A field-cycling NMR investigation of resonant spin-lattice relaxation features arising from tunnelling methyl groups.
(1)H nuclear spin-lattice relaxation has been investigated in sodium acetate trihydrate and sorbic acid using field-cycling NMR in the solid state. The relaxation is dominated by the reorientation of the methyl groups. Resonant features arising from coherent tunnelling are observed in both the magnetic field dependence of the spin lattice relaxation rate, T(1)(-1)(B(z)) and in the inverse temperature dependence, T(1)(-1)(1/T). The two systems have different barrier heights and tunnelling frequencies, providing different perspectives on the tunnel resonance phenomena. The magnetic field dependence enables different spectral density components to be separately investigated and in the carboxylic acid, sorbic acid, concerted proton transfer in the hydrogen bonds is also identified at low field and low temperature. The methyl hindering barriers and the correlation times characterising the reorientational dynamics has been accurately determined in both materials.


[Red cell distribution width and mortality risk in acute heart failure patients].
Red cell distribution width (RDW) is a quantitative measure of the variability in size of erythrocytes, and it is used for the differential diagnosis of anemia. Recent reports have suggested that high RDW could play a role for risk stratification in patients with chronic heart failure. However, the prognostic role of RDW in unselected population with acute heart failure (AHF), after a thoroughly multivariate adjustment, has not been well established. The aim of this study was to establish the association between RDW and long-term mortality in patients admitted for AHF. We analyzed 1,190 consecutive patients admitted for AHF in our center. RDW measurement was performed on admission. RDW values were stratified into quartiles (Q) and the association of RDW with total mortality was assessed using Cox regression. After a median follow-up of 15 months (interquartile range 3-33 months) 458 (38%) deaths were identified. There was a progressive increase in mortality rates from Q1 to Q4: 1.34, 1.82, 2.56 and 3.53 per 10 patients-year of follow-up (for Q1, Q2, Q3 and Q4 respectively, P for trend <.001). In the multivariate analysis, this association remained independent for patients in Q3 (15-16%) and Q4 (>16%) versus Q1 (≤14%), hazard ratio (HR): 1.66, 95% confidence interval (95% CI) 1.24-2.22, P<.01, HR: 1.80, 95% CI 1.33-2.43, p<.01, respectively, in a model adjusted for established prognostic markers in AHF. In patients with AHF, higher RDW values were associated with increased long-term mortality.


Trajectories of Low Back Pain From Adolescence to Young Adulthood.
Despite the high prevalence and burden of low back pain (LBP), understanding of its course during the transition from adolescence to adulthood is limited. The aim of this study was to identify and describe trajectories of LBP and its impact among a general population sample followed from adolescence to young adulthood. Data from followup assessments at years 17, 20, and 22 of the Western Australian Pregnancy Cohort (Raine) Study were used (n = 1,249). Self-reported LBP and its impact on daily life were assessed, and latent class analysis was used to identify clusters. Resultant clusters were profiled on sex, waist circumference, diagnosed comorbid pain, and health-related quality of life. Four clusters were identified: a cluster of participants with a consistently low prevalence of LBP and its impact (53%) during the period from adolescence to young adulthood, a cluster with an increase in the prevalence of LBP and its impact (22%), a cluster with a decrease in the prevalence of LBP and its impact (15%), and a cluster with a consistently high prevalence of LBP and its impact (10%). These clusters differed markedly on the profiling variables. The identified clusters provide unique information on LBP and its impact during the transition from adolescence to young adulthood. Consideration of these trajectories could be important in the design of early prevention and management strategies.


Cervical screening: population-based comparisons between self-reported survey and registry-derived Pap test rates.
To compare self-reported cervical screening rates, as recorded in the 1998 NSW Health Survey, with registry-based cervical screening rates for NSW for the same period; and to examine factors associated with over-estimates of cervical screening rates by self-report. Self-reported cervical screening data was extracted from the 1998 NSW Health Survey, biennial screening rates estimated and compared with biennial cervical screening rates for 1997-98, as recorded on the NSW Pap Test Register (PTR). Rates and differences were related to socio-demographic characteristics of the 17 Area Health Services of NSW. According to the 1998 NSW Health Survey, 74% of women reported having a Pap test during the previous two years. The equivalent rate recorded on the NSW PTR for 1997-98 was 62% (p<0.0001). Among the 17 Area Health Services of NSW these differences ranged from nine to 19 percentage points. Area-specific differences between self-reported and registry-based screening rates were negatively correlated with the registry-based screening rate. Age-specific differences between self-reported and registry-based screening rates were positively correlated with registry-based screening rates. No SES, regional or migrant population characteristics were predictive of differences between recorded and surveyed screening rates. Cervical screening rates in NSW derived from self-reported survey data exceed the rate recorded by the NSW Pap Test Register by 12 percentage points (equivalent to 19% inflation). The data in this paper can be used indicatively where necessary to adjust for over-reporting in cervical cancer screening surveys.


Enhanced sludge solubilization by microbubble ozonation.
A microbubble ozonation process for enhancing sludge solubilization was proposed and its performance was evaluated in comparison to a conventional ozone bubble contactor. Microbubbles are defined as bubbles with diameters less than several tens of micrometers. Previous studies have demonstrated that microbubbles could accelerate the formation of hydroxyl radicals and hence improve the ozonation of dyestuff wastewater. The results of this study showed that microbubble ozonation was effective in increasing ozone utilization and improving sludge solubilization. For a contact time of 80 min, an ozone utilization efficiency of more than 99% was obtained using the microbubble system, while it gradually decreased from 94% to 72% for the bubble contactor. The rate of microbial inactivation was obviously faster in the microbubble system. At an ozone dose of 0.02g O(3)g(-1) TSS, about 80% of microorganisms were inactivated in the microbubble system, compared with about 50% inactivation for the bubble contactor. Compared to the bubble contactor, more than two times of COD and total nitrogen, and eight times of total phosphorus content were released from the sludge into the supernatant by using the microbubble system at the same ozone dosage. The application of microbubble technology in ozonation processes may provide an effective and low cost approach for sludge reduction.


