Phosphorylated 1,6-diphenyl-1,3,5-hexatriene.
A lipophilic dye consisting of a (1E,3E,5E)-1,6-diphenyl-1,3,5-hexatriene (DPH) fluorophore attached to a phosphate diester was prepared, and its fluorescence behavior in different solvent systems and in a liposomal membrane bilayer was examined. The key step in the synthesis of the functionalized end of the dye is a Sonogashira coupling of protected iodophenol with propargyl alcohol; the remaining phenyl ring and double bonds of the all-trans polyene core arise from a Wittig reaction with trans-cinnamaldehyde. Like DPH itself, the emission intensity of its phosphorylated derivative is quenched in polar media.


A PF6 - -Permselective Polymer Electrolyte with Anion Solvation Regulation Enabling Long-Cycle Dual-Ion Battery.
Graphitic carbon that allows reversible anion (de)intercalation is a promising cathode material for cost-efficient and high-voltage dual-ion batteries (DIBs). However, one notorious but overlooked issue is the incomplete interfacial anion desolvation, which not only reduces the oxidative stability of electrolytes, but also results in solvent co-intercalation into graphite layers. Here, an "anion-permselective" polymer electrolyte with abundant cationic quaternary ammonium motif is developed to weaken the PF6 - -solvent interaction and thus facilitates PF6 - desolvation. This strategy significantly inhibits solvent co-intercalation as well as enhances the oxidation resistance of electrolyte, ensuring the structural integrity of graphite. As a result, the as-assembled graphite||Li cell achieves a superior cyclability with an average Coulombic efficiency of 99.0% (vs 95.7% for baseline electrolyte) and 87.1% capacity retention after 2000 cycles even at a high cutoff potential of 5.4 V versus Li+ /Li. Besides, this polymer also forms a robust cathode electrolyte interface, working together to enable a long-life DIB. This strategy of tuning anion coordination environment provides a promising solution to regulate solvent co-intercalation chemistry for DIBs.


Inappropriate secretion of antidiuretic hormone, polydipsia and hypothalamic calcifications.
We studied a 41 year old patient who had pathologic fluid intake of 10 1/day together with syndrome of inappropriate antidiuretic hormone. Imaging studies revealed a lesion of the anterior wall of the third cerebral ventricle. A review of relevant literature indicated several different disturbances by which alterations of thirst, vasopressin-secretion and abnormalities of anterior third ventricle may be associated. The present case presents an unusual and potentially dangerous combination in this spectrum of changes.


Movements of carabid beetles (Coleoptera: Carabidae) inhabiting cereal fields: a field tracing study.
The individual movements of four carabid species were investigated by tracing beetles in the field using a portable radar system (harmonic radar). The field-inhabiting a Pterostichus melanarius Illiger, P. niger Schaller and Harpalus rufipes De Geer were traced in cereal fields. The movements of P. melanarius Mnd P. niger were also tracked in a wood and then compared with the movements of the forest-species Carabus nemoralis Müller. P. melanarius and P. niger displayed directed movements in cereal fields, although P. niger moved faster than P. melanarius. The movement pattern of H. rufipes in the field, and C. nemoralis and P. malanarius in the wood can be described as a c correlated random walk. In cereal fields, P. melanarius burrowed actively into the soil, and P. niger searched out crevices. In contrast, none of these two carabids burrowed in the forest soil, whereas C. nemoralis did. No statistically significant difference was observed between the movements of hungry and satiated beetles, although starved beetles tended to disperse shorter distances per move and turned back more often (especially P. niger). The significance of the various movement patterns exhibited by the species studied for their reproduction and survival on arable land is discussed.


Royal honour for airshow crash hero.
A nurse has been honoured for risking his life to save the pilot in last summer's Shoreham Airshow crash.


Thyroid-stimulating hormone (TSH) is associated with 30-day mortality in hip fracture patients.
The aim of this study is to assess the possible association between thyroid-stimulating hormone (TSH) and mortality in hip fracture patients. The study is based on a hip fracture database from Bispebjerg University Hospital (Copenhagen, Denmark). This database includes all hip fracture patients (ICD-10 codes DS720 (femoral neck), DS721 (pertrochanteric), and DS722 (subtrochanteric)) admitted to Bispebjerg Hospital from 1996 to 2012. From this database, we identified all surgically treated hip fracture patients aged > 60 years with available plasma TSH-measurements at admission. Of the 914 included patients (24% men and 76% women), 10.5% died within 30 days. At inclusion, 161 (17.6%) of the patients were hyperthyroid (TSH < 0.65 mIU/L), 58 (6.4%) were hypothyroid (TSH > 4.8 mIU/L), while 695 (76.0%) were euthyroid (0.65 < TSH < 4.80 mIU/L), p = 0.03. Mortality was significantly higher in the two higher quartiles of TSH [Q3 (13.0%) and Q4 (15.4%)] compared to the two lower quartiles [Q1 (7.4%) and Q2 (6.2%), p = 0.0003. After adjustment for age, sex and Charlson Comorbidity Index (CCI) in a Cox proportional hazard model, the risk of 30-day mortality continued to be increased in patients with TSH above the median as compared to patients with TSH below the median (HR 2.1 (1.4-3.3), p = 0.0006]. The study demonstrates increased 30-day mortality in surgically treated hip fracture patients with plasma TSH levels above the median (1.41 mIU/L) at admission, even after adjusting for age, sex and CCI.


Rapid inhalation induction with halothane-nitrous oxide for myasthenic patients.
Rapid inhalation induction (RII) was successfully employed for patients without myopathy. Inhalatory agents can be used for anaesthetic induction of myasthenics, avoiding the use of neuromuscular blocking agents. We studied the use of RII in 15 myasthenics (MG) and in 15 normal subjects (nMG), measuring induction time (TI), cardiorespiratory effects, complications, and evaluated the patient's reaction to RII. The patients were submitted to elective transsternal thymectomy (MG) and gynaecological or lower abdominal surgery (nMG). No premedication was used. After preoxygenation, RII was started using a mixture of 4% halothane and O2:N2O (1:2). They performed three vital capacity breaths, followed by normal spontaneous ventilation. The TI was assessed by timing the loss of verbal command (TLVC) and loss of eyelid reflex (TLER). Systolic and diastolic pressure, pulse oximetry, capnometry, respiratory rate (RR) and heart rate (HR) were measured during induction at each minute, for four minutes. After a postanaesthetic questionnaire only two normal subjects did not like the RII technique. Mean values for TLVC and TLER were 67 and 73 sec for MG and 64 and 69 sec for nMG, respectively. There was no change in HR for MG or blood pressure. The RR increased in both groups, but no change in PetCO2 was observed; SaO2 was > 97%. In conclusion, RII can be performed rapidly and safely in myasthenic patients and is a technique that should be considered for the induction of anaesthesia in myasthenic patients.


Midkine that promotes survival of fetal human neurons is produced by fetal human astrocytes in culture.
Midkine (MK), a retinoic acid responsive gene product, is a novel heparin-binding growth factor with an apparent molecular weight of 14-kDa. In fetal human neuron cultures, addition of recombinant human MK (10-100 ng/ml) resulted in a 3-fold increase in the number of surviving neurons under the serum-free culture condition. Production of MK was identified in the conditioned medium of astrocyte-enriched cultures by immunoblotting but not in the medium of neuron-enriched cultures. The level of MK production was not affected by treatment with retinoic acid. These results indicate that in the developing human central nervous system, astrocytes secrete MK that exhibits potent trophic activity to neurons.


Response to Comment on "Eocene Fagaceae from Patagonia and Gondwanan legacy in Asian rainforests".
Denk et al agree that we reported the first fossil Fagaceae from the Southern Hemisphere. We appreciate their general enthusiasm for our findings, but we reject their critiques, which we find misleading and biased. The new fossils unequivocally belong to Castanopsis, and substantial evidence supports our Southern Route to Asia hypothesis.


Postaxial limb hypoplasia (PALH): the classification, clinical features, and related developmental biology.
Postaxial limb hypoplasia (PALH) is a group of nonhereditary diseases with congenital lower limb deficiency affecting the fibular ray, including fibular hemimelia, proximal femoral focal deficiency, and tarsal coalition. The etiology and the developmental biology of the anomaly are still not fully understood. Here, we review the previous classification systems, present the clinical features, and discuss the developmental biology of PALH.


Hawk owl irruptions: spatial and temporal variation in rodent abundance drive push and pull dynamics.
Bird irruptions are thought to be triggered by low food availability in breeding areas, thereby causing emigration (push factor). However, few studies have tested whether emigrating individuals are drawn towards areas of high food availability (pull factor). The Northern hawk owl (Surnia ulula), a rodent specialist, occurs irruptively to southern parts of Fennoscandia. We analysed whether irruption size during 1980-2020 in southeastern Norway was related to rodent abundance at four sites 450-990 km to the north-northeast (potential source areas) and at two sites in southeastern Norway to test push and pull dynamics of irruptions. Irruptions occurred when rodent abundance in potential source areas were low, supporting the push hypothesis. High rodent abundance in potential source areas 1-2 years before irruptions suggested that irruptions were preceded by high reproduction. Upon arrival to southeastern Norway, hawk owls did not encounter high rodent abundance in their main habitat (boreal forest). However, hawk owls stayed in boreal forest in hills in years with higher microtine rodent abundance, but occurred in farmland areas in the lowlands when microtine rodents were less abundant. Use of lowlands coincided with higher than median numbers of wood mouse (Apodemus sylvaticus) for 87% of the hawk owls settling in the lowlands, thus suggesting support for the pull hypothesis. In conclusion, hawk owl irruptions to southern Fennoscandia were triggered by low food availability in northern areas (push factor), and appeared to be drawn by high food availability in southeastern Norway to some degree (pull factor).


OX40 signaling is involved in the autoactivation of CD4+CD28- T cells and contributes to the pathogenesis of autoimmune arthritis.
CD4+CD28- T cells exhibit autoreactive potential in autoimmune disorders, including rheumatoid arthritis (RA). It is not well known which costimulator functions as an alternative second signal in the activation of this subset after CD28 expression is downregulated. Tumor necrosis factor receptor superfamily member OX40 is a key costimulator in the activation of T cells. The aim of this study was to investigate the costimulatory effects of OX40 on CD4+CD28- T cells in autoimmune arthritis. Clinical samples were collected from patients with RA and control subjects. Collagen-induced arthritis (CIA) was induced with collagen type II (CII) in DBA/1 mice. The CD4+CD28-OX40+ T-cell subset and its cytokine production were detected by flow cytometry. After T-cell purification, adoptive transfer was performed in CIA mice. The regulatory role of OX40 was determined by blocking experiments in vitro and in vivo. OX40 and OX40L were abnormally expressed in patients with RA and CIA mice. Further analysis showed that CD4+CD28-OX40+ T cells accumulated in patients with RA and in animal models. These cells produced higher levels of proinflammatory cytokines and were closely correlated with the clinicopathological features of the affected individuals. Adoptive transfer of CII-specific CD4+CD28-OX40+ T cells remarkably aggravated arthritic development and joint pathology in CIA mice. Moreover, OX40 blockade significantly reduced the proinflammatory responses and ameliorated arthritis development. OX40 acts as an alternative costimulator of CD4+CD28- T cells and plays a pathogenic role in autoimmune arthritic development, suggesting that it is a potential target for immunomodulatory therapy of RA.


