. The acute side effects of aminoglutethimide therapy were significant and consisted of transient lethargy (41.5%) and a cutaneous rash (35.8%). Chronic toxicity was negligible. The medical adrenalectomy regimen of aminoglutethimide plus glucocorticoid offers a suitable alternative to surgical adrenalectomy or hypophysectomy in the management of postmenopausal patients with metastatic breast carcinoma.


Bronchoplastic Procedure Versus Pneumonectomy After High-dose Radiation for Non-small Cell Lung Cancer.
Studies have revealed that salvage surgery after definitive chemoradiotherapy (CRT) for unresectable advanced non-small cell lung cancer improves survival with acceptable surgical adverse events. Few reports exist regarding pneumonectomy or the bronchoplastic procedure in this setting. Between 2008 and 2018, 27 patients (21 men; median age, 61 years) underwent salvage surgery after definitive CRT for non-small cell lung cancer. We investigated postoperative short- and long-term outcomes of salvage surgery and aimed to elucidate the feasibility of pneumonectomy or the bronchoplastic procedure. The median radiation dose was 60 Gy. The median period from the last day for irradiation to the operative day was 8.5 months. Pneumonectomy was performed in 9 patients, including 2 carinal resections; lobectomy was performed in 18 patients, including 5 bronchoplasties. Bronchial wrapping was performed in 9 cases (33%), R0 resection was achieved in 24 (89%), and postoperative complications were detected in 16 (59%). Although bronchopleural fistulas were found in only 2 patients who underwent pneumonectomy, arrhythmia was observed more frequently in patients who underwent the bronchoplastic procedure (P = .05). Regarding major complications, no relationship with any factors were found. The 90-day mortality was 0%. The 5-year overall and recurrence-free survival were 63% and 27%, respectively. R0 resection was a good prognostic factor for recurrence-free survival (P = .001). Perioperative short- and long-term outcomes of salvage surgery after definitive CRT for non-small cell lung cancer were acceptable. Complete resection offered a better recurrence-free survival. The bronchoplastic procedure or pneumonectomy should be considered as an option even after administration of high-dose CRT.


Comprehensive characterization of a time-course transcriptional response induced by autotoxins in Panax ginseng using RNA-Seq.
As a valuable medicinal plant, the yield of Panax ginseng is seriously affected by autotoxicity, which is a common phenomenon due to continuous cropping. However, the mechanism of autotoxicity in P. ginseng is still unknown. In total, high throughput sequencing of 18 RNA-Seq libraries produced 996,000,000 100-nt reads that were assembled into 72,732 contigs. Compared with control, 3697 and 2828 genes were significantly up- and down-regulated across different tissues and time points, respectively. Gene Ontology enrichment analysis showed that 'enzyme inhibitor activity', 'carboxylesterase activity', 'pectinesterase activity', 'centrosome cycle and duplication' and 'mitotic spindle elongation' were enriched for the up-regulated genes. Transcription factors including AP2s/ERFs, MYBs, and WRKYs were up-regulated in roots after benzoic acid treatment. Moreover, reactive oxygen species, peroxidases and superoxide dismutase contigs were up-regulated in roots after benzoic acid treatment. Physiological and biochemical indexes showed that the proline and malondialdehyde content were restored to lower levels at a later stage after benzoic acid treatment. Benzoic acid inhibited the root hair development in a dose-dependent manner, and several differential expressed genes potentially involved in hair development were identified. Several key contigs in the flavonoid and ginsenoside biosynthesis pathways were repressed. Finally, 58,518 alternative splicing (AS) events from 12,950 genes were found after benzoic acid treatment. Interestingly, contigs in the ginsenoside biosynthetic pathway underwent AS, providing useful information about post-transcriptional regulation in P. ginseng. This study revealed the stress-response molecular mechanisms in P. ginseng induced by benzoic acid.


The dynamics of leaf extension in plants with diverse altitudinal ranges : I. Field observations on temperature responses at one altitude.
Rates of leaf extension have been studied with electronic auxanometers at mid-altitude in the Austrian Alps, where both low and high altitude species co-occur. The results demonstrate a clear differentiation in the temperature responses of extension between these two groups of species. For the low or mid-altitude species of Achillea millefolium, Agrostis stolonifera, Poa alpina and Rumex arifolius, the average rate of leaf extension increases from 0.1 to 0.4 mm h-1 between 10 and 20° C. For the high-alpine species of Achillea erba-rotta ssp moschata, Poa alpina ssp vivipara and Polygonum viviparum the average rate of leaf extension was considerably lower from 0.016 to 0.064 mm h-1, between 10 and 20° C.Leaf extension in the lowland species was not observed below an average temperature of about 5° C, whilst no limit was observed for the upland species, down to a temperature of about 0° C.In the cases of the dicotyledons that were studied, leaf plus petiole shrinkage was observed to occur, for as much as 2 to 4 h, during periods of high water vapour pressure deficits. This response was not observed for the monocotyledons.The observations of leaf extension show that daily totals of extension in species from high altitudies will be much less sensitive to day, to day variations in local climate than will the species from low altitudes. The lowland species will have higher rates of extension during clear and warm weather conditions but lower rates in cold, cloudy weather.


Determinants of physicians' attitude towards prescribing.
To identify the primary care physicians' (PCP) characteristics that are associated with their prescribing attitude. A validated questionnaire was sent to randomly selected PCPs stratified in three groups according to any higher qualification in family medicine. The best predictor for orientation of quality of care in prescribing was the country of qualification. Duration after qualification was negatively associated with PCP's belief in the use of drugs. Physicians who were female, with higher qualification, sooner after qualification, and working in group practice were less likely to perceive pressure from patients to prescribe, with group practice being the most significant determinant. Different physician factors affect different aspects of PCPs' prescribing attitude. As duration after qualification was an important but negative attribute, quality use of medication should be emphasized in continuing medical education.


In vitro preparation and assessment of radical reducing peptide from Octopus aegina using digestive proteases.
Antioxidant peptides protect biological macromolecules against radical damages. The use of these peptides was evaluated using free radicals scavenging assays [2,2-diphenyl-1 picrylhydrazyl (DPPH) and hydroxyl] with the help of UV-visible and electron spin resonance (ESR) spectroscopy methods. The Octopus aegina mantle protein were tested upon hydrolysis using gastrointestinal enzymes up to 12 h, where pepsin hydrolysate exhibited superior properties (DPPH: 44.39±0.67% and hydroxyl: 38.84±1.07%) compared with trypsin and α-chymotrypsin. Consequently, the antioxidant activity of the purified hydrolysate increased on a successive purification, and the peptide sequence was determined to be 368.9 Da with Gly-Glu-Tyr amino acids. Tripeptide exerted free radical scavenging efficiency in DNA damage, lipid peroxidation and cellular destruction (MCF7 cells) under stress condition. The results obtained with octopus antioxidant peptide suggested its role as an adjunct in food and pharmaceutical industries.


Epigenetically regulated Fibronectin leucine rich transmembrane protein 2 (FLRT2) shows tumor suppressor activity in breast cancer cells.
To identify dysregulated genes by abnormal methylation and expression in breast cancer, we genome-wide analyzed methylation and expression microarray data from the Gene Expression Omnibus and the Cancer Genome Atlas database. One of the genes screened in silico, FLRT2, showed hypermethylation and downregulation in the cancer dataset and the association was verified both in cultured cell lines and cancer patients' tissue. To investigate the role of FLRT2 in breast cancer, its expression was knocked down and upregulated in mammary cell lines, and the effect was examined through three levels of approach: pathway analysis; cell activities such as proliferation, colony formation, migration, and adhesion; target gene expression. The top pathway was "Cellular growth and proliferation", or "Cancer"-related function, with the majority of the genes deregulated in a direction pointing to FLRT2 as a potential tumor suppressor. Concordantly, downregulation of FLRT2 increased cell proliferation and cell migration, while overexpression of FLRT2 had the opposite effect. Notably, cell adhesion was significantly decreased by FLRT2 in the collagen I-coated plate. Taken together, our results provide insights into the role of FLRT2 as a novel tumor suppressor in the breast, which is inactivated by hypermethylation during tumor development.