Decisional Conflict During Major Medical Treatment Decision-making: a Survey Study.
Both patients and surrogate decision-makers experience decisional conflict when making a major medical treatment decision with life or death implications. The relationship between health literacy and decisional conflict while making a major medical treatment decision is not understood. To identify the prevalence of individuals making major medical treatment decisions for themselves or someone else and to explore the relationships between decisional conflict and circumstances of the decision as well as the decision-maker. Two-phase survey study: in phase 1, we screened for who made a major treatment decision; in phase 2, we asked eligible respondents about their experience making the decision. Address-based random sample of 4000 Wisconsin residents; 1072 completed phase 1 and 464 completed phase 2. We asked respondents about types of decisions made, the most difficult decision made, and characteristics of the decision-maker and the decision. We included the Decisional Conflict Scale and four domains of the Health Literacy Questionnaire. Open-ended questions also allowed respondents to describe their experiences. About 43% of respondents reported making a major medical treatment decision. Decisions about major surgery and life support were regarded as the most difficult decisions. Respondents who made the decision for a spouse/partner (β = 6.65, p = 0.012), parent (β = 9.27, p < 0.001), or someone else (β = 10.7, p < 0.001) had higher decisional conflict. Respondents who reported higher ability to actively engage with healthcare providers (β = - 5.24, p = 0.002) and to understand health information well enough to know what to do (β = - 6.12, p = 0.001) had lower decisional conflict. The need to make major treatment decisions is likely to increase and making decisions on someone else's behalf appeared to be especially difficult. Improving communication to encourage patient and family engagement in the decision-making conversation, particularly for individuals with limited health literacy, may be helpful.


Genome-wide identification, phylogeny and expression analysis of the SPL gene family in wheat.
Members of the plant-specific SPL gene family (squamosa promoter-binding protein -like) contain the SBP conserved domain and are involved in the regulation of plant growth and development, including the development of plant flowers and plant epidermal hair, the plant stress response, and the synthesis of secondary metabolites. This family has been identified in various plants. However, there is no systematic analysis of the SPL gene family at the genome-wide level of wheat. In this study, 56 putative TaSPL genes were identified using the comparative genomics method; we renamed them TaSPL001 - TaSPL056 on their chromosomal distribution. According to the un-rooted neighbor joining phylogenetic tree, gene structure and motif analyses, the 56 TaSPL genes were divided into 8 subgroups. A total of 81 TaSPL gene pairs were designated as arising from duplication events and 64 interacting protein branches were identified as involve in the protein interaction network. The expression patterns of 21 randomly selected TaSPL genes in different tissues (roots, stems, leaves and inflorescence) and under 4 treatments (abscisic acid, gibberellin, drought and salt) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The wheat genome contains 56 TaSPL genes and those in same subfamily share similar gene structure and motifs. TaSPL gene expansion occurred through segmental duplication events. Combining the results of transcriptional and qRT-PCR analyses, most of these TaSPL genes were found to regulate inflorescence and spike development. Additionally, we found that 13 TaSPLs were upregulated by abscisic acid, indicating that TaSPL genes play a positive role in the abscisic acid-mediated pathway of the seedling stage. This study provides comprehensive information on the SPL gene family of wheat and lays a solid foundation for elucidating the biological functions of TaSPLs and improvement of wheat yield.


Effects of the brominated flame retardant tetrabromobisphenol-A (TBBPA) on cell signaling and function of Mytilus hemocytes: involvement of MAP kinases and protein kinase C.
Brominated flame retardants (BFRs) are a large group of compounds added to or applied as a treatment to polymeric materials to prevent fires. Tetrabisphenol A (TBBPA) is the most important individual BFR used in industry. Although TBBPA and its derivatives can be found in environmental samples, data are very limited on the presence of this compound in biota. Research on mammals indicates that TBBPA has low toxicity in vivo; however, in vitro TBBPA can act as a cytotoxicant, neurotoxicant, immunotoxicant, thyroid hormone agonist and has a weak estrogenic activity; in particular, the effects of TBBPA have been recently ascribed to its interactions with cellular signaling pathways, in particular with mitogen activated protein kinases (MAPKs). TBBPA has high acute toxicity to aquatic organisms, such as algae, molluscs, crustaceans and fish; however, little is known on the mechanisms of action of this compound in the cells of aquatic species. In this work, we investigated the possible effects and mechanisms of action of TBBPA on the immune cells, the hemocytes, of the marine mussel Mytilus galloprovincialis. The results demonstrate that TBBPA in the low micromolar range induces hemocyte lysosomal membrane destabilization. The effect was reduced or prevented by hemocyte pre-treatment by specific inhibitors of MAPKs and of protein kinase C (PKC). TBBPA stimulated phosphorylation of MAPK members and PKC, as evaluated by electrophoresis and Western blotting with anti-phospho-antibodies, although to a different extent and with distinct time-courses. A rapid (from 5 min) and transient increase in phosphoryation of the stress-activated JNK MAPKs and of PKC was observed, followed by a later increase (at 30-60 min) in phosphorylation of extracellularly regulated MAPKs (ERK2 MAPK) and of the stress-activated p38 MAPK. TBBPA significantly stimulated the hemocyte microbicidal activity towards E. coli, lysosomal enzyme release, phagocytic activity and extracellular superoxide (O2-) production. The results demonstrate that TBBPA in vitro activates the immune function of mussel hemocytes through kinase-mediated cell signaling and that common transduction pathways are involved in mediating the effects of this BFR in mammalian and aquatic invertebrate cells.