The effect of delayed refrigeration on red blood cells, platelet concentrates and cryoprecipitable AHF.
The effect of delaying blood processing for six hours while maintaining it at ambient temperature was investigated. Blood drawn from volunteers on two occasions was processed immediately (I) or after a six-hour delay (D). The effects of the delay on the efficacy and safety of red blood cells, platelet concentrates and cryoprecipitable AHF were studied. There was a more rapid decrease in 2,3-DPG in the delayed group during 21 days of refrigerated storage. ATP levels declined at similar rates. 24-hour survival of 51CR-labeled autologous cells was slightly better (p = .05) in the (I) group but excellent for both. Total platelets, per cent recovery and pH at 72 hours were identical for both groups. All cultures were sterile. There was no difference in total AHF recovered or per cent recovery between the two groups. To increase the availability of blood components, a six-hour processing delay seems warranted.


3D porous metal-organic framework as an efficient electrocatalyst for nonenzymatic sensing application.
Novel electroactive materials with high surface area and stability have great potential for electrochemical sensor. Herein, we demonstrate the exploitation of a porous Cu-based metal-organic framework (Cu-MOF) with large pore size as nonenzymatic sensors for the electrochemical determination of hydrogen peroxide (H2O2) and glucose. The Cu-MOF shows high stability even in NaOH solution. The as-prepared Cu-MOF modified carbon paste electrode (CPE) presents a well-behaved redox event from electroactive metal centers in the MOF at the physiological pH which can be utilized to catalyze the electroreduction of H2O2. It also exhibited excellent electrocatalytic activity towards the oxidation of glucose in alkaline solution. The results showed that the nonenzymatic sensors based on the Cu-MOF display excellent analytical performances, which make it a promising candidate in electrochemical sensor.


Human platelet lysates stimulate in vitro proliferation of human endometrial cells from patients with a history of recurrent implantation failure.
To optimize and compare the isolation of platelet-rich plasma (PRP) and its cryopreserved derivative, platelet lysate (PL), to a commercial human platelet lysate (HPL) product PLUS and investigate their proliferative stimulation on primary human endometrial cells in vitro. Basic research. Academic fertility center. Three healthy blood donors and eight patients with a history of recurrent implantation failure. Stimulated proliferation of isolated primary endometrial epithelial cells and endometrial stromal cells in vitro with autologous and nonautologous HPL (PLUS; Compass Biomedical). Platelet-derived growth factor BB homodimer protein content in isolated PRP/PL and commercial HPL and endometrial epithelial cell and endometrial stromal cell proliferation after 24- or 48-hour stimulation with PL (measured by metabolic activity and Ki67 expression). To optimize and compare the isolation of autologous PRP/PL, three double-centrifugation protocols were assessed by flow cytometry for platelet yield (CD45-CD41+CD61+) and platelet-derived growth factor BB homodimer protein content by enzyme-linked immunosorbent assay. Cryopreserved PL, especially isolated by our fastest protocol, contained higher protein concentrations and, thus, was optimal for experimental flexibility compared with fresh PRP. The autologous and commercial PLs displayed comparable immune and growth factor content and stimulation of cell proliferation in vitro. Our results provide the groundwork for the isolation and use of HPL to stimulate endometrial growth. Furthermore, commercial PL consistently stimulated cell proliferation and may allow standardization of clinical treatment for recurrent implantation failure.


Diagnostic accuracy of new handheld echocardiography with Doppler and harmonic imaging properties.
The first generation of handheld echocardiography devices was evaluated with divergent results because of inherent technical limitations. New handheld devices with continuous/pulsed wave Doppler and tissue harmonic imaging were introduced recently. In this study, comparisons were drawn among standard echocardiography, invasively measured systolic pulmonary artery pressure, and these new devices. We sought to evaluate new handheld echocardiography and its diagnostic accuracy compared with standard echocardiography. Two consecutive echocardiographic examinations were performed by experienced and independent examiners using handheld and standard echocardiography. Systolic pulmonary artery pressure was measured by Swan-Ganz catheter. In all, 177 (56.2%) patients had normal cardiac function; 138 (43.8%) had underlying cardiac pathology. Handheld echocardiography had an overall agreement of 94.8% and kappa of 0.89 to detect the main echocardiographic finding. Handheld echocardiography detected valve disease with an agreement of 96.7% and kappa of 0.93; global left ventricular function was assessed correctly in 85.6% of cases. Pericardial effusion was diagnosed with an agreement of 91.2%. Dyssynergy was found by handheld echocardiography with an agreement of 95.4% and kappa value of 0.88. Systolic pulmonary artery pressure measured by handheld echocardiography and Swan-Ganz catheter had a correlation of 0.97. This study demonstrates the high diagnostic accuracy of handheld devices with continuous/pulsed wave Doppler and harmonic imaging, and that these devices broaden the diagnostic spectrum while allowing for enhanced mobility in everyday clinical applications.


MTP-1307, a novel antidiabetic agent, improves the glucose intolerance of viable yellow obese-diabetic mice.
MTP-1307 is an oral antidiabetic agent with a unique profile. It improves the glucose intolerance of viable yellow obese-diabetic mice at 25 mg/kg whereas at 300 mg/kg, it only marginally lowers the basal glucose levels of the same mice. This selective activity on exogenous glucose makes MTP-1307 potentially a useful agent to treat postprandial glucose intolerance without causing hypoglycemia.


Efficacy and safety of artemether against a natural Fasciola hepatica infection in sheep.
Triclabendazole is the current drug of choice against Fasciola spp. infections in livestock, but resistance has become a major problem. In this study, we assessed the efficacy and safety of artemether, a derivative of artemisinin, in sheep with a low natural Fasciola hepatica infection. Artemether was administered orally or intramuscularly; sheep were monitored for 8 h posttreatment and then once daily for adverse events, and drug efficacy was estimated by fecal egg count reductions and worm burden reductions. Single 40- and 80-mg/kg oral doses of artemether showed no effect on F. hepatica egg and worm burden. Treatment with a single 160-mg/kg intramuscular dose of artemether significantly reduced the egg burden (64.9%) and worm burden (91.3%). At half this dose, a worm burden reduction of 65.3% was obtained, which was still statistically significant (P < 0.05). The lowest intramuscular dose of artemether investigated (40 mg/kg) yielded no effect on egg counts and worm burden. There were no adverse events due to artemether; however, two abortions were observed 7 days posttreatment. In conclusion, artemether shows interesting fasciocidal properties in sheep, but embryotoxicity is of concern. Further studies are warranted to assess the potential of additional artemisinin derivatives and other peroxidic compounds for the treatment of Fasciola spp. infections in different ruminants.


Successful Treatment of 3 Dogs With Fluoroquinolone-Resistant Escherichia coli Associated Granulomatous Colitis.
Successful resolution of Escherichia coli associated granulomatous colitis (ECGC) is becoming a challenge due to the development of fluoroquinolone resistant E coli, which is associated with poor prognosis. Three dogs presented with signs of chronic colitis and were diagnosed with ECGC. All 3 were initially treated with enrofloxacin and trimethoprim-sulfamethoxazole, without clinical improvement. Despite the fact that culture and susceptibility testing results demonstrate resistance to fluoroquinolone and trimethoprim-sulfamethoxazole, the addition of amikacin fully resolved the clinical signs in all 3 cases. This case series describes the clinical presentation, diagnostic findings, and successful treatment of 3 dogs with fluoroquinolone-resistant ECGC. It suggests an alternative strategy for multidrug-resistance ECGC patients. Further investigations are required to confirm the efficacy of and to determine the molecular mechanisms underpinning the apparent success of aminoglycoside antibiotic combinations for treatment of ECGC.


A supplementary tool to existing approaches for assessing ecosystem community structure.
Measures of biological or species diversity are central to ecology and conservation biology. Although there are several commonly used indices, each has shortcomings and all vary in the relative emphasis they place on the number of species and their relative abundance. We propose utilizing Fisher Information, not as a replacement for existing indices, but as a supplement to other indices because it is sensitive to community structure. We demonstrate how Shannon's and Simpson's diversity indices quantify the diversity of two different systems and how Fisher Information can enhance the analyses by comparing, as example, body size, and phylogenetic diversity of the different communities. Fisher Information is sensitive to the order in which species are entered into the analysis, and therefore, it can detect differences in community structure. Thus, the Fisher Information index can be useful in helping understand and analyze biodiversity of ecosystems and in comparing ecological communities.


Enhancement of anti-inflammatory activity of glycyrrhizic acid by encapsulation in chitosan-katira gum nanoparticles.
Efforts were made to improve the bioavailability and efficacy of Glycyrrhizic acid, a triterpentine saponin obtained from Glycyrrhiza glabra, having several pharmacological properties, by its encapsulation in biocompatible biopolymeric nanoparticles. Polycationic chitosan and polyanionic gum katira were used to prepare nanoparticles by ionic complexation method. Glycyrrhizic acid was loaded into the nanoparticles and was then examined for change in its in vivo anti-inflammatory activity against carrageenan-induced rat hind paw inflammation. The effects of concentrations of glycyrrhizic acid, chitosan and katira gum, upon particle size and encapsulation efficiency of glycyrrhizic acid were studied with the help of response surface methodology employing 3-factor, 3-level central composite experimental design. Particle size and encapsulation efficiency of optimized nanoparticulate formulation were 175.8nm and 84.77%, respectively. Particles were observed in transmission electron microscopy to be spherical in shape and 80nm in size. FTIR analysis indicated electrostatic interactions between carboxyl groups of ammonium glycyrrhizinate and amino groups of chitosan. In vitro drug release studies indicated that glycyrrhizic acid was released from the nanoparticles following zero-order kinetics and that there was a sustained release of the drug with 90.71% of it being released over a 12h period, and that the mechanism of release of glycyrrhizic acid from the nanoparticles was a combination of diffusion and erosion of the polymer matrix. In-vivo anti inflammatory efficacy of glycyrrhizic acid clearly improved upon encapsulation in chitosan-katira gum nanoparticles, by overcoming the limited bioavailability of its other forms.