A 76-year-old man with a right lung adenocarcinoma and invasive Aspergillosis.
A 76-year-old male with adenocarcinoma on the right lung underwent five cycles of chemotherapy with pemetrexed disodium, cisplatin, and dexamethasone. Imaging studies of control showed a node in a cavitary lesion on the left lung, and the main hypothesis was Aspergillus infection. PCR was utilized and contributed to establish the early diagnosis in this patient with invasive aspergillosis. Furthermore, the species Aspergillus fumigatus was characterized by its growing at 50 °C but not at 10 °C, typical culture features, and presence of subclavate vesicles. Diagnosis criteria for Aspergillus pulmonary infection include characteristic clinical and imaging findings, elevated C-reactive protein and erythrocyte sedimentation rate, positive specific serological test, and isolation of Aspergillus from bronchoalveolar cultures. Molecular methods, as PCR, have been useful to complement the conventional microbiological investigations in immunocompromised people with invasive fungal infections. The patient was successfully treated with a schedule of voriconazole 4 mg/kg intravenous infusion every 12 h for 21 days and then switched to oral administration of 200 mg twice a day. He has been comfortable, maintaining normal vital signs, and the results of the periodical microbiologic tests of control are negative. Pathogenesis of invasive aspergillosis in patients with lung cancer is not completely understood. Case studies may contribute to a better knowledge about Aspergillus infection in this setting.


Case of adrenal lymphangioma with atypical lymphocytes in aspirate cytology.
Cytological diagnosis of adrenal cysts is becoming more important, with the increase in cases identified due to the widespread use of imaging modalities. Adrenal cysts have been classified into four main groups: endothelial, epithelial, parasitic, and pseudocyst, with endothelial cysts further classified as lymphangiomatous or angiomatous. We report on a case of adrenal lymphangioma with atypical lymphocytes found in the intraoperative aspirate, suggesting an inconclusive diagnosis, although immunohistochemical study led us to suppose their B-cell origin. This case provided important cytological findings that may assist in the prevention of cytological overdiagnosis.


Evaluation of a straightforward and rapid method for the therapeutic drug monitoring of digitoxin by LC-MS/MS.
Therapeutic drug monitoring of digitoxin is strongly recommended but metabolites of digitoxin and digitoxin-like immunoreactive substances may interfere with widely used immunoassays. Recently evaluated assays on LC-MS/MS have the drawback of long turnaround time. We sought to evaluate a specific method on LC-MS/MS optimizing sample preparation thereby significantly reducing turnaround time. Linearity, functional sensitivity, and precision of the method were established. External quality control samples were used for the evaluation of accuracy of the LS-MS/MS method. In addition, digitoxin concentrations in 221 samples were measured by LC-MS/MS and immunoassay. Linearity was validated between 0.15 and 80 ng/mL. Limit of quantification was established at 0.14 ng/mL. Between-day imprecision lay between 1.4 and 4.9% and meets the conditions required for routine analysis. Comparison to results obtained by immunoassay revealed a mean difference of -1.2 ng/mL. By optimizing preparation steps turnaround time was shorter for LC-MS/MS than for immunoassay. This did not result in increased susceptibility to matrix effects. Analytical performance was sufficient for routine analysis. Therefore, the method is suitable for routine therapeutic drug monitoring of digitoxin.


Selective Sampling of Species and Fossils Influences Age Estimates Under the Fossilized Birth-Death Model.
The fossilized birth-death (FBD) model allows the estimation of species divergence times from molecular and fossil information in a coherent framework of diversification and fossil sampling. Some assumptions of the FBD model, however, are difficult to meet in phylogenetic analyses of highly diverse groups. Here, I use simulations to assess the impact of extreme model violations, including diversified sampling of species and the exclusive use of the oldest fossils per clade, on divergence times estimated with the FBD model. My results demonstrate that selective sampling of fossils can produce dramatically overestimated divergence times when the FBD model is used for inference, due to an interplay of underestimates for the model parameters net diversification rate, turnover, and fossil-sampling proportion. In contrast, divergence times estimated with CladeAge, a method that uses information about the oldest fossils per clade together with estimates of sampling and diversification rates, are accurate under these conditions. Practitioners of Bayesian divergence-time estimation should therefore ensure that the dataset conforms to the expectations of the FBD model, or estimates of sampling and diversification rates should be obtained a priori so that CladeAge can be used for the inference.


Plasmonic evolution of atomically size-selected Au clusters by electron energy loss spectrum.
The plasmonic response of gold clusters with atom number (N) = 100-70 000 was investigated using scanning transmission electron microscopy-electron energy loss spectroscopy. For decreasing N, the bulk plasmon remains unchanged above N = 887 but then disappears, while the surface plasmon firstly redshifts from 2.4 to 2.3 eV above N = 887 before blueshifting towards 2.6 eV down to N = 300, and finally splitting into three fine features. The surface plasmon's excitation ratio is found to follow N 0.669, which is essentially R 2. An atomically precise evolution picture of plasmon physics is thus demonstrated according to three regimes: classical plasmon (N = 887-70 000), quantum confinement corrected plasmon (N = 300-887) and molecule related plasmon (N < 300).


Hormone Concentrations in Transgender Women Who Self-Prescribe Gender Affirming Hormone Therapy: A Retrospective Study.
Self-prescribed gender-affirming hormone therapy (GAHT) is common practice among transgender women, especially in resource-limited countries, yet the effectiveness of each GAHT regimen to achieve female range sex hormone concentrations is not known. To describe the use and sex hormone concentrations of various GAHT regimens among transgender women who self prescribe in Thailand. This was a retrospective study in a community-based setting. Five hundred and 27 records of transgender women taking GAHT who were receiving care at a community health center between January 1, 2018, and December 31, 2020 were included for the analysis. Blood total testosterone and estradiol concentration after at least a 6-month period of GAHT. Multiple GAHT regimens were identified including oral estradiol valerate (EV), transdermal 17β-estradiol gel, injectable EV with hydroxyprogesterone caproate, injectable estradiol benzoate with progesterone, oral EV with cyproterone acetate (CPA), and oral contraceptive pills (OCPs). The most common GAHT regimen used by 49.1% of the participants was OCPs that contained 0.035 mg of ethinyl estradiol and 2 mg of CPA. Only 25.2% of this group had female range testosterone concentrations (<50 ng/dL). Oral EV and CPA were used by 23.1% of the participants. Most of them used 12.5 mg of CPA and 47.7% of this group had female range testosterone concentrations. There was no statistical significance between mean testosterone concentrations in CPA 12.5 and 25 mg groups, (P = .086). The inadequate sex hormone levels found in these commonly self-prescribed GAHT regimens provide information regarding the efficacy and safety of GAHT regimens for health care providers working with transgender women in a community-based setting. This study reflected a real-world situation and provided hormonal profiles among transgender women taking self-prescribed GAHT. However, issues in recall, medical literacy, and adherence to the medication may limit the results. Combined hormonal contraceptive pill was a commonly used GAHT regimen in Thai transgender women who self prescribe GAHT. However, this regimen was not effective to decrease testosterone concentrations to the recommended range of less than 50 ng/dL. Overall, self-prescription of GAHT does not appear to be effective in reaching target sex hormone concentrations. Including health care providers in the prescription and monitoring of GAHT may be a more effective approach in the delivery of GAHT. Salakphet T, Mattawanon N, Manojai N, et al. Hormone Concentrations in Transgender Women Who Self-Prescribe Gender Affirming Hormone Therapy: A Retrospective Study. J Sex Med 2022;19:864-871.