Proprotein convertase FURIN regulates T cell receptor-induced transactivation.
Antigen emergence rapidly stimulates T cells, which leads to changes in cytokine production, cell proliferation, and differentiation. Some of the key molecules involved in these events, such as TGF-β1 and NOTCH1, are synthesized initially as inactive precursors and are proteolytically activated during T cell activation. PCSKs regulate proprotein maturation by catalyzing the proteolytic cleavage of their substrates. The prototype PCSK FURIN is induced upon TCR activation, and its expression in T cells is critical for the maintenance of peripheral immune tolerance. In this study, we tested the hypothesis that FURIN regulates T cell activation. Our data demonstrate that IL-2 is increased initially in FURIN-deficient mouse CD4(+) T cells, but the TCR-induced IL-2 mRNA expression is not sustained in the absence of FURIN. Accordingly, the inhibition of FURIN in human Jurkat T cell lines also results in a decrease in IL-2 production, whereas the overexpression of WT FURIN is associated with elevated IL-2 levels. In Jurkat cells, FURIN is dispensable for immediate TCR signaling steps, such as ERK, ZAP70, or LAT phosphorylation. However, with the use of gene reporter assays, we demonstrate that FURIN regulates the AP-1, NFAT, and NF-κB transcription factors. Finally, by performing a transcription factor-binding site enrichment analysis on FURIN-dependent transcriptomes, we identify the FURIN-regulated transcription factors in mouse CD4(+) T cell subsets. Collectively, our work confirms the hypothesis that the TCR-regulated protease FURIN plays an important role in T cell activation and that it can specifically modulate TCR-activated transactivation.


Neurourological assessment in people with multiple sclerosis (MS): a new evaluated algorithm.
Neurogenic lower urinary tract dysfunction (NULTD) is common in patients with multiple sclerosis (MS); nevertheless, it is often underestimated, underdiagnosed, and undertreated due to patients' sense of shame, variability of symptoms, as well as lack of communication between neurologists and urologists, despite the availability of several guidelines based on scientific evidence and expert opinion. This study was conducted to develop an easy-to-perform algorithm for diagnosing neurogenic lower urinary tract disease in patients with MS for daily neurological and urological routine, including the identification of red flags. In consensus group meetings, interprofessional experts (neurologists, urologists, neurourologists, nurses, nurse practitioners, occupational therapists, physical therapists as well as representatives of national MS centers, self-care groups, social care, residential care, and health-aid-providers) developed a diagnostic algorithm to detect NULTD in patients with MS. Subsequently, the group evaluated the algorithm in 121 patients with MS using micturition diary, post-void residual volume, uroflowmetry, and urodynamic studies. Statistical analysis was conducted on the basis of logistic regression models to compare patients with normal and abnormal urodynamic examinations. Differentiation was performed using selected diagnostic parameters as well as standard performance measures for binary classifiers to assess prognostic quality. The following four parameters allowed to diagnose NLUTD in patients with MS: post-void residual urine volume, rate of urinary tract infections during the past 6 months, micturition frequency, and incontinence. According to statistical analysis, the following thresholds could be defined: post-void residual volume (PVR) ≥70 mL (Odds Ratio (OR) = 1.24; 95% CI:[1.07,1.62]), urinary tract infection (UTI) rate - none in 6 months (OR = 2.03; 95% CI:[1.04,6.68]), and micturition frequency >13/day, standardized on 2000 mL urine excretion (OR = 1.24; 95% CI:[1.07,1.49]). Uroflowmetry served as a further predictor of urodynamically measurable urinary bladder dysfunction (OR = 4.80; 95% CI: [1.41, 19.21]). Interestingly, patients without any complaints of NLUTD had an abnormal urodynamic examination in >50% of the cases. The entire algorithm has a sensitivity of 95%. All patients with MS should undergo a basic examination to detect NLUTDs. Within the algorithm developed in this study, four easy-to-collect parameters may reveal NLUTD in patients with MS.


The internal auditory canal revisited. The high-definition approach.
The internal auditory canal (IAC) is a bony canal that contains nerves and vessels and is lined by meninges. Pathologic processes may arise from each of these structures. Congenital, developmental, and acquired pathologic conditions may involve the bone of the canal and lead to excessive narrowing or expansion. Lesions formed within the canal include hemangiomas, vascular malformations, and inflammatory and neoplastic processes arising from the facial and acoustic nerves and meninges. Finally, other rare lesions, such as choristomas and metastases, may occur within the IAC, which are not related to its normal content. High-definition computed tomography, MR imaging, and MR angiography allow diagnoses of IAC or cerebellopontine-angle cistern lesions, some of which could not be identified by older techniques.


A sustainable composite of rice-paper/BaMoO4 nanoparticles for the photocatalytic elimination of the recalcitrant 2,6-dichlorobenzamide (BAM) pesticide in drinking water and its mechanisms of degradation.
This research reports the use of biodegradable and flexible composites for the removal of the 2,6-dichlorobenzamide (BAM) pesticide from drinking water. Rice paper (a biodegradable substrate) and Ag/BaMoO4 (MOBA) nanoparticles were employed to fabricate these composites. The SEM images showed that the MOBA nanoparticles with sizes of 300-800 nm decorated the surface of the biodegradable substrate and formed porous agglomerates, which have sizes of 1-3 μm. The MOBA powders were dispersed in drinking water polluted with BAM and were exposed to 4 h of UV-VIS irradiation, producing a maximum degradation of 82% for the BAM. Moreover, the flexible and biodegradable rice/MOBA composite produced a maximum removal percentage of 95% for the BAM. Also, we studied the effect of pH of the initial solution utilizing both powders and composites. From here, we found that a pH of 10 leads to a complete degradation of BAM after 4h, while a pH of 3 degraded only 37-47% of BAM for the same reaction time. According to the scavenger experiments, the •OH radical and the h+ were the main oxidizing agents for the BAM. Overall, the biodegradable photocatalytic composites are a reliable and a low-cost alternative to eliminate pesticides from the drinking water and can find application in water purification processes.