Facilities for digital pattern recognition: an ECG detective trick.
Algorithms for digital pattern recognition optimized for the demands of the physician are urgently needed. They have to provide high levels of recognition, accuracy, reliability, artefact rejection and flexibility in detecting different types of signal time-course. The microcomputer algorithm presented here works on the principle of Walsh-transformation of signal sections and in-image judging. The algorithm efficiently solves simple tasks, and also recognizes, for instance, ECG P-waves using the same algorithm. A test with 1054 randomly selected outpatient's ECG and with an additional 72 ECGs of inpatients with clinically proved myocardial infarcts produced the following results: The recognition ratio for the R-wave amounted to 98.8% with a failure ratio of 2.3%, while an initial common P-T-pattern was correctly recognized in 80.3% of cases, with a failure ratio of 4.9%. The algorithm was implemented on a Z80 microprocessor and on a single-chip computer Z8.


Antibiotic-induced microbial depletion enhances murine small intestinal epithelial growth in a serotonin-dependent manner.
Regulation of small intestinal epithelial growth by endogenous and environmental factors is critical for intestinal homeostasis and recovery from insults. Depletion of the intestinal microbiome increases epithelial proliferation in small intestinal crypts, similar to the effects observed in animal models of serotonin potentiation. Based on prior evidence that the microbiome modulates serotonin activity, we hypothesized that microbial depletion-induced epithelial proliferation is dependent on host serotonin activity. A mouse model of antibiotic-induced microbial depletion (AIMD) was employed. Serotonin potentiation was achieved through either genetic knockout of the serotonin transporter (SERT) or pharmacological SERT inhibition, and inhibition of serotonin synthesis was achieved with para-chlorophenylalanine. AIMD and serotonin potentiation increased intestinal villus height and crypt proliferation in an additive manner, but the epithelial proliferation observed after AIMD was blocked in the absence of endogenous serotonin. Using Lgr5-EGFP-reporter mice, we evaluated intestinal stem cell (ISC) quantity and proliferation. AIMD increased the number of ISCs per crypt and ISC proliferation compared with controls, and changes in ISC number and proliferation were dependent on the presence of host serotonin. Furthermore, Western blotting demonstrated that AIMD reduced epithelial SERT protein expression compared with controls. In conclusion, host serotonin activity is necessary for microbial depletion-associated changes in villus height and ISC proliferation in crypts, and microbial depletion produces a functional serotonin-potentiated state through reduced SERT protein expression. These findings provide an understanding of how changes to the microbiome contribute to intestinal pathology and can be applied therapeutically.NEW & NOTEWORTHY Antibiotic-induced microbial depletion of the murine small intestine results in a state of potentiated serotonin activity through reduced epithelial expression of the serotonin transporter. Specifically, serotonin-dependent mechanisms lead to increased intestinal surface area and intestinal stem cell proliferation. Furthermore, the absence of endogenous serotonin leads to blunting of small intestinal villi, suggesting that serotonin signaling is required for epithelial homeostasis.


Pegylated interferon and ribavirin therapy for chronic hepatitis C virus genotype 4 infection.
Hepatitis C Virus (HCV) is classified into six genotypes. Genotype 4 is now spreading in Europe, especially among drug users, who are often infected with both HCV and the human immunodeficiency virus (HIV). Previous studies have shown that HCV-4 responds poorly to interferon. Pegylated interferon (peg-IFN) associated with ribavirin is now the most effective treatment for eradicating the virus. We have now studied the response of HCV-4 to peg-IFN and ribavirin and investigated the influence of HIV infection on anti-HCV therapy. Twenty-eight patients infected with HCV-4 were given peg-IFN plus ribavirin for 48 weeks. Patients infected with HCV alone tended to have a better initial response (66%) than patients infected with both HCV and HIV (30%, P = 0.06) and eradication was better (50%) than in doubly infected patients (15%, P = 0.06). After controlling for major factors influencing virus response, the virus response 12 weeks after the beginning of treatment in patients infected with HCV-4 (50%) was similar to that of patients infected with genotype 1 (53%) and lower than that of patients infected with genotypes 2 or 3 (82%, P < 0.05). The response 24 weeks after the end of therapy in patients infected with HCV-4 (32%) was similar to that of patients infected with HCV-1 (28%) and lower than that of patients with HCV-2 or HCV-3 (62% P < 0.05). These results indicate that HCV-4 patients should be considered to be difficult-to-treat.


Unilateral Diaphragmatic Paralysis After Stereotactic Ablative Radiation Therapy to a Lung Tumor Abutting the Course of the Phrenic Nerve.
We present the case of a woman with metastatic adenoid cystic carcinoma who received stereotactic ablative radiation therapy with a total dose of 50 Gy in 4 fractions to 2 lung metastases and developed symptomatic left phrenic nerve injury 2 years after radiation. The maximum dose to the approximate location of the phrenic nerve was 57.7 Gy, which corresponds to a biologically effective dose for late effects (using α/β ratio = 3) of 335.14 Gy. Here, we discuss the case, planning considerations by radiation oncologists and medical physicists, and the multidisciplinary medical management of this patient.


Mutations in 3β-hydroxysteroid-δ8, δ7-isomerase paradoxically benefit epidermal permeability barrier homeostasis in mice.
Inherited or acquired blockade of distal steps in the cholesterol synthetic pathway results in ichthyosis, due to reduced cholesterol production and/or the accumulation of toxic metabolic precursors, while inhibition of epidermal cholesterol synthesis compromises epidermal permeability barrier homeostasis. We showed here that 3β-hydroxysteroid-δ8, δ7-isomerase-deficient mice (TD), an analog for CHILD syndrome in humans, exhibited not only lower basal transepidermal water loss rates, but also accelerated permeability barrier recovery despite the lower expression levels of mRNA for epidermal differentiation marker-related proteins and lipid synthetic enzymes. Moreover, TD mice displayed low skin surface pH, paralleled by increased expression levels of mRNA for sodium/hydrogen exchanger 1 (NHE1) and increased antimicrobial peptide expression, compared with wild-type (WT) mice, which may compensate for the decreased differentiation and lipid synthesis. Additionally, in comparison with WT controls, TD mice showed a significant reduction in ear thickness following challenges with either phorbol ester or oxazolone. However, TD mice exhibited growth retardation. Together, these results demonstrate that 3β-hydroxysteroid-δ8, δ7-isomerase deficiency does not compromise epidermal permeability barrier in mice, suggesting that alterations in epidermal function depend on which step of the cholesterol synthetic pathway is interrupted. But whether these findings in mice could be mirrored in humans remains to be determined.


Alpha-sarcin impairs the N-glycosidase activity of ricin on ribosomes.
In a recently described method the RNA N-glycosidase activity of ricin is measured by h.p.l.c. determination of the adenine released from ribosomes after conversion of the base into its fluorescent 1-N6-etheno derivative [Zamboni et al. (1989) Biochem. J., 259, in press]. Unlike previously available methods, based on the separation of RNA fragments by gel electrophoresis, the new method allows one to investigate the activity of ricin on ribosomes pretreated with alpha-sarcin, a cytotoxin which cleaves 28S rRNA at one nucleotide distance from the site of attack of ricin. alpha-Sarcin makes ribosomes a poor substrate for ricin, the release of adenine requiring concentrations of ricin 50-times higher than those effective on untreated ribosomes.


Could the use of a new novel bipolar radiofrequency device (Aerin) improve nasal valve collapse? A systematic review and meta-analysis.
Surgical treatment for nasal obstruction caused by nasal valve collapse requires a significant recovery period and risks of complications, while nasal dilators are uncomfortable. Recently, radiofrequency treatment of lateral walls has been used under local anesthesia as an office base surgery. This work aims to assess the efficacy of a new radiofrequency device, the Vivaer™ System (Aerin Medical, Sunnyvale, CA), to treat nasal obstruction through a systematic review and meta-analysis. Two researchers independently reviewed the literature up to December 2021. Studies on patients seeking treatment for nasal obstruction due to nasal valve collapse were included in the analysis. Four studies (218 patients) met the inclusion criteria and treated the nasal valve regions bilaterally with the Aerin Medical Vivaer™ System. After the treatment, the NOSE score was reduced at three months postoperatively. Minor adverse events were reported in the included studies, and two showed no complications. None of the studies reported changes in the external appearance of the nose. The radiofrequency treatment using the Vivaer device can be useful for treating nasal valve collapse, improving significantly subjective breathing symptom scores. Further studies on a large scale are needed to confirm these results.


Biophysical characterization and in vitro imaging of carbonized MOFs.
Nanoparticles have been widely used in biological imaging and treatments of various diseases, especially for studies of tumors, due to their high efficiency in drug delivery and many other functions. Metal-organic frameworks have been an important research area in recent years because of advantages such as large apertures, adjustable structural compositions, adjustable sizes, multifunctionality, high drug loading, good biocompatibility and so on, and they show promise as multifunctional drug carriers. In this study, a carbonized MOF with photothermal therapeutic potential and dual-mode imaging capability was prepared. The biophysical properties of MIL-100 and C-MIL nanoparticles were determined, such as particle size, zeta potential and saturation magnetization strength. CCK-8 cell assays and mouse HE sections confirmed that C-MIL nanoparticles have good in vitro and in vivo biocompatibility. The solution temperature of C-MIL nanoparticles reached 58.1 °C during sustained laser irradiation at 808 nm, which confirmed the photothermal potential of the nanoparticles. Moreover, in biological imaging, C-MIL nanoparticles showed the ability to support in vitro nuclear magnetic and photoacoustic dual-mode imaging. C-MIL nanoparticles provide new options for tumor therapy, drug delivery and biological imaging.


The apical conjugate efflux pump ABCC2 (MRP2).
ABCC2 is a member of the multidrug resistance protein subfamily localized exclusively to the apical membrane domain of polarized cells, such as hepatocytes, renal proximal tubule epithelia, and intestinal epithelia. This localization supports the function of ABCC2 in the terminal excretion and detoxification of endogenous and xenobiotic organic anions, particularly in the unidirectional efflux of substances conjugated with glutathione, glucuronate, or sulfate, as exemplified by leukotriene C(4), bilirubin glucuronosides, and some steroid sulfates. The hepatic ABCC2 pump contributes to the driving forces of bile flow. Acquired or hereditary deficiency of ABCC2, the latter known as Dubin-Johnson syndrome in humans, causes an increased concentration of bilirubin glucuronosides in blood because of their efflux from hepatocytes via the basolateral ABCC3, which compensates for the deficiency in ABCC2-mediated apical efflux. In this article we provide an overview on the molecular characteristics of ABCC2 and its expression in various tissues and species. We discuss the transcriptional and posttranscriptional regulation of ABCC2 and review approaches to the functional analysis providing information on its substrate specificity. A comprehensive list of sequence variants in the human ABCC2 gene summarizes predicted and proven functional consequences, including variants leading to Dubin-Johnson syndrome.