Backbone spiking sequence as a basis for preplay, replay, and default states in human cortex.
Sequences of spiking activity have been heavily implicated as potential substrates of memory formation and retrieval across many species. A parallel line of recent evidence also asserts that sequential activity may arise from and be constrained by pre-existing network structure. Here we reconcile these two lines of research in the human brain by measuring single unit spiking sequences in the temporal lobe cortex as participants perform an episodic memory task. We find the presence of an average backbone spiking sequence identified during pre-task rest that is stable over time and different cognitive states. We further demonstrate that these backbone sequences are composed of both rigid and flexible sequence elements, and that flexible elements within these sequences serve to promote memory specificity when forming and retrieving new memories. These results support the hypothesis that pre-existing network dynamics serve as a scaffold for ongoing neural activity in the human cortex.


Tanshinone production in roots of micropropagated Salvia przewalskii Maxim.
Production of tanshinones (tanshinone I and IIA) was determined in roots of Salvia przewalskii micropropagated plants. It was found that the total tanshinone content (tashinone I and tashinone IIA) was dependent on the age of the analyzed plants. The roots of 2-year-old in vitro regenerated plants at flowering stage produced highest tanshinone levels (3.8 mg/g dry weight of tanshinone I and 7.6 mg/g dry weight of tanshinone IIA).


Non-equivalent natures of the coordinated imidazole rings of cytochrome c3 from D. vulgaris Miyazaki F as studied by 1H NMR.
All of the C2 proton signals of the coordinated histidine residues in the 1H NMR spectrum of cytochrome c3 from D. vulgaris Miyazaki F were assigned by specific deuteration. They appeared at extremely high fields and scattered in a wide range from -4 to -22 ppm. This clearly shows that the chemical properties of the imidazole groups are quite different from one another. The extremely high-field shift of the C2 signal indicates that some of them must carry the imidazolate-like nature to some extent. This might be responsible for the extremely low redox potentials of the four hemes. On changing temperature, most of them showed Curie-type change. All of the C2 signals showed a small p2H dependence in the range of p2H 4.8-10.0.


COVID-19 concomitant with infective endocarditis: A case report and review of management.
Coronavirus disease 2019 (COVID-19) has emerged as a pandemic and public health crisis across the world. With its high infectivity and rapid spread, the severity of the disease is escalating in certain populations, especially in patients with pre-existing cardiovascular disease. In developing countries, infective endocarditis remains a problem in patients with rheumatic heart disease. We report the case of a patient with a diagnosis of infective endocarditis concomitant with COVID-19, including the diagnosis, management, and main outcomes.


A novel method for the intracellular delivery of siRNA using microbubble-enhanced focused ultrasound.
Short interfering RNA (siRNA) has attracted much attention for clinical use in various diseases. However, its delivery, especially through the cell membrane, continues to present a challenge. Advances in ultrasound- and ultrasound contrast-agent technologies have made it possible to change transiently the permeability of the cell membrane and, using a focused ultrasound transducer, to narrow and focus the ultrasound energy on a small target, thereby avoiding damage to surrounding tissue. In this in vitro study, we demonstrate that it is possible to deliver siRNA intracellularly via microbubble-enhanced focused ultrasound. Although further optimization is necessary, our novel method for siRNA transduction represents a powerful tool for using siRNA in vivo and possibly in the clinical setting.


A protocol for phenotypic detection and characterization of vascular cells of different origins in a lung neovascularization model in rodents.
The goal of many current studies of neovascularization is to define the phenotype of vascular cell populations of different origins and to determine how such cells promote assembly of vascular channel. Here, we describe a protocol to immunophenotype vascular cells by high-resolution imaging and by fluorescence-activated flow cytometry in an in vivo rodent model of pulmonary microvascular remodeling. Analysis of cells by this combined approach will characterize their phenotype, quantify their number and identify their role in the assembly of vascular channels.


Immunological adjuvant effect of the peptide fraction from the larvae of Musca domestica.
The larvae of Musca domestica (Diptera: Muscidae) have been used traditionally for malnutritional stagnation, decubital necrosis, osteomyelitis, ecthyma and lip scald and also to treat coma and gastric cancer in the traditional Chinese medicine. Its immunomodulatory effects in naïve mice in relation to the traditional uses were also reported. However, the immunological adjuvant potentials of this insect have not yet been studied. The peptide fraction from the larvae of Musca domestica L. (MDPF) was evaluated for its adjuvant potentials on the immune responses to ovalbumin (OVA) and avian influenza vaccine (rL-H5) by determining antigen-specific antibody titers, splenocyte proliferation, activity of natural killer (NK) cell, the secretion of cytokines from splenocytes in the immunized mice. MDPF significantly enhanced not only the concanavalin A (Con A)-, lipopolysaccharide (LPS)- and antigen-stimulated splenocyte proliferation, but serum antigen-specific IgG, IgG1, IgG2a, and IgG2b antibody titers in the mice immunized with OVA and rL-H5. MDPF also remarkably promoted the killing activities of NK cells in splenocytes from the mice immunized with rL-H5. Furthermore, MDPF significantly promoted the production of Th1 (IL-2 and IFN-γ) and Th2 (IL-10) cytokines from splenocytes in the immunized mice. The results indicated that MDPF had a potential to increase both cellular and humoral immune responses and elicit a balanced Th1/Th2 response, and that MDPF may be a safe and efficacious vaccine adjuvant candidate.


Wound exudate reduction from retroperitoneum with facilitation of healing by triamcinolone injection: A case report.
Maintaining a moderately moist environment is important in the treatment of chronic skin ulcers. Excessive exudate inhibits wound healing, although it may be difficult to control. We report a case of successful treatment with triamcinolone to suppress retroperitoneal exudates and facilitate wound healing. A 78-year-old man presented to our department with excessive exudative oozing from a chronic ulcer in the gluteal region. The retroperitoneum was exposed for a prolonged period after colon cancer surgery and developed chronic granulation. The exposed retroperitoneum was covered using an island flap, with the left superior gluteal artery perforator providing the feeding vessels and skin graft, which covered part of the flap harvesting area. The flap and lower bed did not adhere because of the presence of an excessive retroperitoneal exudate. Skin grafts to the flap harvesting area were not accepted, and secondary healing did not proceed because of exudate leakage. A single dose of 2.5-mg triamcinolone was injected inferiorly to the flap. After injection of triamcinolone, the exudate decreased, and secondary healing in the residual ulcer progressed satisfactorily. Injection of triamcinolone might be an option for controlling exudates to heal skin ulcers.