Novel mechanisms of the regulation of protein kinase B in adipocytes; implications for protein kinase A, Epac, phosphodiesterases 3 and 4.
Crosstalk between insulin and cAMP signalling pathways has a great impact on adipocyte metabolism. Whilst Protein kinase B (PKB) is a pivotal mediator of insulin action, in some cells regulation of PKB by cAMP has also been demonstrated. Here we provide evidence that, in a phosphatidyl inositol 3-kinase dependent manner, beta3-adrenergic stimulation (using CL316243) in adipocytes induces PKB phosphorylation in the absence of insulin and also potentiates insulin-induced phosphorylation of PKB. Interestingly, insulin- and CL316243-induced PKB phosphorylation was found to be inhibited by pools of cAMP controlled by PDE3B and PDE4 (mainly in the context of insulin), whereas a cAMP pool controlling protein kinase A appeared to mediate stimulation of PKB phosphorylation (mainly in the context of CL316243). Furthermore, an Epac (exchange protein directly activated by cAMP) agonist (8-pCPT-2'-O-Me-cAMP) mimicked the effect of the PDE inhibitors, giving evidence that Epac has an inhibitory effect on PKB phosphorylation in adipocytes. Further, we put the results obtained at the level of PKB in the context of possible downstream signalling components in the regulation of adipocyte metabolism. Thus, we found that overexpression of PKB induced lipogenesis in a PDE3B-dependent manner. Furthermore, overexpression or inhibition of PDE3B was associated with reduced or increased phosphorylation of the key lipogenic enzyme acetyl-CoA carboxylase (ACC), respectively. These PDE3B-dependent effects on ACC correlated with changes in lipogenesis. The Epac agonist, 8-pCPT-2'-O-Me-cAMP, mimicked the effect of PDE3B inhibition on ACC phosphorylation and lipogenesis.


Enhancement of the immune responses to foot-and-mouth disease vaccination in mice by oral administration of a novel polysaccharide from the roots of Radix Cyathulae officinalis Kuan (RC).
Foot-and-mouth disease (FMD) is a kind of the important animal infectious disease caused by the foot-and-mouth disease virus (FMDV). Thus, the aim of this study was to determine the effects of the polysaccharide from the Radix Cyathulae officinalis Kuan (RCPS) for its adjuvant potential on the FMDV-specific cellular and humoral immune responses in mice. In this study, our findings shows that oral administration of RCPS significantly enhanced the phagocytic capacity of peritoneal macrophage, splenocyte proliferation, the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) and IgG, IgG1, IgG2a, and IgG2b antibody titers. Furthermore, RCPS promoted the level of IL-2, IFN-γ and IL-4 in CD4(+)T cells and level of IFN-γ in CD8(+)T cells. In addition, RCPS enhanced the expression of CD40(+), CD80(+) and CD86(+) on DCs. Importantly, RCPS could up-regulated the mRNA level of MHC I, MHC II, TLR-2, TLR-4. Interestingly, RCPS down-regulated the frequency of CD4(+)CD25(+)Foxp3(+)Treg cells. Taken together, these results demonstrate that RCPS can enhance both cellular and humoral immune responses via up-regulating DCs maturation through TLR2, TLR4 signaling pathway, and suppressing Treg frequency.


Reaction pathways of glucose during esterification: effects of reaction parameters on the formation of humin type polymers.
The formation of humin-type polymers and other products during exposure of glucose to methanol/water mixtures with methanol/water mass ratios from 10 to 0.22 in the presence of the acid catalyst Amberlyst 70 was investigated. In water-rich medium (methanol/water mass ratio: 0.22), dehydration of glucose produced 5-(hydroxymethyl)furfural (HMF), furfural, and substantial amounts of polymer. In methanol-rich medium (methanol/water mass ratio: 10), the hydroxyl and carbonyl groups of glucose, HMF or furfural were protected via etherification and acetalisation. These protections stabilized these reactive compounds and significantly lowered the polymer formation (1.43% of the glucose loaded). The polymerization of glucose and HMF was also favored at high temperatures and long residence times. Conversely, high catalyst dosage mainly accelerated the conversion of glucose to methyl levulinate. Thus, the polymerization of glucose and HMF can be suppressed in methanol/water mixtures with high methanol ratios, at low temperatures and short residence times.


Identification of transcripts regulated by CUG-BP, Elav-like family member 1 (CELF1) in primary embryonic cardiomyocytes by RNA-seq.
CUG-BP, Elav-like family member 1 (CELF1) is a multi-functional RNA binding protein that regulates pre-mRNA alternative splicing in the nucleus, as well as polyadenylation status, mRNA stability, and translation in the cytoplasm [1]. Dysregulation of CELF1 has been implicated in cardiomyopathies in myotonic dystrophy type 1 and diabetes [2-5], but the targets of CELF1 regulation in the heart have not been systematically investigated. We previously demonstrated that in the developing heart CELF1 expression is restricted to the myocardium and peaks during embryogenesis [6-8]. To identify transcripts regulated by CELF1 in the embryonic myocardium, RNA-seq was used to compare the transcriptome of primary embryonic cardiomyocytes following siRNA-mediated knockdown of CELF1 to that of controls. Raw data files of the RNA-seq reads have been deposited in NCBI's Gene Expression Omnibus [9] under the GEO Series accession number GSE67360. These data can be used to identify transcripts whose levels or alternative processing (i.e., alternative splicing or polyadenylation site usage) are regulated by CELF1, and should provide insight into the pathways and processes modulated by this important RNA binding protein during normal heart development and during cardiac pathogenesis.


Earliest evidence of primate captivity and translocation supports gift diplomacy between Teotihuacan and the Maya.
A multimethod archaeometry study (zooarchaeological, isotopic, ancient DNA, paleobotanical, and radiocarbon dating) of a spider monkey sacrificed in the ceremonial center of Teotihuacan, Mexico (1 to 550 CE) is interpreted as a diplomatic gift exchange with neighboring Maya. Not only does this spider monkey provide the earliest known instance of primate translocation and captivity in Mesoamerica, it helps date incipient modes of interregional diplomacy between two major powers during Early Classic Mesoamerica: Teotihuacan and the Maya. Details of human-primate interaction include age at capture and transport (before ∼3 y of age), captive duration (over 2 y), anthropogenic diet (staple was maize, though secondary resources unique to anthropogenic diet including arrowroot and chili pepper were also found), context of sacrifice (tethered and associated with complete golden eagle and an array of other statecrafts), and general site context (including presence of Maya vessels and Maya-style murals). The timing of the spider monkey's sacrifice (250 to 300 CE) and its life history suggest a reconsideration of epigraphically attested militaristic involvement of Teotihuacan at certain Maya sites. We propose that a period of more multilateral and fluid ritual exchange with Maya dignitaries preceded the Teotihuacan state's eventual ascent to prominence.