Propofol-ketamine technique.
Case reports are presented demonstrating a new, safe, and simple intravenous technique for outpatient anesthesia. Vinnik's technique requires hypnotic doses of diazepam (Valium) to prevent ketamine-induced hallucinations. The initial hypothesis tested in this clinical series was whether hypnotic doses of propofol would prevent hallucinations from ketamine as satisfactorily as diazepam. Once the initial hypothesis was confirmed, consideration was given to moderating the cost of propofol by determining the effect of two levels of midazolam premedication on propofol requirements. Hypnotic doses of propofol do prevent ketamine-induced hallucinations. It is possible to achieve significant propofol savings by premedication with midazolam without compromising patient readiness for discharge by the end of the first postoperative hour.


Quality of life and side effects in patients with actinic keratosis treated with ingenol mebutate: a pilot study.
Actinic keratosis (AK) lesions are in situ squamous cell carcinoma. These lesions have a low risk of progressing to invasive disease but significant impact on patients' quality of life (QoL). The aim of this study was to assess QoL and side effects in patients with AK receiving treatment with ingenol mebutate. This was a prospective, non-randomized pilot study carried out in Spain. The target population was adults with a clinical diagnosis of AK affecting any part of the body. Outcomes were assessed on the basis of a QoL questionnaire (Skindex-29), local skin response, the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4), and clinical response. A total of 19 patients were studied. Most of the participants were men (89.5%) and mean age was 76.2 years. After treatment with ingenol mebutate, significant improvement was observed in the Skindex-29 subscales relating to symptom severity (P=.041), the patients' emotional state (P=.026), and in the overall score (P=.014). Erythema, crusting, and flaking or scaling were the local skin responses with highest median score (2.0 in all 3 cases). Imiquimod 5% and ingenol mebutate achieved higher median scores for effectiveness and global satisfaction than any other previous treatments (as measured by TSQM 1.4). In the patients' assessment of convenience, ingenol mebutate had a higher median score than previous treatments. Over half of the patients (52.6%) had an improvement of at least 75% at month 3. QoL in patients with AK improves after treatment with ingenol mebutate. The presence of side effects did not affect QoL or patient satisfaction with treatment.


Thrombocytosis associated with a myeloproliferative disorder in a dog.
A dog with a myeloproliferative disorder and thrombocytosis had clinical signs that were consistent with a diagnosis of essential thrombocythemia. The dog was treated with aspirin, radioactive phosphorus, and melphalan. Eighteen months after referral, the disorder progressed to chronic granulocytic leukemia, and treatment was switched to hydroxyurea. Fourteen months later, the dog was euthanatized because of uncontrollable atrial fibrillation.


Growth-related changes in non-essential and essential metals in the liver of star-spotted smooth-hounds (dogfish) Mustelus manazo from the northern region of Japan.
We analyzed Cd, Hg, Zn, Cu, Mn and Fe concentrations in liver samples from male and female star-spotted smooth-hounds at various life stages. Male sharks of this species are known to reach their maximum body length (BL) more quickly than females, while females are known to mature later and live longer than males. Hepatic Cd and Hg concentrations in males and females markedly increased after maturation, but these increases proceeded earlier in males than in females. Hepatic Zn and Cu concentrations decreased during the growth stage of males and females, and thereafter increased concomitantly with increases of Cd and Hg burdens, forming a U-shaped curve over their lifespan, and the BL at which the lowest concentrations of Zn and Cu were observed was smaller in males than in females. These gender-related differences in those metals could reflect the faster growth and earlier cessation of growth in males.


Identification and partial characterization of the unglycosylated peptide of carcinoembryonic antigen synthesized by human tumor cell lines in the presence of tunicamycin.
Unglycosylated peptide backbones of carcinoembryonic antigen (CEA) synthesized by human tumor cell lines in the presence of tunicamycin were identified and analyzed by SDS-polyacrylamide gel electrophoresis. Three tumor cell lines, QGP-1 (pancreas), FCC-1 (colon) and KNS-62 (lung) were found to produce CEA molecules of 180,000-190,000 mol. wts labeled with both [3H]leucine and [14C]glucosamine under conventional culture conditions. In contrast, in the presence of tunicamycin, the native CEA molecules disappeared, and a new component that was precipitated with anti-CEA antibodies and labeled only with [3H]leucine but not with [14C]glucosamine was identified in each cell line. Monoclonal antibodies each directed to different major antigenic determinants on the native CEA molecules also reacted with this unglycosylated peptide. The apparent mol. wts of the naked CEA peptides from QGP-1 and FCC-1 were equally about 78,000, whereas that from KNS-62 was somewhat larger than the other two, suggesting some differences in the peptide structure of the CEA molecules.


Pharmacokinetic investigation on a novel antitumour platinum compound in rabbit plasma by inductively coupled plasma mass spectrometry after intravenous administration.
The purpose of this study was to investigate a novel platinum anticancer compound named as SM54111 [cis-3, 5-diisopropylsalylic cyclohexanodiaminoplatinum (II)], which is under development as a new drug candidate, on its pharmacokinetics in plasma after intravenous administration to rabbits at concentration of 2.5, 5.0, and 9.0 mg/kg. The concentration of SM54111 in plasma expressed as Pt was determined utilizing ICP-MS method, and the method was thoroughly validated. The data were analyzed with 3P97 pharmacokinetic software to find the parameters. The results showed that the linear range lay at the 1 approximately 1000 ng/mL level, and the LOD and LOQ were 0.4 ng/mL and 1 ng/mL, respectively. It proved that this new drug candidate underwent disposition in rabbit plasma by a two-compartment open model at the three doses above, and the main pharmacokinetic parameters were obtained as the initial concentrations of three doses (C(0)) were 8.68 +/- 0.80, 20.04 +/- 1.92, and 28.88 +/- 2.32 mg/L, respectively; the areas under concentration-time profile from time 0 to 72 h (AUC(0 approximately t)) were 90.0 +/- 13.0, 251.3 +/- 45.3, and 396.9 +/- 61.1 mg*h/L, respectively; the terminal elimination half-life times (t(1/2beta)) 29.1 +/- 4.8, 35.2 +/- 7.5, and 29.4 +/- 2.8 h, respectively; and the total clearances (CL(tot)) were 0.026 +/- 0.004, 0.019 +/- 0.002, and 0.022 +/- 0.004 L/h, respectively. First order rate pharmacokinetics were observed for SM54111 with the doses used, and it showed a long retention and slow elimination in vivo, There showed no prolongation of the t(1/2beta) with larger dose, and the CLs of the three doses were proximate. It is reasonable to surmise that SM54111 follows first order rate pharmacokinetics, and no saturation was detected at concentrations from 2.5 to 9.0 mg/kg. This result suggested that SM54111 experienced an amiable procedure in vivo and was worthy of the further development.


Conductive hearing loss after removal of acoustic neuroma.
To report 4 patients who have developed a conductive and/or mixed hearing loss due to dehiscence of the inner ear after retrosigmoid approach for removal of acoustic neuroma. Four patients who presented with conductive and/or mixed hearing loss after retrosigmoid approach for removal of acoustic neuroma. Evidence of inner ear dehiscence on postoperative computed tomographic scan of the temporal bones. The occurrence of conductive hearing loss after the surgical removal of an acoustic neuroma has not previously been documented. Computed tomographic scan of the temporal bones showing inner ear dehiscence may explain this finding. Formal documentation of such cases may allow techniques to be developed to reduce its occurrence or reconstruction of the defect at the time of primary surgery.


Oxidative derivatization of V-type nerve agents as a tool for their structural elucidation by liquid chromatography/tandem mass spectrometry.
The identification of V-type nerve agents poses an analytical challenge. Their spectra obtained by electron ionization mass spectrometry (EI-MS) and electrospray ionization tandem mass spectrometry (ESI-MS/MS) are dominated by ions originating from the N,N-dialkylaminoethyl moiety, while ions representative of the alkyl phosphonothiolate part are absent from the spectra or present at negligible abundance. Hence, analogs or isomers with the same amine residue exhibit similar mass spectral patterns, leading to unavoidable ambiguity in their identification. Chemical derivatization was utilized for the structural elucidation of a series of five V-type nerve agents, including O-ethyl S-(2-diisopropylamino)ethyl methylalkyl phosphonothiolate (VX), O-isobutyl S-(2-diethylamino)ethyl methylalkyl phosphonothiolate (RVX) and O-ethyl S-(2-diethylamino)ethyl methylalkyl phosphonothiolate (VM). The procedure consisted of "in-vial" oxidation of the tertiary amine group with 3-chloroperbenzoic acid (m-CPBA) at ambient temperature followed by liquid chromatography (LC)/Orbitrap-ESI-MS/MS analysis with no other sample preparation. The generated N-oxide of the V-type nerve agents altered the charge distribution occurring during fragmentation and produced informative ESI-MS/MS spectra characteristic of the alkyl phosphonothiolate structure, enabling a higher degree of certainty in their identification. Moreover, two VX isomers possessing an identical tertiary amine moiety that coeluted at practically the same retention time and displayed high mass spectral similarity were easily differentiated, and their structures elucidated once derivatized. In contrast to the ESI-MS/MS spectra of the V-type nerve agents, which exhibited mostly/only information on the amine-containing residue, the ESI-MS/MS spectra of the V-type nerve agent N-oxides revealed ions indicative of both the alkyl phosphonothiolate and the amine parts, enabling their reliable structural elucidation.


Nucleophilic addition of carborane anion to Ir, Rh-coordinated Cp* ring: C-C bond formation accompanied by reduction of metal center.
Reaction of carboranyl anion or its thiolate derivative with a fully-substituted Cp*-based group 9 (Ir, Rh) metal complex affords respectively a C-C bond formation complex and a salt metathesis product. This example represents the first nucleophilic addition attempt in the area of M-Cp* chemistry.


A prospective comparison of perioperative morbidity in advanced epithelial ovarian cancer: Primary versus interval cytoreduction - experience from India.
The objective was to compare perioperative morbidity and mortality of patients with advanced epithelial ovarian cancer (EOC) treated with either of the two treatment approaches; neoadjuvant chemotherapy (NACT) followed by interval debulking versus upfront surgery. Prospective comparative observational study. In total, 51 patients were included in the study. All patients with diagnosed advanced EOC (International Federation of Gynecology and Obstetrics IIIC and IV) presenting for the 1(st) time were included in the study. Patients were either operated upfront (n = 19) if deemed operable or were subjected to NACT followed by interval debulking (n = 32). Intra- and postoperative morbidity and mortality were the primary outcome measures. Patients with interval cytoreduction were noted to have significantly lesser operative time, blood loss, and extent of surgery. Their discharge time was also significantly earlier. However, they did not differ from the other group vis. a vis. postoperative complications or mortality. Neoadjuvant chemotherapy although has a positive impact on various intraoperative adverse events, fails to show any impact on immediate postoperative negative outcomes.