Changes in the frequency of family meals from 1999 to 2010 in the homes of adolescents: trends by sociodemographic characteristics.
To examine secular trends from 1999 to 2010 in family meal frequency in a population-based sample of adolescents across sociodemographic characteristics. A repeated cross-sectional design was used. Participants were from middle schools and high schools in the Minneapolis/St. Paul area and included 3,072 adolescents (mean age = 14.6 ± 1.8 years) in 1999 and 2,793 adolescents (mean age = 14.4 ± 2.0 years) in 2010 from diverse ethnic/racial and socioeconomic backgrounds. Trends in family meal frequency were examined using inverse probability weighting to control for changes in sociodemographic characteristics over time. Family meal frequency remained fairly constant from 1999 to 2010 in the overall sample, but decreases were found in population subgroups including girls, middle school students (grade: 6-8), Asians, and youth from low socioeconomic backgrounds. Among youth from the lowest socioeconomic backgrounds, the mean number of family meals in the past week decreased from 4.0 in 1999 to 3.6 in 2010 (p = .003). Furthermore, the percentage of youth from low socioeconomic backgrounds eating five or more meals in the past week decreased from 46.9% in 1999 to 38.8% in 2010 (p < .001). In contrast, family meal frequency tended to increase over time among youth from higher socioeconomic backgrounds. The widening gap in family meal frequency between youth from low and high socioeconomic backgrounds is concerning, particularly given the greater risk for poor health outcomes among low-income youth. Given findings from other studies suggesting multiple benefits of family meals, interventions to increase family meal frequency are needed that target adolescents and their families from the most vulnerable segments of the population.


Experimental study on trans-nodal cancer chemotherapy for metastatic lymph nodes.
As complete dissection of metastatic lymph nodes in the upper mediastinum is impossible in conventional surgery for esophageal carcinoma, we devised a form of intraoperative local adjuvant cancer chemotherapy for metastatic lymph nodes of the mediastinum, via tracheal bifurcation lymph nodes located at the anatomical pivot in the upper mediastinal lymph flow. Emulsion type bleomycin (BLM) was injected into the bifurcation lymph nodes of mongrel dogs, and BLM was identified in the pulmotracheal lymph nodes within 20 minutes. When the cervicothoracic lymph nodes in the ipsilateral side were dissected beforehand, the BLM levels in the contralateral side doubled those seen in the controls. In rabbits with VX2 carcinoma, the level of BLM decreased in lymph nodes with metastasis, however, the spread was still evident even when about 75 per cent of the nodes were occupied with metastasis.


The TaxUMAP atlas: Efficient display of large clinical microbiome data reveals ecological competition in protection against bacteremia.
Longitudinal microbiome data provide valuable insight into disease states and clinical responses, but they are challenging to mine and view collectively. To address these limitations, we present TaxUMAP, a taxonomically informed visualization for displaying microbiome states in large clinical microbiome datasets. We used TaxUMAP to chart a microbiome atlas of 1,870 patients with cancer during therapy-induced perturbations. Bacterial density and diversity were positively associated, but the trend was reversed in liquid stool. Low-diversity states (dominations) remained stable after antibiotic treatment, and diverse communities had a broader range of antimicrobial resistance genes than dominations. When examining microbiome states associated with risk for bacteremia, TaxUMAP revealed that certain Klebsiella species were associated with lower risk for bacteremia localize in a region of the atlas that is depleted in high-risk enterobacteria. This indicated a competitive interaction that was validated experimentally. Thus, TaxUMAP can chart comprehensive longitudinal microbiome datasets, enabling insights into microbiome effects on human health.


Amyloid and amyloidosis.
Cutaneous lesions are present in up to 40% of patients with primary and myeloma-associated systemic amyloidosis and occur as a result of tissue deposition of immunoglobulin light chain material derived from a circulating paraprotein. The occurrence of waxy, purpuric mucocutaneous lesions provides a crucial early pointer to underlying occult plasma cell dyscrasia; the combination of the symptoms of the carpal tunnel syndrome, macroglossia, and specific mucocutaneous lesions is highly characteristic. Although secondary systemic (reactive) amyloidosis rarely gives rise to clinically evident cutaneous lesions, it may be etiologically related to a number of chronic dermatoses. Lesions of nodular primary localized cutaneous amyloidosis are indistinguishable from those of primary and myeloma-associated systemic amyloidosis, and they result from local plasma cell infiltration. Macular and papular (lichen amyloidosus) variants of primary localized cutaneous amyloidosis may have a familial or racial basis and are characterized by a tendency for keratinocytes to undergo filamentous degeneration and apoptosis. The prognosis of patients with plasma cell dyscrasia-related systemic amyloidosis remains poor, since there is little response to therapy with cytotoxic agents, colchicine, or dimethylsulfoxide. Colchicine is the drug of choice in the prevention and treatment of the renal amyloidosis associated with familial Mediterranean fever, and dimethylsulfoxide may be useful in the management of patients with secondary systemic amyloidosis. Macular amyloid and lichen amyloidosus generally follow a chronic course with intractable pruritus; there have been isolated reports of the beneficial effect of dermabrasion, topical dimethylsulfoxide, and therapy with the aromatic retinoid, etretinate.


Arthroscopic synovectomy in sarcoid synovitis.
Chronic synovitis is an unusual manifestation of sarcoidosis but may be significantly disabling. Arthroscopic synovectomy can provide an excellent result, relieving discomfort and arresting the disease process, and should be considered in any patient whose synovitis has not responded to medical management.


A multidisciplinary approach to solving computer related vision problems.
This paper proposes a multidisciplinary approach to solving computer related vision issues by including optometry as a part of the problem-solving team. Computer workstation design is increasing in complexity. There are at least ten different professions who contribute to workstation design or who provide advice to improve worker comfort, safety and efficiency. Optometrists have a role identifying and solving computer-related vision issues and in prescribing appropriate optical devices. However, it is possible that advice given by optometrists to improve visual comfort may conflict with other requirements and demands within the workplace. A multidisciplinary approach has been advocated for solving computer related vision issues. There are opportunities for optometrists to collaborate with ergonomists, who coordinate information from physical, cognitive and organisational disciplines to enact holistic solutions to problems. This paper proposes a model of collaboration and examples of successful partnerships at a number of professional levels including individual relationships between optometrists and ergonomists when they have mutual clients/patients, in undergraduate and postgraduate education and in research. There is also scope for dialogue between optometry and ergonomics professional associations. A multidisciplinary approach offers the opportunity to solve vision related computer issues in a cohesive, rather than fragmented way. Further exploration is required to understand the barriers to these professional relationships.


Chromosomal in situ hybridization and Southern blot analyses using c-abl, c-sis, or bcr probe in chronic myelogenous leukemia cells with variant Philadelphia translocations.
The Philadelphia (Ph) chromosome is a cytogenetic hallmark of chronic myelogenous leukemia (CML). Whereas the majority of Ph-positive CML patients show the standard Ph translocation involving chromosomes 9 and 22, t(9;22)(q34;q11), the minority of cases exhibit a variant type of Ph translocation involving these two and other chromosomes (complex type) or those involving #22 and chromosomes other than #9 (simple type). To get an insight into the nature of variant Ph translocations and the process of their formation, we examined the localization of the c-abl and c-sis oncogenes and the breakpoint cluster region (bcr) gene by chromosomal in situ hybridization in ten variant Ph translocations of CML including five simple and five complex ones as initially interpreted. In situ hybridization showed that c-abl localized to band 9q34 and c-sis localized to band 22q12-q13 were translocated on the Ph and on one of the rearranged chromosomes other than #9, respectively, in all the variant translocations examined. On the other hand, bcr localized to band 22q11 was translocated on various chromosomes but mostly on chromosome 9. Parallel Southern blot analyses on DNA from leukemic cells of five patients including two with simple translocations and three with complex ones revealed rearrangements of bcr with breakpoints occurring mostly in a 5' portion of 5.8-kb BamHI/BglII sequences, which are quite similar to those detected so far in CML cases with the standard Ph translocation. The present findings strongly suggest that variant Ph translocations of CML are all complex, and some of them are formed stepwisely from the standard translocation.