Ultrasound biomicroscopy and claudication test for in vivo follow-up of muscle repair enhancement based on platelet-rich plasma therapy in a rat model of gastrocnemius laceration.
To track the regeneration process of lateral gastrocnemius due to a muscle laceration in rats, and to treatment with plateletrich plasma (PRP). Ultrasound (40 MHz) images were used for measuring pennation angle (PA), muscle thickness (MT) and mean pixel intensity, along with claudication scores, of treated (PRPG) and non-treated (NTG) groups of rats. NTG showed a PA increase for the non-injured leg (p<0.05) and a tendency of MT to increase, whereas for PRPG there were no differences. There was a progressive reduction of the claudication score for the PRPG group throughout the entire period, with an immediate difference after seven days (p<0.05), whereas the NTG had a significant reduction only at day 28 (p<0.05). It was observed a compensatory hypertrophic response due to the overload condition imposed to healthy leg for NTG that did not occur in PRPG, suggesting an accelerated repair process of the injured leg due to treatment, anticipating its use.


Occupational therapists' application of the Do-Live-Well framework: A Canadian health promotion approach.
Background. The Do-Live-Well (DLW) framework is an occupation-focused health promotion approach. Online and in-person DLW educational workshops were offered to encourage occupational therapists to apply the DLW concepts. Purpose. The purpose of this study was to understand workshop participants' experiences of and perspectives on using the DLW framework to support its application in the future. Method. Interpretative description was used to understand workshop participants' perspectives on benefits, facilitators, and challenges of using DLW. Semi-structured interviews were conducted and analysed using a thematic analysis. Findings. Eight themes were identified as follows: (a) environmental factors of practice settings, (b) co-workers' support, (c) DLW enhanced occupational therapy practice, (d) confidence in using DLW, (e) nature of the DLW framework, (f) DLW promoted healthy occupational engagement, (g) DLW was not suitable for everyone, and (h) pandemic effects. Implications. The DLW framework supports occupationally focused practices, and continuous learning support will be needed.


Factors associated with parents' willingness to vaccinate their children against COVID-19: The LA pandemic surveillance cohort study.
Children age 5-11 became eligible for COVID-19 vaccination in November 2021 in the United States, but vaccine uptake in this age group remains low. Understanding reasons why parents are hesitant to vaccinate their children may provide critical insights to help protect children from COVID-19 infection. This study examines factors associated with parents' willingness to vaccinate their children. We conducted a cross-sectional survey focusing on the Los Angeles County adult residents between March and June 2021. Our analytic sample focused on a subgroup of participants who self-report having a child. Predictors included parents' vaccination status and beliefs about COVID-19. We used multivariable logistic regression analysis and calculated the predicted probabilities of parents' willingness to vaccinate their children. Parents (n = 401) who worried about catching the virus, had trust in vaccine development and the COVID-19 vaccine approval process, and vaccinated against COVID-19 were more likely to be willing to vaccinate their children. Socio-economic, racial and ethnic differences were no longer statistically significant in the adjusted model. Predicted probabilities of parents who were willing to vaccine their children were 55% among the vaccinated and 36% among the unvaccinated. Parents' intent to vaccinate their children is influenced by their perceived severity of the pandemic, trust in the vaccine development process, and their vaccination status, which can be the potential drivers of hesitancy to vaccinate their children.


Educational feedback in the operating room: a gap between resident and faculty perceptions.
Immediate feedback regarding performance in the operating room remains a key component of resident education. The aim of this study was to assess resident and faculty perceptions regarding postoperative feedback. Anonymous surveys were distributed to residents and faculty members. Questions addressed the timing, amount, and specificity of feedback; satisfaction; and the definition and importance of feedback. Additional questions regarded the importance and frequency of feedback in 7 specific areas of surgical competency. Resident satisfaction with timing, amount, and specificity of feedback was significantly lower than faculty satisfaction. Perceptions of the importance of feedback for each of the 7 specific areas did not differ. Faculty members' perceptions on the frequency of feedback were higher than residents' perception in all competencies of feedback (5-point scale, all P values = .001). There are significant differences between resident and faculty perceptions regarding postoperative feedback. Although faculty members believed they delivered appropriate amounts of timely, quality feedback, this perception was not shared by residents.


Concordance in communication between surgeon and patient.
To examine (1) the capability of using interactive voice response (IVR) system technology for clinical research studies involving assessment of clinician-patient interactions and (2) the concordance of surgeons and their breast cancer patients about the content of a postbiopsy pre-treatment decision meeting. A descriptive comparison of the perceptions of 2 volunteer groups--surgeons and their patients--using interactive voice technology. Surgeons' offices. Twenty-six dyads of surgeons and their patients with newly diagnosed breast cancer. Concordance as determined through a 15-item patient questionnaire and a parallel 11-item surgeon questionnaire addressing surgical and psychosocial aspects of breast cancer treatment. Fifty-four percent to 100% of the 26 dyads indicated concordance about treatment preference, treatment choice, how treatment was chosen, preference for how treatment was chosen, time for discussion about treatment, and discussion about lymph-node removal. Only 27% to 50% of dyads agreed about patient understanding of lymph-node removal, the thoroughness of discussions about adjuvant treatment, the thoroughness of discussion about emotional coping, and the sufficiency of time for the discussion of patient's concerns. In these areas of disagreement surgeons often underestimated the patient's ability to understand and underestimated the patient's perception of the thoroughness of discussions about the psychosocial aspects of the illness (concerns and coping). Surgeons and patients demonstrated concordance on their perceptions of the type of treatment desired and needed but were discordant on their perceptions of the degree of patients' understanding about post-treatment and psychosocial issues.