Prevalence of proximal adenomas after an adenoma is found on flexible sigmoidoscopy.
Adenomatous polyps are a precursor of colorectal cancer and a frequent finding on screening flexible sigmoidoscopy (FS). Performance of colonoscopy when a diminutive (<6mm) adenoma is found on FS has been the subject of considerable debate. We retrospectively reviewed the data from our colorectal cancer screening program for patients with adenoma(s) found on FS. Patients were divided into three groups based on FS findings: (1) an adenoma <6mm in size, (2) multiple non-advanced adenomas or an adenoma 6-10mm in size, or (3) advanced adenoma defined as an adenoma >10mm or with villous histology or high-grade dysplasia or cancer. A comparison of the proximal findings was then made. 5291 FS reports were reviewed with 606 (12%) patients having at least one adenoma. Colonoscopy reports were available in 550 patients. Of the 258 patients with a diminutive distal adenoma, 69 (27%) had a proximal adenoma and 13 (5%) had an advanced proximal adenoma on colonoscopy. Of the 164 patients with an adenoma 6-10mm or multiple non-advanced adenomas, 59 (36%) had a proximal adenoma and 13 (8%) had an advanced proximal adenoma. Of the 128 patients with a distal advanced adenoma, 58 (45%) had a proximal adenoma and 15 (12%) had an advanced proximal adenoma. The increase in proximal adenomas across the three groups was significant (P=0.001), and there was a trend for increased prevalence of advanced adenomas (P=0.061). The prevalence of proximal adenomas increased significantly with more advanced lesions found distally at FS, and there was a trend towards a higher prevalence of advanced proximal adenomas. Based on current guidelines, flexible sigmoidoscopy is a screening option that can be used to identify average-risk patients at increased risk of proximal neoplasia.


Calibration of bone mineral and heavy metal measurements using doped wall-less gel phantoms of arbitrary form.
Cylindrical gel phantoms of 2% agarose concentration were used as wall-less phantoms of arbitrary shape for calibration purposes in non-destructive measurements of bone mineral and heavy metal concentration using XRF. The counts of the coherently and incoherently scattered photons with no sample present should be subtracted as "background" to get a linear relationship between the ratio of the coherently and incoherently scattered photons and the bone mineral concentration for phantoms of arbitrary diameters.


Inhibition of cell spreading in CHO cells transfected with cDNA of a glycosylphosphatidyl inositol-anchored protein, GPI-80.
We have previously cloned a glycosylphosphatidyl inositol (GPI)-anchored protein, designated GPI-80 that associated with integrin and may modulate leukocyte adherence and migration. Recent studies have shown that GPI-80 belongs to a Vanin family that is related to pantetheinase, but the regulatory function of GPI-80 in cell adherence is still unclear. To clarify the possible functions of GPI-80, we transfected GPI-80 cDNA into Chinese hamster ovary (CHO) cells and observed adherence and morphological changes. Adherence of GPI-80 transfectants was significantly decreased when signal strength for the cell adhesion is weak, and the cell spreading of the transfectants was strongly inhibited. This inhibitory effect of GPI-80 expression was largely canceled by GPI-80 shedding with phosphatidy-linositol-specific phospholipase C. Interestingly, spreading of GPI-80 transfectants was temporarily recovered from the round shape but not maintained by stimulation with known activators of beta1 integrins, phorbol myristate acetate and manganese ions. Taken together, these results suggest that the expression of GPI-80 on CHO cells can influence cell spreading in weak adhesive signal conditions via extracellular matrix molecules.


Prolonged unloading in growing rats reduces cortical osteocyte lacunar density and volume in the distal tibia.
Bone dynamically adapts its structure to the environmental demands placed upon it. Load-related stimuli play an important role in this adaptation. It has been postulated that osteocytes sense changes in these stimuli and initiate adaptive responses, across a number of scales, through a process known as mechanotransduction. While much research has focused on gross and tissue-level adaptation, relatively little is known regarding the relation between cellular-level features (e.g. osteocyte lacunar density, volume and shape) and loading. The increasing availability of high resolution 3D imaging modalities, including synchrotron-based techniques, has made studying 3D cellular-level features feasible on a scale not previously possible. The primary objective of this study was to test the hypothesis that unloading (sciatic neurectomy) during growth results in altered osteocyte lacunar density in the tibial diaphysis of the rat. Secondarily, we explored a potential effect of unloading on mean lacunar volume. Lacunar density was significantly (p<0.05) lower in immobilized bones (49,642 ± 11,955 lacunae per mm(3); n=6) than in control bones (63,138 ± 1956 lacunae per mm(3); n=6). Mean lacunar volume for immobilized bones (209 ± 72 μm(3); n=6) was significantly smaller (p<0.05) than that for the control bones (284 ± 28 μm(3); n=6). Our results demonstrate that extreme differences in loading conditions, such as those created by paralysis, do indeed result in changes in osteocyte lacunar density and volume. Further investigation is warranted to examine relations between these measures and more subtle variation in loading as well as pathological states, which have been linked to alterations in mechanotransduction.


Usefulness of taping in lower limb osteoarthritis. French clinical practice guidelines.
To develop clinical practice guidelines about the use of taping in the management of lower limb osteoarthritis. We used the methodology advocated by the SOFMER (French Society for Physical and Rehabilitation Medicine), which combines a literature review, collection of data on current practice patterns, and validation of the recommendations by a multidisciplinary panel of experts. Our evaluation focused on the effectiveness of taping in relieving symptoms of lower limb osteoarthritis. Ankle taping for osteoarthritis is not recommended, given the absence of published data and very low level of use in France. Few studies are available on knee taping for osteoarthritis. Published studies exhibit a number of methodological weaknesses. There is no strong evidence that taping is effective in knee osteoarthritis, and this treatment modality is rarely used in France. Therefore, there is no strong basis at present for recommending taping as part of the management of knee osteoarthritis. Well-designed studies of patellar taping to modify the relationships between the patellar and the trochlea are desirable to determine whether this treatment modality benefits patients with knee osteoarthritis, most notably those with involvement of the femoropatellar compartment.


[Paralysis of the intrinsic muscles of the hand].
Intrinsic muscles of the fingers are the interosseous, lumbricals and hypothenar muscles. Their main action is metacarpophalangeal (MP) flexion and interphalangeal (IP) extension. If extrinsic muscles remain active, intrinsic paralysis results in a claw deformity: MP hyperextension and IP flexion. Bouvier's test is positive if IP extension is actively possible when MP hyperextension is passively prevented. Surgical operations to correct claw deformity are divided into passive and active palliative procedures. Passive palliative procedures are tenodeses and capsuloplasties. Active palliative procedures have either a proximal action (MP flexion only): lasso and direct interosseous activation, or a distal action (MP flexion and IP extension). When Bouvier's maneuver is positive, a simple claw deformity may be treated by a passive procedure and/or an active palliative with proximal action procedure. This last procedure should be preferably indicated on index and middle finger if a few muscular motors are available. When claw deformity is complicated by MP stiffness in extension, a capsulectomy-capsuloplasty is indicated. When Bouvier's test is negative, and passive IP extension is possible, an active palliative with distal action procedure is indicated. Even when there is no claw deformity, intrinsic paralysis may be treated by an active palliative with proximal action procedure, in order to stabilize pinch and grasp. Capsuloplasties, lassos and interosseous activation procedures were all invented by Eduardo Zancolli.


Severe food-allergic reactions in children across the UK and Ireland, 1998-2000.
Medical and lay concerns about food allergy are increasing. Whilst food allergy may be becoming more common, fatal reactions to food in childhood are very rare and their rate is not changing. We sought to establish how common severe reactions are. Prospective survey, 1998 to 2000, of hospital admissions for food-allergic reactions-conducted primarily through the British Paediatric Surveillance Unit, covering the 13 million children in the United Kingdom and Ireland. 229 cases reported by 176 physicians in 133 departments, yielding a rate of 0.89 hospital admissions per 100,000 children per year. Sixty-five per cent were male, 41% were under 4 y and 60% started at home. Main allergens were peanut (21%), tree nuts (16%), cow's milk (10%) and egg (7%). Main symptoms were facial swelling (76%), urticaria (69%), respiratory (66%), shock (13%), gastrointestinal (4%). Fifty-eight cases were severe. Three were fatal, six near fatal, and 8 of these 9 had asthma with wheeze being the life-threatening symptom. Three near-fatal cases received excess intravenous epinephrine. None of the non-fatal reactions resulted in mental or physical impairment. Seven of 171 non-severe and 6/58 severe cases might have had a worse outcome if epinephrine auto-injectors had been unavailable. Six of the severe cases might have benefited if auto-injectors had been more widely prescribed. In the United Kingdom and Ireland, the incidence of severe reactions is low. The study highlights that: asthma is a strongly significant risk factor for a severe reaction and therefore warrants optimal management; severe wheeze is a prominent feature of severe reactions and warrants optimal management; intravenous epinephrine should be used with great care if needed. Epinephrine auto-injectors do not always prevent death, but our study design and data do not allow a definite statement about whether overall they are beneficial.


Financial Management Skills in Aging, MCI and Dementia: Cross Sectional Relationship to 18F-Florbetapir PET Cortical β-amyloid Deposition.
There is a need to more fully characterize financial capacity losses in the preclinical and prodromal stages of Alzheimer's disease (AD) and their pathological substrates. To test the association between financial skills and cortical β-amyloid deposition in aging and subjects at risk for AD. Cross-sectional analyses of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI-3) study conducted across 50 plus sites in the US and Canada. Multicenter biomarker study. 243 subjects (144 cognitively normal, 79 mild cognitive impairment [MCI], 20 mild AD). 18F-Florbetapir brain PET scans to measure global cortical β-amyloid deposition (SUVr) and the Financial Capacity Instrument Short Form (FCI-SF) to evaluate an individual's financial skills in monetary calculation, financial concepts, checkbook/register usage, and bank statement usage. There are five sub scores and a total score (range of 0-74) with higher scores indicating better financial skill. FCI-SF total score was significantly worse in MCI [Cohen's d= 0.9 (95%CI: 0.6-1.2)] and AD subjects [Cohen's d=3.1(CI: 2.5-3.7)] compared to normals. Domain scores and completion times also showed significant difference. Across all subjects, higher cortical β-amyloid SUVr was significantly associated with worse FCI-SF total score after co-varying for age, education, and cognitive score [Cohen's f2=0.751(CI: 0.5-1.1)]. In cognitively normal subjects, after covarying for age, gender, and education, higher β -amyloid PET SUVr was associated with longer task completion time [Cohen's f2=0.198(CI: 0.06-0.37)]. Using a multicenter study sample, we document that financial capacity is impaired in the prodromal and mild stages of AD and that such impairments are, in part, associated with the extent of cortical β-amyloid deposition. In normal aging, β-amyloid deposition is associated with slowing of financial tasks. These data confirm and extend prior research highlighting the utility of financial capacity assessments in at risk samples.