Spindle activity and monosynaptic reflex excitability during foreperiod.
Healthy volunteers were instructed to perform an isometric plantar foot flexion as quickly as possible after a foreperiod (FP) of 1000 msec defined by two clicks (warning signal (WS) and response signal (RS). In 6 volunteers the H reflex was evoked in triceps surae muscle and recorded by surface electrodes (stimulus intensity 30% of maximum). The H reflex was elicited at WS and RS as well as during FP at intervals of 100 msec. H reflex amplitudes were taken as a sign of monosynaptic reflex excitability (MSRE). Amplitudes during FP were compared with the average control values at rest. Relaxation of lower limb muscles before and during FP was controlled by EMG. MSRE was increased in the first part of FP with a maximum at 300 msec after WS and decreased in the second part, with a minimum at 800 msec after WS. In a second series of experiments, in 10 volunteers, single fiber activity from primary muscle spindle afferents was recorded with tungsten electrodes from deep peroneal nerve (6 records) and from tibial nerve (3 records). The activity of primary spindle afferents before and during the FP was calculated by instantaneous discharge frequency and histograms of spike distribution. The EMG was taken from sural triceps and anterior tibial muscles with needle electrodes; a mechanogram of tendon deflection was taken by an appropriate strain gauge. In 5 primary afferents without spontaneous activity at rest and during FP, discharge started with a delay of 10-15 msec after the onset of EMG activity during the motor reaction.(ABSTRACT TRUNCATED AT 250 WORDS)


Design, synthesis and 3D-QSAR analysis of novel thiopyranopyrimidine derivatives as potential antitumor agents inhibiting A549 and Hela cancer cells.
Four series of thiopyranopyrimidine AZD9291 derivatives containing acrylamide structure were designed, synthesized and evaluated for their antiproliferative activity against A549 and Hela cancer cells. Most of the compounds exhibited excellent antiproliferative activity against A549 cells. Moreover, the compounds with indole ring fluorine substituted exhibited better antiproliferative activity against Hela cells. The most promising compound 23g exhibited excellent enzymatic inhibitory activity and selectivity for EGFRL858R/T790M double mutations. The IC50 value against EGFRL858R/T790M kinase was 16 nM. The compound 23g inhibits selectively against the mutated form of EGFR, with the selectivity more than 125-fold. Furthermore, compound 23g also inhibited A549 cells, Hela cells and H1975 cells proliferation at a low concentration, and the IC50 values were 0.057 μM, 0.104 μM and 0.916 μM, respectively. To further investigate the QSARs of thiopyranopyrimidine derivatives, the CoMFA (q [2] = 0.765, r2 = 0.965) and CoMSIA (q [2] = 0.875, r2 = 0.956) models on Hela cancer cells were established. The generated 3D-QSAR model was validated to be reliable and can be used for further design and optimization of novel and selective EGFR inhibitors.


Evolving standards of care and new challenges in the management of HER2-positive breast cancer.
The management of human epidermal growth factor receptor (HER2)-positive breast cancer (BC) has rapidly evolved over the last 20 years. Major advances have led to US Food and Drug Administration approval of 7 HER2-targeted therapies for the treatment of early-stage and/or advanced-stage disease. Although oncologic outcomes continue to improve, most patients with advanced HER2-positive BC ultimately die of their disease because of primary or acquired resistance to therapy, and patients with HER2-positive early BC who have residual invasive disease after preoperative systemic therapy are at a higher risk of distant recurrence and death. The concept of treatment de-escalation and escalation is increasingly important to optimally tailor therapy for patients with HER2-positive BC and is a major focus of the current review. Research efforts in this regard are discussed as well as updates regarding the evolving standard of care in the (neo)adjuvant and metastatic settings, including the use of novel combination therapies. The authors also briefly discuss ongoing challenges in the management of HER2-positive BC (eg, intrinsic vs acquired drug resistance, the identification of predictive biomarkers, the integration of imaging techniques to guide clinical practice), and the treatment of HER2-positive brain metastases. Research aimed at superseding these challenges will be imperative to ensure continued progress in the management of HER2-positive BC going forward.


Guanosine 3':5'-monophosphate-dependent protein kinase from bovine cerebellum. Purification and characterization.
Guanosine 3':5'-monophosphate (cyclic GMP)-dependent protein kinase was assayed with calf thymus histone as substrate and partially purified from the soluble fraction of bovine cerebellum. The enzyme was selectively activated by cyclic GMP at lower concentrations; the Ka value for cyclic GMP was 1.7 times 10- minus 8 M whereas that for adenosine 3':5'-monophosphate (cyclic AMP) was 1.0 times 10- minus 6 M. The Km value for ATP was 1.0 times 10- minus 5 M. A high concentration of Mg-2+ (100 mM) was needed for maximum stimulation by cyclic GMP and maximum reaction rate. The pH optimum was 7.5 to 8.0. The isoelectric point was pH 5.7. The molecular weight was about 140,000 as estimated by gel filtration. The enzyme was unable to activate muscle glycogen phosphorylase kinase, and was clearly distinguishable from cyclic AMP-dependent protein kinase in kinetic and catalytic properties. Comparative data on cyclic GMP-dependent and cyclic AMP-dependent protein kinases in this tissue are presented.


Correction to: Gender Discrimination and Excess Female Under-5 Mortality in India: A New Perspective Using Mixed-Sex Twins.
The article Gender Discrimination and Excess Female Under-5 Mortality in India: A New Perspective Using Mixed-Sex Twins, written by Ridhi Kashyap & Julia Behrman, was originally published electronically on the publisher's internet portal on 25th September without open access.


Synthesis and antiproliferative activity of imidazole and imidazoline analogs for melanoma.
We have previously reported substituted 2-aryl-thiazolidine-4-carboxylic acid amides as potent and selective antiproliferative agents for melanoma. To understand the importance of the thiazolidine ring and to reduce potential complications associated with the two chiral centers, we designed and synthesized sets of new analogs by modifying this ring. These new analogs were tested in two melanoma cell lines and fibroblast cells (negative controls). Compared with the older analogs containing the thiazolidine ring, these new analogs have lower potency in general, but some of these analogs still have very good selectivity. These structure-activity studies indicated that the thiazolidine ring is very critical for the activity for these series of compounds.


Rapid and effective CD3 T-cell depletion with a magnetic cell sorting program to produce peripheral blood progenitor cell products for haploidentical transplantation in children and adults.
Effective T-cell depletion is a prerequisite for haploidentical peripheral blood progenitor cell (PBPC) transplantation. This study was performed to investigate the performance of magnetic cell sorting-based direct large-scale T-cell depletion, which is an attractive alternative to standard PBPC enrichment procedures. PBPCs were harvested from 11 human leukocyte antigen (HLA)-haploidentical donors. T cells labeled with anti-CD3-coated beads were depleted with a commercially available magnetic separation unit (CliniMACS, Miltenyi Biotec) with either the Depletion 2.1 (D2.1, n=11) or the novel Depletion 3.1 (D3.1, n=12) program. If indicated, additional CD34+ selections were performed (n=6). Eleven patients received T-cell-depleted grafts after reduced-intensity conditioning. The median log T-cell depletion was better with the D2.1 compared to the D3.1 (log 3.6 vs. log 2.3, p<0.05) and was further improved by introducing an immunoglobulin G (IgG)-blocking step (log 4.5 and log 3.4, respectively). The D3.1 was superior to the D2.1 (p<0.05) in median recovery of CD34+ cells (90% vs. 78%) and in median recovery of CD3- cells (87% vs. 76%). The median processing times per 10(10) total cells were 0.90 hours (D2.1) and 0.35 hours (D3.1). The transplanted grafts (directly T-cell-depleted products with or without positively selected CD34+ cells) contained a median of 10.5 x 10(6) per kg CD34+, 0.93x10(5) per kg CD3+, and 11.6x10(6) per kg CD56+. Rapid engraftment was achieved in 10 patients. The incidences of acute graft-versus-host disease were less than 10 percent (Grade I/II) and 0 percent (Grade III/IV). The novel D3.1 program with IgG blocking enables highly effective, time-saving large-scale T-cell depletion. Combining direct depletion techniques with standard CD34+ selection enables the composition of grafts optimized to the specific requirements of the patients.