Does level of ligation influence results in a murine biliary obstruction model?
Despite advances in perioperative management, patients with extrahepatic biliary obstruction still experience a high rate of complications and death after surgery. The rat is commonly used as an experimental animal for research in obstructive jaundice. Ligation of the rat bile duct high in the liver hilum is assumed to produce a more severe model of biliary obstruction than low ligation. The differences are attributed to the ability of the rat bile duct to dilate. Differences in level of ligation may, thus, explain some discrepancies between studies. To test this hypothesis, female Lewis rats underwent high ligation (HL), low ligation (LL), and sham celiotomy. Colloidal carbon clearance, bilirubin, total serum bile acids, and hematocrit were measured 12 days later. Liver and spleen weight, presence or absence of ascites, infection, and adequacy of ligation were noted and the liver was processed for routine histology and electron microscopy. Although bilirubin levels were higher after HL than after LL, liver and spleen weight, total serum bile salts, and phagocytic constants K and alpha were not different between these two groups. Gross, histologic, and ultrastructural appearance did not differ between HL and LL groups. High ligation causes greater hyperbilirubinemia than low ligation, but does not alter other parameters including phagocytic constants. The present study does not confirm the hypothesis that HL creates a more severe model than LL; therefore, it is unlikely that differences in level of ligation explain variability in results between studies.


Enhancement of colonic motor response to feeding by central endogenous opiates in the dog.
The role of endogenous opiates in the colonic motor response to feeding has been investigated in four dogs chronically fitted with two strain gages on the proximal and distal colon and a cannula in cerebral lateral ventricle. A daily meal stimulated the colonic motility during 8-10 hrs. The colonic motility index was significantly higher during this period when an enkephalinase inhibitor, tiorphan, was intracerebroventricularly (i.c.v.) administered at a dose of 0.1 mg/kg before the meal. This effect was blocked by a previous i.c.v. administration of naltrexone (0.1 mg/kg) and reproduced by (D-Ala2, Met5) enkephalinamide (DALAMIDE) at a dose of 50 mg/kg. I.c.v. administration of tiorphan or DALAMIDE did not modify the colonic motility in dogs fasted for 48 hrs. The postprandial motility index remained unchanged after intravenous administration of tiorphan or DALAMIDE at the same dosages. These results provide evidence for a central control of the colonic motor response to feeding by endogenous enkephalins in dogs.


Profile fluctuation of peripheral blood in advanced melanoma patients treated with nivolumab.
Melanoma is a malignant tumor of the melanocytes with an unfavorable clinical behavior. Nivolumab, a representative anti-programmed death 1 (PD-1) antibody, has recently been used for the treatment of metastatic malignant melanoma. However, there have been few appropriate biomarkers predicting the effect of nivolumab before the administration. Furthermore, the detailed characteristics of peripheral blood mononuclear cell (PBMC) profiles during nivolumab treatment remains unclear. In this study, we investigated fluctuations of PBMC profile during nivolumab treatment. PBMC analysis showed T-helper (Th)2-dominant conditions after a first course of nivolumab treatment. In a favorable case treated with nivolumab, a Th1/T-cytotoxic 1 shift was observed after nivolumab was administrated. These results suggest that flow cytometric analysis of PBMC may be helpful for the treatment of nivolumab.


Frege and the origins of model theory in nineteenth century geometry.
The aim of this article is to contribute to a better understanding of Frege's views on semantics and metatheory by looking at his take on several themes in nineteenth century geometry that were significant for the development of modern model-theoretic semantics. I will focus on three issues in which a central semantic idea, the idea of reinterpreting non-logical terms, gradually came to play a substantial role: the introduction of elements at infinity in projective geometry; the study of transfer principles, especially the principle of duality; and the use of counterexamples in independence arguments. Based on a discussion of these issues and how nineteenth century geometers reflected about them, I will then look into Frege's take on these matters. I conclude with a discussion of Frege's views and what they entail for the debate about his stance towards semantics and metatheory more generally.


Allergic bronchopulmonary aspergillosis (ABPA): studies on the general and specific humoral response.
Serum specimens from 138 patients suffering from chronic respiratory disorders including 63 with allergic bronchopulmonary aspergillosis (ABPA), 2o with suspected ABPA, 15 with pulmonary tuberculosis, 14 with bronchial asthma, 10 with chronic bronchitis and 6 with miscellaneous pulmonary conditions were studied for circulating antibodies to Aspergillus. The ammonium sulfate test was empolyed with an iodine-125 labeled mycelial component derived from Aspergillus fumigatus. When compared to normal controls from the same area, this test indicated that sera from 82 per cent of patients with ABPA had elevated binding titers to the radiolabeled antigenic component. Immunodiffusion using a culture filtrate antigen from A. fumigatus, revealed precipitating antibody to this fungus in 89 percent of sera from ABP patients. The majority of patients with ABPA demonstrated marked elevations of total serum IgE, moderate elevations of serum IgA and IgD and slightly increased levels of IgG and IgM.


Differences in risk factors and outcome after acute stroke in patients with tandem occlusion and those with isolated intracranial occlusion after endovascular treatment.
This study aimed to compare the clinical features, treatment, and clinical outcome of patients with tandem occlusion and isolated intracranial occlusion through endovascular treatment (EVT). Patients with acute cerebral infarction who received EVT in two stroke centers were retrospectively included. According to MRI or CTA results, the patients were divided into tandem occlusion group or isolated intracranial occlusion group. The baseline data, etiological classification, treatment, post-stroke complications, image features, and clinical outcome were compared. Multivariate logistic regression analysis was used to evaluate the related factors affecting the prognosis of patients with EVT. Among 161 patients with acute cerebral infarction, there were 33 cases (20.5%) in the tandem occlusion group and 128 cases (79.5%) in the isolated intracranial occlusion group. Compared with isolated intracranial occlusion, the patients with tandem occlusion had higher rates of large artery atherosclerosis (P = 0.028), symptomatic intracerebral hemorrhage (sICH) (P = 0.023), bilateral infarction (P = 0.042), and longer time for endovascular procedure (P = 0.026). There was no significant statistical difference in 90-day mRS score between the two groups (P = 0.060). Multivariate logistic regression identified the following independent predictors of poor functional outcome: older age, high fasting blood glucose, infarction area > 1/3, and hemorrhagic transformation. Compared with isolated intracranial occlusion, there was not a worse prognosis among patients with tandem occlusion who received EVT.