An independent inter- and intra-observer agreement assessment of the AOSpine upper cervical injury classification system.
The complex anatomy of the upper cervical spine resulted in numerous separate classification systems of upper cervical spine trauma. The AOSpine upper cervical classification system (UCCS) was recently described; however, an independent agreement assessment has not been performed. To perform an independent evaluation of the AOSpine UCCS. Agreement study. Eighty-four patients with upper cervical spine injuries. Inter-observer agreement; intra-observer agreement. Complete imaging studies of 84 patients with upper cervical spine injuries, including all morphological types of injuries defined by the AOSpine UCCS were selected and classified by six evaluators (from three different countries). The 84 cases were presented to the same raters randomly after a 4-week interval for repeat evaluation. The Kappa coefficient (κ) was used to determine inter- and intra-observer agreement. The interobserver agreement was almost perfect when considering the fracture site (I, II or III), with κ=0.82 (0.78-0.83), but the agreement according to the site and type level was moderate, κ=0.57 (0.55-0.65). The intra-observer agreement was almost perfect considering the injury, with κ=0.83 (0.78-0.86), while according to site and type was substantial, κ=0.69 (0.67-0.71). We observed only a moderate inter-observer agreement using this classification. We believe our results can be explained because this classification attempted to organize many different injury types into a single scheme.


Chromatin-associated protein phosphokinases of rat ventral prostate. Characteristics and effects of androgenic status.
Protein phosphokinase activity endogenous to rat ventral prostate chromatin was assayed by using edphosphophosvitin as an exogenous substrate. For maximal activity of the kinase reaction, the presence of 200 mM NaCl, 5 mM MgCl2, and 1 mM dithiothreitol was essential. Two apparent pH optima were observed, a broad one between pH 7 and 7.4, and one at pH 7.89. At pH 7.4 the apparent Km for 31% dephosphophosvitin was 0.3 mg per ml. With respect to ATP, two apparent Km values (0.04 and 0.41 mM) were found. The kinase activity was minimal toward exogenous histones when used as substrates (3% for lysine-rich and 0.3% for arginine-rich (f3) histones, compared with dephosphophosvitin controls). The protein phosphokinases were not significantly stimulated by cyclic adenosine 3':5'-monophosphate (cyclic AMP) when histones used as substrate. With dephosphophosvitin as substrate, cyclic AMP produced a small inhibition (5 to 15%). Orchiectomy of adult rats resulted in a rapid decline in the chromatin-associated protein phosphokinase activity assayed using optimal experimental condition described above. At 9 hours postorchiectomy, a 30% decline in the activity was observed; this was further reduced to about 50% of the control by 18 hours. This decrease in the kinase activity (e.g. at 9 hours postorchiectomy) appears to precede measurable changes in the protein and RNA complements of chromatin. Testosterone replacement following orchiectomy abolished this decline in the chromatin-associated activity. The chromatin-associated protein phosphokinase activity toward lysine-rich and arginine-rich histones was also sensitive to androgenic status of the animals and declined rapidly postorchiectomy. The results suggest the presence of multiple and androgen-sensitive protien phosphokinases associated with rat ventral prostate chromatin, which may modulate the phosphorylation of nuclear nonhistone phosphoproteins with changing gene action mediated by testosterone in this target tissue.


Polyclonal antibodies to elliptinium acetate: structure-activity relationships and comparison with human anti-elliptinium IgM.
In order to elucidate the immune-mediated hemolytic disease induced in man by elliptinium acetate, a quaternary ammonium compound with antineoplastic activity, polyclonal antibodies directed against this hapten were raised in rabbits. The coupling step between drug and carrier was performed according to a putative human in vivo hapten conjugation mechanism. Structure-activity relationships of the resulting IgG were compared with the epitope site recognized by human anti-elliptinium IgM by using a panel of twelve elliptinium acetate analogues. Although both antibodies were directed principally against the quaternary ammonium ion, a poor correlation between the cross-reactivity indices was obtained. In fact, it appeared that both antibodies recognized specifically the ammonium group plus different regions of the molecule: the indole ring for human antibodies, the N-alkyl group and its vicinity for rabbit ones. The specificity of the obtained rabbit polyclonal antisera is discussed, with regard to the conjugation mechanism of the drug occurring in man.


Untangling the Mechanochromic Properties of Benzothiadiazole-Based Luminescent Polymorphs through Supramolecular Organic Framework Topology.
Two new luminophore polymorphs of 4-bromo-7-(4-nonylphenyl)benzo[c][1,2,5]thiadiazole (1α and 1β) exhibiting different color emissions, which switch into each other in response to shear force and solvent vapors, are presented and their X-ray structure is determined. Supramolecular organic framework topology (SOFT) studies on the two polymorphic structures led us to conclude that the mechanochromic phase transformation can be explained on the basis of modifications in their respective topological nets: mab and pcu for 1α and 1β, respectively, as a result of the breaking and restoration of a number of weak supramolecular interactions. The color changes accompanying this transformation have been rationalized with the help of time-dependent density functional theory. We firmly believe that our findings will inspire future research on the design of novel stimuli-responsive organic materials with switchable properties based on their supramolecular interactions by establishing clear SOFT-property relationships.


Productivity Loss of Temporary Work Absenteeism Due to COVID-19 and Its Determinant Factors in Northeastern Iran.
This study aimed to estimate the lost productivity cost of temporary work absenteeism due to COVID-19. This study conducted on all hospitalized patients with COVID-19 in northeastern Iran between February 2020 and March 2022 (10,406 cases). Data were collected from the Hospital Information System. Indirect costs were estimated using the human capital approach. Data were analyzed with the STATA version 17. The total indirect cost of work absenteeism due to COVID-19 was estimated at $513,688. There was a statistically significant relationship between the mean lost productivity cost and COVID-19 peak, sex, insurance type, age, and hospitalization. Because the absenteeism costs of COVID-19 had increased in the second peak, which coincided with the summer holidays, the country's crisis management headquarters should pay more attention to formulating and implementing appropriate preventive programs in future epidemics.


Infrared ion spectroscopy: New opportunities for small-molecule identification in mass spectrometry - A tutorial perspective.
Combining the individual analytical strengths of mass spectrometry and infrared spectroscopy, infrared ion spectroscopy is increasingly recognized as a powerful tool for small-molecule identification in a wide range of analytical applications. Mass spectrometry is itself a leading analytical technique for small-molecule identification on the merit of its outstanding sensitivity, selectivity and versatility. The foremost shortcoming of the technique, however, is its limited ability to directly probe molecular structure, especially when contrasted against spectroscopic techniques. In infrared ion spectroscopy, infrared vibrational spectra are recorded for mass-isolated ions and provide a signature that can be matched to reference spectra, either measured from standards or predicted using quantum-chemical calculations. Here we present an overview of the potential for this technique to develop into a versatile analytical method for identifying molecular structures in mass spectrometry-based analytical workflows. In this tutorial perspective, we introduce the reader to the technique of infrared ion spectroscopy and highlight a selection of recent experimental advances and applications in current analytical challenges, in particular in the field of untargeted metabolomics. We report on the coupling of infrared ion spectroscopy with liquid chromatography and present experiments that serve as proof-of-principle examples of strategies to address outstanding challenges.


Design and Development of an Electrostatic Screen Battery for Emission Control (ESBEC).
Current diesel particulate filters (DPFs) can effectively capture the exhaust particles, but they add to engine backpressure and accumulate particles during their operation, which results in the need to regenerate the DPFs by burning off the collected particles periodically. This regeneration results in aerosol emissions, especially in the 10-30 nanometer size range and contributes to ultrafine particle pollution. In this research, we designed and developed a prototype of a novel diesel exhaust control device: the Electrostatic Screen Battery for Emissions Control (ESBEC). The device features high particle collection efficiency without adding to the exhaust backpressure and without the need for thermal regeneration of the collected particles. The ESBEC consists of a series of metal mesh screens coated with a superhydrophobic substance and an integrated carbon fiber ionizer to charge the incoming particles. Multiple pairs of screens (e.g., 5 pairs) are arranged in a battery, in which one screen of each pair is supplied with high voltage, and the other is grounded, producing electrostatic field produced across the screens. The application of a superhydrophobic coating onto the screens allows easy removal of the collected particles using liquid without the need for thermal regeneration. The current prototypes of the device were tested with fluorescent polystyrene latex (PSL) particles of 0.2 and 1.2 μm in size and at 25 and 105 L/min sampling flow rates. The average collection efficiency was ~87% for 0.2 μm and ~95% for 1.2 μm PSL particles. In addition, the ESBEC was tested with actual diesel exhaust particles; here its performance was verified by visually inspecting deposition of particles on an after-filter with the device ON and OFF. In the next stages of this work, the ESBEC will be challenged with diesel exhaust at different mass concentrations and for different collection time periods.


Reflections on Rodent Implantation.
Embryo implantation is a complex process involving endocrine, paracrine, autocrine, and juxtacrine modulators that span cell-cell and cell-matrix interactions. The quality of implantation is predictive for pregnancy success. Earlier observational studies formed the basis for genetic and molecular approaches that ensued with emerging technological advances. However, the precise sequence and details of the molecular interactions involved have yet to be defined. This review reflects briefly on aspects of our current understanding of rodent implantation as a tribute to Roger Short's lifelong contributions to the field of reproductive physiology.


High-dose phenobarbital with intermittent short-acting barbiturates for acute encephalitis with refractory, repetitive partial seizures.
Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is characterized by repetitive seizures during the acute and chronic phases and has a poor neurological outcome. Burst-suppression coma via continuous i.v. infusion of a short-acting barbiturate is used to terminate refractory seizures, but the severe side-effects of short-acting barbiturates are problematic. We report on a 9-year-old boy with AERRPS who was effectively treated with very-high-dose phenobarbital (VHDPB) combined with intermittent short-acting barbiturates. VHDPB side-effects were mild, especially compared with those associated with continuous i.v. infusion of short-acting barbiturates (dosage, 40-75 mg/kg/day; maximum blood level, 290 μg/mL). Using VHDPB as the main treatment, short-acting barbiturates were used intermittently and in small amounts. This is the first report to show that VHDPB, combined with intermittent short-acting barbiturates, can effectively treat AERRPS. After treatment, convulsions were suppressed and daily life continued, but intellectual impairment and high-level dysfunction remained.