Heart team consultations for patients with severe coronary artery disease or valvular heart disease in the era of the COVID-19 pandemic: a single-center experience.
The Heart Team (HT) as a group of experienced specialists is responsible for optimal decision-making for high-risk cardiac patients. The aim of this study was to investigate the impact of the COVID-19 pandemic on HT functioning. In this retrospective, single-center study, we evaluated the cooperation of HT in terms of the frequency of meetings, the number of consulted patients, and the trends in choosing the optimal treatment strategies for complex individuals with severe coronary artery disease (CAD) or valvular heart disease (VHD) before and during the COVID-19 pandemic in Poland. From 2016 to May 2022, 301 HT meetings were held, and a total of 4,183 patients with severe CAD (2,060 patients) or severe VHD (2,123 patients) were presented. A significant decrease in the number of HT meetings and consulted patients (2019: 49 and 823 vs. 2020: 44 and 542 and 2021: 45 and 611, respectively, P < 0.001) as well as changes in treatment strategies-increase of conservative, reduction of invasive (2019: 16.7 and 51.9 patients/month vs. 2020: 20.4 and 24.8 patients/month and 2021:19.3 and 31.6 patients/month, respectively, P < 0.001)-were demonstrated with the spread of the COVID-19 pandemic. As the pandemic slowly receded, the observed changes began to return to the pre-pandemic trends. The COVID-19 pandemic resulted in a decrease in the number of HT meetings and consulted patients and significant reduction of invasive procedures in favor of conservative management. Further studies should be aimed to evaluate the long-term implications of this phenomenon.


A return to maternal mortality studies: a necessary effort.
This report reviews the experience of the Santa Clara County Maternal Mortality Study Committee, which continued its local activity after the termination of California state-supported study groups in 1970. A study of 36 maternal deaths among approximately 262,000 live births was compiled over a 13-year period, between 1971 and 1983, in a population group representative of much of California. Although based on a small population sample, the results indicate an imperative need for such reviews to improve the quality of clinical care and to develop significant statistical information on the incidence and causes of maternal mortality. The historical development of study committees throughout the United States illustrates the necessity of standardized definitions and uniform methodology among study groups in all states and territories. A nationwide study is proposed to obtain a broad-based, cumulative maternal mortality series, directed toward the eventual elimination of preventable maternal deaths. The current effort by a special interest group in the American College of Obstetricians and Gynecologists is commended for beginning this task.


The interaction of the SARS coronavirus non-structural protein 10 with the cellular oxido-reductase system causes an extensive cytopathic effect.
The pathological mechanism of SARS-CoV infection was investigated. The gene for the SARS-CoV non-structural protein 10, which is located in the open reading frame of pp1a/pp1ab gene, was synthesized and used to screen for the specific cellular gene coding for the protein interacting with this nsp10 protein in a human embryo lung cDNA library using a yeast trap method. The results indicated that apart from the two subunits of cellular RNA polymerase complex, BTF3 and ATF5, this nsp10 protein was also able to interact specifically with the NADH 4L subunit and cytochrome oxidase II. Further study revealed that the activity of the NADH-cytochrome was altered and the inner mitochondrial membrane was depolarized in the transfected human embryo lung fibroblast by the nsp10 protein gene. The cytopathic effect of the Coronavirus 229E strain appeared more extensive in these cells than in the control cells.


The economic impact of introducing serotonin-noradrenaline reuptake inhibitors into the Brazilian national drug formulary: cost-effectiveness and budget-impact analyses.
To determine the cost effectiveness, from the Brazilian Ministry of Health viewpoint, of three antidepressant classes for major depressive disorder (MDD), and the budget impact of introducing serotonin-noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) into the current Brazilian national drug formulary, assuming a 6-month treatment duration. An existing decision-tree model was adapted to Brazil, based on local guidelines. Clinical data were obtained from published meta-analyses. Patients included adults aged > or =18 years with MDD, diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, third and fourth editions (DSM-III/IV), with moderate-to-severe disease (Hamilton Depression Rating Scale [HAMD] > or =15 or Montgomery-Asberg Depression Rating Scale [MADRS] > or =18), without co-morbidities or co-medications, receiving > or =6 weeks of treatment with SNRIs, selective serotonin reuptake inhibitors (SSRIs) and/or tricyclic antidepressants (TCAs). Clinical outcome was remission (HAMD < or =7 or MADRS < or =12). Direct costs (drugs, physician visits, hospitalisations) were included. Drug costs were obtained from the 2006 Brazilian National Drug Price List, and hospitalisation and physician costs from the 2006 Healthcare System database. Costs were valued in Brazilian Reais ($Brz), year 2006 values ($Brz1 = $US0.47). Univariate and Monte Carlo sensitivity analyses tested model robustness. Expected costs per patient treated were SNRIs $Brz4848; SSRIs $Brz5466; and TCAs $Brz5046, and overall success rates (primary plus secondary treatment across all decision tree branches) were SNRIs 78.1%; SSRIs 74.0%; and TCAs 76.4%. Average costs/success were SNRIs $Brz6209; SSRIs $Brz7385; and TCAs $Brz6602. SNRIs dominated in incremental cost-effectiveness analyses. Monte Carlo analysis confirmed drug classes' relative positions; however, there was considerable uncertainty. Introducing SNRIs into the formulary could generate average savings of 1% of the total budget, with a 52% probability of savings. SNRIs appear to be cost effective against SSRIs and TCAs when prescribed to patients with MDD in Brazil. However, their inclusion into the national drug list would generate minor savings compared with the current formulary of SSRIs and TCAs. Thus, we considered such inclusion as 'cost-neutral', since no major probability of savings or increased expenditures were observed.


Size- and surface charge-dependent hormetic effects of microplastics on bacterial resistance and their interactive effects with quinolone antibiotic.
The facilitation of microplastics (MPs) on bacterial resistance has attracted wide concern, due to the widespread presence of MPs in environmental media and their ubiquitous contact with bacteria strains. Furthermore, MPs possibly co-exist with antibiotics to trigger combined stress on bacterial survival. Therefore, it is significant to reveal the dose-responses of MPs and MP-antibiotic mixtures on bacterial endogenous and exogenous resistance. In this study, 0.1 and 5 μm polystyrenes with no surface functionalization (PS-NF, no charge), surface functionalized with amino groups (PS-NH2, positive charge) and carboxyl groups (PS-COOH, negative charge) were selected as the test MPs, and norfloxacin (NOR) was set as the representative of antibiotics. It was found that six types of PS all inhibited the growth of Escherichia coli (E. coli) but induced hormetic dose-responses on the mutation frequency (MF) and conjugative transfer frequency (CTF) of RP4 plasmid in E. coli. Moreover, these hormetic effects exhibited size- and surface charge-dependent features, where 0.1 μm PS-NH2 (100 mg/L) triggered the maximum stimulatory rates on MF (363.63 %) and CTF (74.80 %). The hormetic phenomena of MF and CTF were also observed in the treatments of PS-NOR mixtures, which varied with the particle size and surface charge of PS. In addition, the interactive effects between PS and NOR indicated that the co-existence of PS and NOR might trigger greater resistance risk than the single pollutants. Mechanistic exploration demonstrated that the increase of cellular reactive oxygen species and the variation of cell membrane permeability participated in the hormetic effects of PS and PS-NOR mixtures on bacterial resistance. This study provides new insights into the individual effects of MPs and the combined effects of MP-antibiotic mixtures on bacterial resistance, which will promote the development of environmental risk assessment of MPs from the perspective of bacterial resistance.