Relationship between the gastric myoelectric and mechanical activity in the genesis of ulcers in indomethacin-insulin-treated rats.
We have proposed that gastric contractile activity mechanically induces ulcers in the nonsteroid antiinflammatory drug (NSAID)-treated rat. This study examines first the relationship between number (dose) of peristaltic contractions applied to the mucosa and the ulcer score. Second, it examines the relative roles of: altered gastric myoelectrical activity (MEA) resulting from indomethacin (Indo) pretreatment, insulin-induced gastric peristalsis, and a combination of the two in the generation of mucosal lesions. Third, it examines the effect of exogenous prostaglandin on the Indo-altered MEA and relates it to ulcerogenesis. Indo pretreatment increased gastric tone and MEA. In such animals, the dose of peristaltic contractions applied to the gastric wall was related to the ulcer score in a dose-dependent manner. Exogenous prostaglandin (PG) reversed the MEA effect of Indo and reduced ulceration. It is postulated that an altered smooth muscle state secondary to inhibition of prostaglandin synthesis (PG-S) renders the mucosa vulnerable to injury by peristaltic action.


The role of perspective-taking in suppressing stereotypes about mathematics.
When people attempt to suppress stereotypes, they often end up making stereotypical judgments. The adverse effects of this form of suppression are called "paradoxical effects." This study examined the effect of perspective-taking as a strategy to reduce the paradoxical effects related to stereotype suppression. Specifically, this study addressed stereotypes within the context of women's mathematical abilities, with Japanese university students as participants. It was predicted that when participants suppressed the stereotype of a woman, those who engaged in perspective-taking toward that woman would make less stereotypical judgments of other women, compared with those who did not. Moreover, as this study focuses on gender stereotypes, an exploratory analysis was conducted to investigate whether the effects of engaging in perspective-taking about women vary depending on the participants' gender. Although no significant effect was observed and the hypothesis was not supported, and while the results of this study were statistically inadequate, they suggest that among the female participants, those who did not engage in perspective-taking showed the paradoxical effects of stereotype suppression. However, those paradoxical effects were not observed among those who performed perspective-taking.


Bladder cancer: results of radical cystectomy for invasive and recurrent superficial tumors.
The operative management of bladder carcinoma was reviewed retrospectively in 76 patients: 57 had muscle invasion and 19 had rapidly recurring or extensive superficial tumors requiring aggressive therapy. Of the patients 9 had been managed initially elsewhere with radiation treatment for cure and underwent salvage cystectomy at our institution. The results are discussed comparing patients receiving no radiation (11 of 20 alive) and 4,000 rad given preoperatively (11 of 20 alive), and patients with no muscle invasion but recurrent or extensive superficial tumors (14 of 19 alive).


Gender-based violence during COVID-19 lockdown: case study of a community in Lagos, Nigeria.
Gender-based violence (GBV) has been identified to be one of the ripple effects of the global pandemic. In countries like Nigeria, the situation is hypothesized to be worse because of widespread poverty and gender inequalities. To examine the exposure of females to GBV during the first 3 months of the COVID-19 lockdown. This cross-sectional study was conducted in a low-income community in Lagos. Semi-structured questionnaires were administered to 130 respondents selected via systematic random sampling. The mean age of the respondents was 26.89 ± 8.67 years. Majority worked informal jobs, while only 50% had attained beyond primary education. Within the period, the respondents had been subjected to sexual (54.6%), physical (52.3%), verbal assault (41.5%), and online sexual harassment (45.4%); of which only 30% reported to the police. Furthermore, respondents subjected to sexual (p=0.004) and physical assault (p=0.032) during the period earned significantly less money than other respondents. The fact that over 1 out of every 2 females was subjected to at least one form of GBV within the short timeframe shows how unsafe girls and women in low-income communities are. This calls for proactive community-level interventions to curb the GBV menace.


[Intraoperative parathyroid hormone monitoring in neck exploration for renal hyperparathyroidism?].
In operations for renal hyperparathyroidism the value of intraoperative parathormone monitoring was investigated. Intraoperative intact parathyroid hormone levels were determined (PTH Quick assay) in 40 patients undergoing first cervical exploration and in two patients with graft-dependent recurrence of renal hyperparathyroidism. In 33 patients, total parathyroidectomy with autotransplantation was carried out. The median parathormone levels decreased from 652 pg/ml to 120 pg/ml (19% of initial level) 5 min after total parathyroidectomy. In seven patients, fewer than 4 parathyroid glands each were identified during cervical exploration and "total parathyroidectomy (?)" without autotransplantation was performed. Intraoperatively median parathormone level decreased from 1193 pg/ml to 116 pg/ml (10% of initial level). In one of these seven patients, hyperparathyroidism persisted due to an ectopic fourth gland within the carotid sheath. In two of these patients, hypoparathyroidism occurred and a delayed autotransplantation of cryopreserved parathyroid tissue was carried out. On the first day after total parathyroidectomy with autotransplantation and "total parathyroidectomy (?)", median levels of intact parathyroid hormone were 1.9 pg/ml and 82.5 pg/ml, respectively. Intraoperative monitoring is not useful in first cervical exploration for renal hyperparathyroidism because it cannot predict complete resection of parathyroid tissue. The parathormone level on the first postoperative day allows precise evaluation of the efficacy of the surgical procedure.