Divergent dispersal strategies in the freshwater bryozoan Plumatella repens: ramet size effects on statoblast numbers.
Evaluation of size-dependent variation in statoblast numbers in Plumatella repens indicates that this freshwater bryozoan employs divergent strategies in dispersing its asexual offspring in space and time. While the numbers of sessoblasts which were cemented to local substrates did not vary per unit ramet size, numbers of floatoblasts which disperse away from the parent to colonize substrates elsewhere varied in a size-dependent manner. Large ramets produced disproportionately more floatoblasts than did small ramets. In general, this result is consistent with the optimal dispersal predictions of three alternative theoretical models. However, the fact that the total number of sessoblasts in a ramet increased with ramet size appears to violate the "constant disperser principle" of one alternative model, and the occurrence of fusion in P. repens may violate the assumption of local competition for sites in another. In order to determine which model represents an appropriate description of dispersal in P. repens, future studies should evaluate the relative importance of local competition, cooperative phenomena like fusion, and mortality among dispersed and nondispersed offspring.


Hemolysin as a virulence factor for systemic infection with isolates of Mycobacterium avium complex.
Isolates of the Mycobacterium avium complex were examined for hemolysin expression. Only invasive isolates of M. avium were observed to be hemolytic (P < 0.001), with activity the greatest for isolates of serovars 4 and 8. Thus, M. avium hemolysin appears to represent a virulence factor necessary for invasive disease.


Identification of the key odor-active compounds responsible for varietal smoky aroma in wines made from the East Asian species.
A smoky aroma was found in wines made from East Asian species that had not been treated with oak products or exposed to smoke. In this study, a combined method of sensory analysis and quantitation of aroma compounds was used to identify the chemical basis of this smoky aroma. Syringol, eugenol, 4-ethylguaiacol, and 4-ethylphenol were confirmed as the key odor-active compounds contributing to the varietal smoky notes in wines of East Asian species. The concentrations of these compounds showed significant variation between grape species. The highest levels of syringol were found in Vitis amurensis wines, with an average of 178.8 μg/L. The average concentration of eugenol in V. davidii wines was 101.5 μg/L, about 10 times higher than in other species. 4-Ethylphenol and 4-ethylguaiacol were both abundant in the wines of the East Asian species. The results of the sensory interaction between the four compounds showed a complete addition effect for eugenol, a partial addition effect for syringol, and a hyper-addition effect for 4-ethylguaiacol and 4-ethylphenol on the smoky attribute.


Incidence, imaging analysis, and early and late outcomes of stroke after cardiac valve operation.
The aim of this study was to analyze the incidence, topography, and mechanisms of stroke, independent predictors, and late outcome after cardiac valve operations. We retrospectively analyzed prospectively collected data from 2,808 patients (mean age 63 +/- 15 years, n = 1,610, 55% men) who underwent valve surgery with or without concomitant coronary artery bypass grafting from January 1998 to December 2006. Stroke was defined as any new permanent focal neurologic deficit. Overall incidence of stroke was 2.2% (n = 63) and decreased during the study period from 3.3% (1998 to 2002) to 1.3% (2003 to 2006; p = 0.001). The highest stroke rate was observed after double aortic/mitral valve replacement (5.4%) and valve/coronary artery bypass grafting procedures (3.6%). Brain imaging was positive in 74% (n = 43 of 58) and showed ischemic stroke in all patients and hemorrhagic conversion in 28%. Distribution of acute stroke was large territory embolic artery (n = 33, 77%), watershed (n = 7, 16%), and mixed pattern (n = 3, 7%). Multivariate analysis revealed calcified ascending aorta (odds ratio [OR] 2.7), female gender (OR 2.6), ejection fraction <30% (OR 2.3), diabetes (OR 2.2), age >70 years (OR 2.0), and cardiopulmonary bypass time >120 minutes (OR 3.7) as predictors of stroke. Hospital mortality was 24% and 4.6% in patients with and without stroke, respectively. Survival of stroke patients was 78% and 54% at 1 year and 5 years, respectively, and was significantly decreased compared with patients without stroke. Valve pathology including endocarditis did not influence the incidence of stroke. Intraoperative epiaortic scanning may contribute in decreasing the incidence of this complication and may be warranted in all patients undergoing valvular surgery. In conclusion, stroke after valvular surgery is associated with an increased hospital mortality and morbidity and decreased long-term survival.


COVID-19 prognostic modeling using CT radiomic features and machine learning algorithms: Analysis of a multi-institutional dataset of 14,339 patients.
We aimed to analyze the prognostic power of CT-based radiomics models using data of 14,339 COVID-19 patients. Whole lung segmentations were performed automatically using a deep learning-based model to extract 107 intensity and texture radiomics features. We used four feature selection algorithms and seven classifiers. We evaluated the models using ten different splitting and cross-validation strategies, including non-harmonized and ComBat-harmonized datasets. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were reported. In the test dataset (4,301) consisting of CT and/or RT-PCR positive cases, AUC, sensitivity, and specificity of 0.83 ± 0.01 (CI95%: 0.81-0.85), 0.81, and 0.72, respectively, were obtained by ANOVA feature selector + Random Forest (RF) classifier. Similar results were achieved in RT-PCR-only positive test sets (3,644). In ComBat harmonized dataset, Relief feature selector + RF classifier resulted in the highest performance of AUC, reaching 0.83 ± 0.01 (CI95%: 0.81-0.85), with a sensitivity and specificity of 0.77 and 0.74, respectively. ComBat harmonization did not depict statistically significant improvement compared to a non-harmonized dataset. In leave-one-center-out, the combination of ANOVA feature selector and RF classifier resulted in the highest performance. Lung CT radiomics features can be used for robust prognostic modeling of COVID-19. The predictive power of the proposed CT radiomics model is more reliable when using a large multicentric heterogeneous dataset, and may be used prospectively in clinical setting to manage COVID-19 patients.


1H-NMR metabolomic profile of healthy and osteoarthritic canine synovial fluid before and after UC-II supplementation.
The aim of the study was to compare the metabolomic synovial fluid (SF) profile of dogs affected by spontaneous osteoarthritis (OA) and supplemented with undenatured type II collagen (UC-II), with that of healthy control dogs. Client-owned dogs were enrolled in the study and randomized in two different groups, based on the presence/absence of OA (OA group and OA-free group). All dogs were clinically evaluated and underwent SF sampling for 1H-Nuclear Magnetic Resonance spectroscopy (1H-NMR) analysis at time of presentation. All dogs included in OA group were supplemented with UC-II orally administered for 30 days. After this period, they were reassessed (OA-T30). The differences in the 1H-NMR metabolic SFs profiles between groups (OA-free, OA-T0 and OA-T30) were studied. The multivariate statistical analysis performed on SFs under different conditions (OA-T0 vs OA-T30 SFs; OA-T0 vs OA-free SFs and OA-T30 vs OA-free SFs) gave models with excellent goodness of fit and predictive parameters, revealed by a marked separation between groups. β-Hydroxybutyrate was identified as a characteristic compound of osteoarthritic joints, showing the important role of fat metabolism during OA. The absence of β-hydroxybutyrate after UC-II supplementation suggests the supplement's effectiveness in rebalancing the metabolism inside the joint. The unexpectedly high level of lactate in the OA-free group suggests that lactate could not be considered a good marker for OA. These results prove that 1H-NMR-based metabolomic analysis is a valid tool to study and monitor OA and that UC-II improves clinical symptoms and the SF metabolic profile in OA dogs.


Breaking the limit: Biological countermeasures for space radiation exposure to enable long-duration spaceflight.
Concerns over the health effects of space radiation exposure currently limit the duration of deep-space travel. Effective biological countermeasures could allow humanity to break this limit, facilitating human exploration and sustained presence on the Moon, Mars, or elsewhere in the Solar System. In this issue, we present a collection of 20 articles, each providing perspectives or data relevant to the implementation of a countermeasure discovery and development program. Topics include agency and drug developer perspectives, the prospects for repurposing of existing drugs or other agents, and the potential for adoption of new technologies, high-throughput screening, novel animal or microphysiological models, and alternative ground-based radiation sources. Long-term goals of a countermeasures program include reduction in the risk of radiation-exposure induced cancer death to an acceptable level and reduction in risks to the brain, cardiovascular system, and other organs.


Monitoring the purification by high-performance liquid chromatography of cardiotoxins from Naja mossambica mossambica using phase-sensitive two-dimensional nuclear magnetic resonance.
High-resolution phase-sensitive two-dimensional proton nuclear magnetic resonance was used to monitor the preparation by high-performance liquid chromatography of homogeneous proteins from the venom of Naja mossambica mossambica. This resulted in the characterization of a heterogeneous protein preparation VII2, which had been used in earlier structural studies by NMR, as well as a homogeneous protein CTXIIb and a nearly homogeneous protein fraction CTXIIa, which are now both subject to further investigations of their solution conformations.


Predicting rupture locations of ascending aortic aneurysms using CT-based finite element models.
Accurate rupture risk assessment of ascending aortic aneurysms is important for reducing aneurysm-related mortality. More recently, computational models have been shown to better predict rupture risk than diameter-based measurements. However, it remains unclear whether finite element (FE) models of the ascending aorta can predict rupture location, and over what timeframe those predictions are reliable. The aim of this study was to evaluate FE models of the ascending aorta generated from computed tomography (CT) scans in predicting rupture location. Pre- and post-rupture CT scans were obtained of 12 patients who underwent emergency surgical repair for ascending aorta rupture with varying time intervals between scans (20 days - 6 years). A rigid iterative closest point (ICP) registration was used to overlay post-rupture aortic geometries with pre-rupture FE models and directly compare predicted regions of high equivalent strain with actual rupture. The FE model predicted the rupture location in the 5 patients with the shortest time intervals between the pre- and post-rupture scans (20 days - 2 years, 3 months). However, rupture location was not predicted in the 4/5 patients with greater than 3 years between scans. Achieving a physiological equivalent strain distribution in the FE model was highly dependent on the resolution of the pre-rupture scan and whether contrast agent was present. The results suggest there may be a time interval beyond which FE predictions of rupture location may not be reliable. The results in this study may help clinical validation of FE models of ascending aortic aneurysms predicting rupture risk.


Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2.
Lipopolysaccharide (LPS), also known as endotoxin, activates the innate immune response through toll-like receptor 4 (TLR4) and its coreceptor, MD-2. MD-2 has a unique hydrophobic cavity that directly binds to lipid A, the active center of LPS. Tetraacylated lipid IVa, a synthetic lipid A precursor, acts as a weak agonist to mouse TLR4/MD-2, but as an antagonist to human TLR4/MD-2. However, it remains unclear as to how LPS and lipid IVa show agonistic or antagonistic activities in a species-specific manner. The present study reports the crystal structures of mouse TLR4/MD-2/LPS and TLR4/MD-2/lipid IVa complexes at 2.5 and 2.7 Å resolutions, respectively. Mouse TLR4/MD-2/LPS exhibited an agonistic "m"-shaped 2:2:2 complex similar to the human TLR4/MD-2/LPS complex. Mouse TLR4/MD-2/lipid IVa complex also showed an agonistic structural feature, exhibiting architecture similar to the 2:2:2 complex. Remarkably, lipid IVa in the mouse TLR4/MD-2 complex occupied nearly the same space as LPS, although lipid IVa lacked the two acyl chains. Human MD-2 binds lipid IVa in an antagonistic manner completely differently from the way mouse MD-2 does. Together, the results provide structural evidence of the agonistic property of lipid IVa on mouse TLR4/MD-2 and deepen understanding of the ligand binding and dimerization mechanism by the structurally diverse LPS variants.


Influence of Lexical Development on Reading and Spelling Skills: Effects of Enhancement on Second-Grade Children in Primary School.
Previous studies suggest that lexical competence is an important factor that influences reading skills and spelling accuracy in primary school children. Understanding the relationship between these skills will provide valuable insights to improve reading and writing enhancement and intervention strategies. The aim of this pre-post longitudinal study is to examine the effectiveness of an enhancement program, in which there are activities proposed through a narrative and metacognitive methodology, designed to develop the cognitive processes of lexical acquisition and its effects on reading and writing ability. A total of 74 primary school children (M-age = 7.04 years) participated in the research. They were divided into groups: experimental, which carried out the enhancement, and control groups, which carried out the typical school program. The results show that children who carried out the enhancement obtained higher scores in reading skills, specifically in reading accuracy and text comprehension and spelling accuracy, in comparison with their peers in the control group. These results suggest that strengthening the lexical semantic pathway, as theorized by Coltheart's two-way model, can lead to improved reading comprehension and diminished reading errors and spelling inaccuracies.


Spatial variability of urban climate in response to quantitative trait of land cover based on GWR model.
Land surface temperature and moisture are central components of the Earth's surface heat budget. China has experienced substantial land use/cover change that has led to deterioration of the urban microclimate, thus affecting global climate change. Understanding the spatial non-stationarity in the relationships between climate and land cover across a highly heterogeneous surface of urban landscapes is important for improving urban planning and management. This study used Landsat-8 OLI/TIRS data to explore the relationship of the three components (index-based built-up index (IBI); bare soil index (SI); and normalized difference vegetation index (NDVI)) with the urban climate (land surface temperature (LST) and land surface moisture (LSM)) using both a global model (ordinary least squares (OLS)) and a local model (geographically weighted regression (GWR)) for a megacity in Southeast China. The global regression results showed that there were significant positive correlations between the LST and the IBI and SI, while significant negative correlations were observed between the LST and the NDVI; opposite results were observed for the LSM. The IBI is the factor having the greatest impact on the LST, while the SI is among the most important factors for the LSM. The local regression results showed that the response of urban climate to land surface is affected greatly by water areas, but the role of the water areas is impacted by their size and surrounding landscape patterns. Moreover, the effects of vegetation and built-up land on the urban climate vary across locations with different wind patterns.


Effects of Ro 15-4513, fluoxetine and desipramine on the intake of ethanol, water and food by the alcohol-preferring (P) and -nonpreferring (NP) lines of rats.
The effects of the IP administration of RO 15-4513 (1, 2 and 4 mg/kg), fluoxetine (5 and 10 mg/kg) and desipramine (5 and 10 mg/kg) on the intake of 10% ethanol, H2O and food were determined in the selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines of rats with daily access to fluids being limited to single 2-hour sessions. The imidazobenzodiazepine Ro 15-4513 (a partial inverse benzodiazepine agonist) significantly reduced the intake of 10% ethanol by the P rats to 50-60% of control levels in the first 30 minutes without altering food or H2O intake. The attenuating actions of 2 mg/kg Ro 15-4513 on ethanol intake could be completely blocked by the central benzodiazepine receptor antagonist Ro 15-1788 (10 mg/kg). Ro 15-1788, by itself, produced no effects on alcohol and H2O consumption. The 5 mg/kg dose of fluoxetine significantly reduced 10% ethanol intake by the P rats to 20% of control values without altering either H2O or food consumption. The 10 mg/kg dose of fluoxetine further reduced ethanol intake by the P rats, but this dose also reduced daily food intake to approximately 70% of normal. Desipramine at both doses significantly (p less than 0.05) reduced both ethanol and food uptake by the P rats and had a tendency to reduce H2O consumption as well. In general, the three drugs had effects in the NP rats similar to those observed for the P group, although the effects on 10% ethanol intake were difficult to compare because of the low, variable intake of alcohol by the NP group.(ABSTRACT TRUNCATED AT 250 WORDS)


Cost-Effectiveness Analysis of Axicabtagene Ciloleucel vs. Tisagenlecleucel for the Management of Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Spain.
The study aimed to assess the cost-effectiveness of axicabtagene ciloleucel (axi-cel) vs. tisagenlecleucel (tisa-cel) for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥2 lines of systemic therapy in Spain. A lifetime partitioned survival mixture cure model, which comprises pre-progression, post-progression, and death health states, was used to estimate the accumulated costs and outcomes in terms of life years gained (LYG) and quality-adjusted life years (QALY). A matching-adjusted indirect comparison was used to reweight patient-level data from ZUMA-1, the pivotal clinical trial for axi-cel, to aggregate-level data from the pivotal tisa-cel trial, JULIET. The analysis was performed from the National Health System perspective, thus only direct costs were included. Sensitivity analyses (SA) were performed. Axi-cel yielded 2.74 incremental LYG and 2.31 additional QALY gained per patient compared to tisa-cel. Total incremental lifetime costs for axi-cel versus tisa-cel were €30,135/patient. The incremental cost-effectiveness ratio of axi-cel versus tisa-cel resulted in €10,999/LYG and the incremental cost-utility ratio in €13,049/QALY gained. SA proved robustness of the results. Considering the frequently assumed willingness-to-pay thresholds in Spain (€22,000/QALY and €60,000/QALY), axi-cel is a cost-effective treatment vs. tisa-cel for adult patients with R/R DLBCL in Spain.


Fumarase activity in NAD-dependent malic enzyme, MaeA, from Escherichia coli.
NAD-dependent malic enzymes catalyze NAD reduction to NADH while converting malate to pyruvate and CO2. In this study, NAD was reduced to NADH by MaeA, NAD-dependent malic enzyme from Escherichia coli, when fumarate was used as substrate. This suggested that MaeA catalyzed the conversion of fumarate to malate and then malate to pyruvate. The K0.5 value for fumarate was determined as 13 mM, different from previously characterized fumarases in Escherichia coli. Fumarate inhibited the malic enzyme activity of MaeA where NAD reduction to NADH was examined in the presence of malate as substrate. Human ME2, an NAD-dependent malic enzyme, also converted NAD to NADH in the presence of fumarate, suggesting that the duplex activity as fumarase and malic enzyme might be conserved in various NAD-dependent malic enzymes. MaeB, NADP-dependent malic enzyme from Escherichia coli, did not reduce NADP to NADPH in the presence of fumarate, suggesting the fumarase activities of MaeA and ME2 were specific.


Phase-controlled and chaos-assisted or -suppressed quantum entanglement for a spin-orbit coupled Bose-Einstein condensate.
It has been demonstrated that the presence of chaos may lead to greater entanglement generation for some physical systems. Here, we find different effects of chaos on the spin-motion entanglement for a two-frequency driven Bose-Einstein condensate with spin-orbit coupling. We analytically and numerically demonstrate that classical chaos can assist or suppress entanglement generation, depending on the initial phase differences between two motional states, which can be manipulated by using the known phase-engineering method. The results could be significant in engineering nonlinear dynamics for quantum information processing with many-body entanglement.


A preliminary study on the evaluation of asparaginase. Polyethylene glycol conjugate against canine malignant lymphoma.
Thirty-seven dogs with malignant lymphoma were treated with either polyethylene glycol conjugated (PEG) asparaginase alone (10-30 IU/kg intraperitoneally [IP] weekly--20 dogs) or PEG-asparaginase combined with one cycle of chemotherapy (vincristine, cyclophosphamide, methotrexate, and prednisone), followed by maintenance PEG-asparaginase (30 IU/kg, IP weekly--17 dogs). In the 20 dogs (eight were chemotherapy resistant) treated with PEG-asparaginase alone, seven had a complete response (CR), seven had a partial response (PR), five had no response (NR), and one was not evaluable (NE). The duration of response (CR + PR) ranged from 14 to 102 days (median, 48 days). In the eight chemotherapy-resistant dogs (seven were previously resistant to L-asparaginase) four had responses (one CR and three PR). In the 17 dogs treated with combined PEG-asparaginase and chemotherapy, 13 had a CR, two had a PR, and two had NR. None of the dogs had had prior chemotherapy, and the duration of response (CR + PR) ranged from 7 to 840+ days, with a median of 126+ days. Four dogs are still on maintenance PEG-asparaginase at 16+, 21+, 26+, and 28+ months. Toxicity consisted of death due to massive tumor breakdown (two dogs), disseminated intravascular coagulation (DIC--one dog), hypersensitivity reaction (one dog), vomiting (three dogs) and soft stools (three dogs). Four normal dogs were given very high doses of PEG-asparaginase (200 IU/kg and 1200 IU/kg) once weekly for two treatments without any significant toxicity. These results indicate that PEG-asparaginase has antitumor activity in dog with spontaneously occurring malignant lymphoma.


Activation-Induced Cytidine Deaminase Links Ovulation-Induced Inflammation and Serous Carcinogenesis.
In recent years, the notion that ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs) has gained evidence. However, the mechanistic pathway for this process has not been revealed yet. In the current study, we propose the mutator protein activation-induced cytidine deaminase (AID) as a link between ovulation-induced inflammation in FTECs and genotoxic damage leading to ovarian carcinogenesis. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in FTECs under physiological conditions, and is induced in vitro upon ovulatory-like stimulation and in vivo in carcinoma-associated FTECs. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights into the etiology of ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early detection.