In situ NMR of lithium ion batteries: bulk susceptibility effects and practical considerations.
The application of in situ nuclear magnetic resonance (NMR) to investigate batteries in real time (i.e., as they are cycling) provides fruitful insight into the electrochemical structural changes that occur in the battery. A major challenge for in situ static NMR spectroscopy of a battery is, however, to separate the resonances from the different components. Many resonances overlap and are broadened since spectra are acquired, to date, in static mode. Spectral analysis is also complicated by bulk magnetic susceptibility (BMS) effects. Here we describe some of the BMS effects that arise in lithium ion battery (LIB) materials and provide an outline of some of the practical considerations associated with the application of in situ NMR spectroscopy to study structural changes in energy materials.


Enhanced uptake of spermidine and methylglyoxal-bis(guanylhydrazone) by rat liver mitochondria following outer membrane lysis.
Isolated rat liver mitochondria rapidly bound the 14C-labeled organic cations spermidine, a physiologically important polyamine, and methylglyoxal-bis(guanylhydrazone) (MGBG), an anticancer drug. This rapid, Mg2+-sensitive, respiration-independent binding is assumed to involve adsorption to anionic surface groups. A slower progressive uptake of the organic cations exhibited respiration dependence, indicating that it involves transport across the inner mitochondrial membrane into the matrix compartment. Addition of digitonin, to lyse the outer mitochondrial membrane, caused an increase in the mitochondrial content of the organic cations and enhanced the rate of progressive, respiration-dependent cation uptake. The data are consistent with the interpretation that the outer mitochondrial membrane limits access of the organic cations, spermidine and MGBG, to the inner mitochondrial membrane. This conclusion is supported also by published data indicating that outer membrane lysis enhances inhibitory effects of the organic cations on mitochondrial respiration. The uptake of spermidine by mitochondria was inhibited by MGBG.


Testing for association in the presence of population stratification: a simulation study comparing the S-TDT, STRAT and the GC.
A novel approach for association testing in the presence of population stratification has been introduced by Pritchard et al. (2000a) and Pritchard et al. (2000b). The structured association approach is a two-tiered procedure that first estimates the population structure and then tests the null hypothesis H0: 'no association within subpopulations' in the second step. A power comparison of the stratified test for association (STRAT) (Pritchard et al., 2000b) and the Transmission-Disequilibrium-Test (TDT) (Spielman and Ewens, 1993a) in a simulation framework showed superiority of STRAT if allele frequencies or associations between allele and disease differ strongly in subpopulations. In more homogeneous situations, the TDT had greater power than STRAT. However, the TDT, based on family trios,that uses population controls, needs 50% more genotyping compared to STRAT. The Sib-Transmission-Disequilibrium-Test (S-TDT) needs the same amount of genotyping since it relays in its minimal configuration on pairs of siblings. This raises the question how the S-TDT (Spielman and Ewens, 1998a) performs compared to the population based methods STRAT and Genomic Controls (GC). In this paper, we present a simulation study accounting for two different models of population stratification in different settings of allele frequencies and under different risk models. The results showed that under a discrete as well as under an admixed population model, STRAT strongly outperformed the S-TDT and the GC when different alleles were associated in different subpopulations. In contrast, the S-TDT had greater power than STRAT when the same allele was associated in both subpopulations. Here, the GC was sometimes even more powerful than the S-TDT, depending on the population model and the allele frequency differences. A general recommendation for the use of one of the tests can therefore not be given.


Action of cromakalim on potassium membrane conductance in isolated heart myocytes of frog.
1. The effects of cromakalim on membrane currents were studied at 20 degrees C in frog atrial and ventricular cells in patch clamp recording using the whole cell configuration. 2. When cromakalim (1 microM) was applied in the external medium, a time-independent current was activated in a few minutes. Cromakalim induced a weak increase of inward membrane currents recorded during hyperpolarization and a large increase of outward membrane currents recorded during depolarization. 3. The current voltage relationship of the cromakalim-induced current reversed near EK and rectified in the outward direction. 4. The cromakalim-activated current was inhibited by external application of cesium (20 mM), barium (1.8 mM), tolbutamide (1 mM) and glibenclamide (1 microM). 5. The effects of cromakalim were insensitive to a cytosolic increase in adenosine 5'-triphosphate (ATP, 3-5 mM). Cromakalim had no effects when applied in the cell. 6. Our results confirm that cromakalim activates an IK(ATP)-like conductance and suggest that the effects of the drug are due to an action on the external side of the membrane and are independent of the ATP cell content.


Primary Purpose for Committing a Crime and Past-30 Day Opioid Misuse: A Statewide Sample of Justice-Involved Children.
The prevalence of opioid misuse (OM) among justice-involved children (JIC) is significantly higher than children in the general population, yet little research has examined the predictors of OM among JIC. Goldstein's "economic compulsive model" hypothesizes that JIC who commit crimes for material gain will have a higher likelihood of meeting past-30 day (P30D) OM criteria. The data in this study were cross-sectional and represented 79,960 Florida JIC. To test the hypothesis, logistic regression analyses were utilized. Over 2000 JIC (2.67%) met P30D OM criteria and JIC who committed crimes for material gain were 2.55 times as likely to meet P30D OM criteria. Findings indicate that children may be incarcerated due to an inability to afford their addiction, contributing to the criminalization of mental health. JIC could benefit from the increased utilization of drug courts and the implementation of a cascade of care model.


Phototransection of vitreal membranes with the carbon dioxide laser in rabbits.
An intravitreal CO2 laser probe phototransected vitreal membranes in rabbits with short pulses of infrared energy delivered through either an optical fiber or an articulated arm. The potential use of the CO2 laser probe appears to be as an adjunct to the mechanical vitrectors.


Modulation of parathyroid hormone-sensitive adenylate cyclase in ROS 17/2.8 cells by dexamethasone 1,25-dihydroxyvitamin D3 and protein kinase C.
We tested whether the protein kinase C (PKC) modulation of PTH-sensitive adenylate cyclase in ROS 17/2.8 cells is affected by the glucocorticoid dexamethasone and the vitamin D hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Basal and PTH- and forskolin-stimulated adenylate cyclase activities were determined in the presence or absence of 100 nM phorbol 12-myristate 13-acetate (PMA), the activator of PKC, in ROS 17/2.8 cells that had been previously cultured with or without dexamethasone or 1,25(OH)2D3. Dexamethasone treatment increased the basal, PMA-, PTH-, (PTH + PMA)- and (forskolin + PMA)-sensitive adenylate cyclase while 1,25(OH)2D3 decreased these effects. The stimulatory and inhibitory effects were dose-dependent with respect to dexamethasone and 1,25(OH)2D3, respectively. Dexamethasone increased, while 1,25(OH)2D3 decreased the maximal activity of both PTH-sensitive and PKC-modulated PTH-sensitive adenylate cyclase without affecting the half-maximal concentration (ED50) of PTH required for the activation of the enzyme. Additionally, dexamethasone, 1,25(OH)2D3 and PKC did not affect each other's ED50. Our results suggest that the effects of dexamethasone, 1,25(OH)2D3 and PKC on PTH-sensitive adenylate cyclase in ROS 17/2.8 cells are independent of each other.


Inflammatory risk stratification individualizes anti-inflammatory pharmacotherapy for acute type A aortic dissection.
The systemic benefits of anti-inflammatory pharmacotherapy vary across cardiovascular diseases in clinical practice. We aimed to evaluate the application of artificial intelligence to acute type A aortic dissection (ATAAD) patients to determine the optimal target population who would benefit from urinary trypsin inhibitor use (ulinastatin). Patient characteristics at admission in the Chinese multicenter 5A study database (2016-2022) were used to develop an inflammatory risk model to predict multiple organ dysfunction syndrome (MODS). The population (5,126 patients from 15 hospitals) was divided into a 60% sample for model derivation, with the remaining 40% used for model validation. Next, we trained an extreme gradient-boosting algorithm (XGBoost) to develop a parsimonious patient-level inflammatory risk model for predicting MODS. Finally, a top-six-feature tool consisting of estimated glomerular filtration rate, leukocyte count, platelet count, De Ritis ratio, hemoglobin, and albumin was built and showed adequate predictive performance regarding its discrimination, calibration, and clinical utility in derivation and validation cohorts. By individual risk probability and treatment effect, our analysis identified individuals with differential benefit from ulinastatin use (risk ratio [RR] for MODS of RR 0.802 [95% confidence interval (CI) 0.656, 0.981] for the predicted risk of 23.5%-41.6%; RR 1.196 [0.698-2.049] for the predicted risk of <23.5%; RR 0.922 [95% CI 0.816-1.042] for the predicted risk of >41.6%). By using artificial intelligence to define an individual's benefit based on the risk probability and treatment effect prediction, we found that individual differences in risk probability likely have important effects on ulinastatin treatment and outcome, which highlights the need for individualizing the selection of optimal anti-inflammatory treatment goals for ATAAD patients.


Frailty assessment can predict textbook outcomes in senior adults after minimally invasive colorectal cancer surgery.
Colorectal cancer (CRC) surgery can be associated with suboptimal outcomes in older patients. The aim was to identify the correlation between frailty and surgical variables with the achievement of Textbook Outcome (TO), a composite measure of the ideal postoperative course, by older patients with CRC. All consecutive patients ≥70years who underwent elective CRC-surgery between January 2017 and November 2021 were analyzed from a prospective database. To obtain a TO, all the following must be achieved: 90-day survival, Clavien-Dindo (CD) < 3, no reintervention, no readmission, no discharge to rehabilitation facility, no changes in the living situation and length of stay (LOS) ≤5days/≤14days for colon and rectal surgery respectively. Frailty and surgical variables were related to the achievement of TO. Four-hundred-twenty-one consecutive patients had surgery (97.7% minimally invasive), 24.9% for rectal cancer, median age 80 years (range 70-92), median LOS of 4 days (range 1-96). Overall, 288/421 patients (68.4%) achieved a TO. CD 3-4 complications rate was 6.4%, 90-day mortality rate was 2.9%. At univariate analysis, frailty and surgical variables (ileostomy creation, p = 0.045) were related to. However, multivariate analysis showed that only frailty measures such as flemish Triage Risk Screening Tool≥2 (OR 1.97, 95%CI: 1.23-3.16; p = 0.005); Charlson Index>6 (OR 1.61, 95%CI: 1.03-2.51; p = 0.036) or Timed-Up-and-Go>20 s (OR 2.06, 95%CI: 1.01-4.19; p = 0.048) independently predicted an increased risk of not achieving a TO. The association between frailty and comprehensive surgical outcomes offers objective data for guiding family counseling, managing expectations and discussing the possible loss of independence with patients and caregivers.


A translational rodent assay of affective biases in depression and antidepressant therapy.
The subjective measures used to study mood disorders in humans cannot be replicated in animals; however, the increasing application of objective neuropsychological methods provides opportunities to develop translational animal tasks. Here we describe a novel behavioral approach, which has enabled us to investigate similar affective biases in rodents. In our affective bias test (ABT), rats encounter two independent positive experiences--the association between food reward and specific digging substrate--during discrimination learning sessions. These are performed on separate days under either neutral conditions or during a pharmacological or affective state manipulation. Affective bias is then quantified using a preference test where both previously rewarded substrates are presented together and the rat's choices recorded. The absolute value of the experience is kept consistent and all other factors are counterbalanced so that any bias at recall can be attributed to treatment. Replicating previous findings from studies in healthy volunteers, we observe significant positive affective biases following acute treatment with typical (fluoxetine, citalopram, reboxetine, venlafaxine, clomipramine) and atypical antidepressants (agomelatine, mirtazapine), and significant negative affective biases following treatment with drugs associated with inducing negative affective states in humans (FG7142, rimonabant, 13-cis retinoic acid). We also observed that acute psychosocial stress and environmental enrichment induce significant negative and positive affective biases, respectively, and provide evidence that these affective biases involve memory consolidation. The positive and negative affective biases induced in our test also mirror the antidepressant and pro-depressant effects of these drugs in patients suggesting our test has both translational and predictive validity. Our results suggest that cognitive affective biases could contribute to drug- or stress-induced mood changes in people and support the hypothesis that a cognitive neuropsychological mechanism contributes to antidepressant drug efficacy.


Glucose biosensor based on the layer-by-layer self-assembling of glucose oxidase and chitosan derivatives on a thiolated gold surface.
The work proposed here deals with the design and characterization of biorecognition layers for the amperometric glucose determination based on the self-assembling of new chitosan derivatives, Nafion and glucose oxidase onto thiolated gold electrodes. The supramolecular multistructure is obtained by deposition of a layer of chitosan derivative (quaternized or hydrophobic) onto the gold surface modified with the sodium salt of 3-mercapto-1-propansulfonic acid, followed by the deposition of a layer of Nafion (as anti-interference barrier) and by the alternate deposition of the chitosan derivative and glucose oxidase (as biocatalytic layer). The influence of the deposition time and concentration of polyelectrolytes, organization and number of layers, and nature of the chitosan derivative on the sensitivity and selectivity of the bioelectrode is examined and optimized in order to obtain a rational design of the biosensor. The system is studied electrochemically from the oxidation at 0.700 V of the hydrogen peroxide enzymatically generated using gold as substrate, and spectrophotometrically from the protein absorption at 277 nm using quartz as substrate. The selected biosensor containing five quaternized chitosan/glucose oxidase bilayers exhibits very good analytical performance with a sensitive ((4.9+/-0.2) x 10(2) nA mM(-1)) and highly selective response (0% interference for maximum physiological levels of ascorbic acid and uric acid), demonstrating that the alternate electrostatic adsorption of conveniently selected polyelectrolytes allows noticeable improvements in the selectivity and sensitivity of a biosensor.


Association between ErbB3 genetic polymorphisms and coronary artery disease in the Han and Uyghur populations of China.
ErbB3 is a member of the epidermal growth factor receptor (EGFR/ERBB) family of receptor tyrosine kinases. Recent research has shown that amplification of this gene is related to prostate, bladder and breast cancers, as well as low-density lipoprotein cholesterol (LDL-C) metabolism. LDL-C plays a considerable role in the development of cardiovascular disease. Thus, the present study assessed the association between human ErbB3 gene polymorphisms and coronary artery disease (CAD) in Han and Uygur populationsin China. We performed two independent case-control studies with a Han population (339 CAD patients and 395 control subjects) and a Uygur population (306 CAD patients and 325 control subjects). All of the CAD patients and controls were genotyped for the same three single nucleotide polymorphisms (rs877636, rs705708, and rs10783779) in the ErbB3 gene by real-time PCR. In the Han population, rs877636 polymorphisms were associated with CAD on the basis of the genotypes, dominant model, additive model, and allele frequency (for genotypes: P = 0.008; for dominant model: P = 0.003; for additive model: P = 0.004; for allele: P = 0.008), and these significant difference was retained (all P < 0.05) after adjusting for the major confounding factors. The CT genotype and C allele of rs877636 in the ErbB3 gene could be a genetic marker of CAD risk for the Han population in China.