Early Glottic Squamous Cell Carcinoma in a 16-Year-Old: Case Report, Review of the Literature and Pediatric Head and Neck Radiotherapy Guidelines.
Squamous cell carcinoma in children and adolescents is extremely rare. Less than 80 case reports have been reported in the literature since it was first reported in 1868. In this article, we intend to report a case where a 16-year-old girl who presented with complaints of change in voice was found to have early-stage vocal cord carcinoma on evaluation.


Bilayer-Coated Nanoparticles Reveal How Influenza Viral Entry Depends on Membrane Deformability but Not Curvature.
Enveloped viruses infect cells via fusion between the viral envelope and a cellular membrane. This membrane fusion process is driven by viral proteins, but slow stochastic protein activation dominates the fusion kinetics, making it challenging to probe the role of membrane mechanics in viral entry directly. Furthermore, many changes to the interacting membranes alter the curvature, deformability, and spatial organization of membranes simultaneously. We have used bilayer-coated silica nanoparticles to restrict the deformability of lipid membranes in a controllable manner. The single-event kinetics for fusion of influenza virus to coated nanoparticles permits independent testing of how the membrane curvature and deformability control the free energy barriers to fusion. Varying the free energy of membrane deformation, but not membrane curvature, causes a corresponding response in the fusion kinetics and fusion protein stoichiometry. Thus, the main free energy barrier to lipid mixing by influenza virus is controlled by membrane deformability and not the initial membrane curvature.


LAMA2-related muscular dystrophy: Natural history of a large pediatric cohort.
To characterize natural history of Laminin-α2 related muscular dystrophies (LAMA2-RD) to help anticipating complications and identifying reliable outcome measures for clinical trial design and powering. We conducted a retrospective, single-center, cross-sectional and longitudinal study on 46 LAMA2-RD pediatric patients (37 families). Patients were seen at the Dubowitz Neuromuscular Centre, London between 1985 and 2019. Data were collected by case note reviews. Time-to-event analysis was performed to estimate median age at complications occurrence. Forty two patients had complete deficiency of Laminin-α2 (CD) and four had partial deficiency (PD). Median age at first and last assessment was 2 years and 12.1 years, respectively. Median follow-up length was 7.8 years (range 0-18 years). Seven CD patients died at median age 12 years. One CD and two PD subjects achieved independent ambulation. We observed a linear increase in elbow flexor contractures in CD subjects. Thirty-two CD and one PD patient developed scoliosis, nine underwent spinal surgery. Twenty-two CD required nocturnal noninvasive ventilation (median age 11.7 years). CD subjects showed a 2.9% linear annual decline in forced vital capacity % predicted. Nineteen CD and one PD patient required gastrostomy insertion for failure to thrive and/or unsafe swallow (median age 10.9 years). Four CD patients had partial seizures. Mild left cardiac ventricular dysfunction and rhythm disturbances were identified in seven CD patients. This retrospective longitudinal study provides long-term natural history of LAMA2-RD. This will help management and identification of key milestones of disease progression that could be considered for future therapeutic intervention.


Is there a current change of maintenance treatment in ovarian cancer? An updated review of the literature.
Maintenance therapy in ovarian cancer has been introduced and evaluated in many large randomized trials; however, its efficacy is still unclear and includes concerns for both short-term and longer-term side effects. Thus far, some therapies that have been studied in this setting showed a delay in tumor progression but unfortunately no improvement in overall survival has been noticed. The introduction of new chemotherapeutic agents redirected research efforts. Assessing benefits of prolonged therapy and its impact in terms of toxicity is considerably important for the decision to administer such treatments. The purpose of this article was to provide an update on the randomized trials and review the role of maintenance therapy in the treatment of ovarian cancer.


In vitro growth suppression of vascular smooth muscle cells using adenovirus-mediated gene transfer of a truncated form of fibroblast growth factor receptor.
Vascular smooth muscle cell (VSMC) proliferation associated with arterial injury causes restenosis, which remains to be resolved in cardiovascular and ischemic cerebrovascular disease, especially after balloon angioplasty. Fibroblast growth factor (FGF) is a potent mitogen and a trophic factor for a variety of cells, including VSMCs. We constructed a replication-deficient adenovirus vector, designated AxCA delta FR, coding a truncated form of fibroblast growth factor receptor-1 (FGFR-1) gene lacking the intracellular domain to interrupt receptor-mediated FGF signaling, and examined its effect on the proliferation of primary-cultured rat VSMCs. We transferred the truncated form of the FGFR-1 gene to the VSMCs and confirmed its expression and localization in infected cells by Western blotting and immunofluorescence study. The VSMCs infected with AxCA delta FR degenerated and the proliferation of these cells was suppressed markedly by the infection with this virus in vitro. Our results suggest that the receptor-mediated signal of FGFs has an important role in VSMC proliferation and gene transfer of a truncated form of FGFR using adenoviral vector may be useful for the treatment of the diseases caused by excessive proliferation of VSMCs like restenosis after percutaneous transluminal angioplasty or carotid endoarterectomy.


Machine learning is a valid method for predicting prehospital delay after acute ischemic stroke.
This study aimed to identify the influencing factors associated with long onset-to-door time and establish predictive models that could help to assess the probability of prehospital delay in populations with a high risk for stroke. Patients who were diagnosed with acute ischemic stroke (AIS) and hospitalized between 1 November 2018 and 31 July 2019 were interviewed, and their medical records were extracted for data analysis. Two machine learning algorithms (support vector machine and Bayesian network) were applied in this study, and their predictive performance was compared with that of the classical logistic regression models after using several variable selection methods. Timely admission (onset-to-door time < 3 hr) and prehospital delay (onset-to-door time ≥ 3 hr) were the outcome variables. We computed the area under curve (AUC) and the difference in the mean AUC values between the models. A total of 450 patients with AIS were enrolled; 57 (12.7%) with timely admission and 393 (87.3%) patients with prehospital delay. All models, both those constructed by logistic regression and those by machine learning, performed well in predicting prehospital delay (range mean AUC: 0.800-0.846). The difference in the mean AUC values between the best performing machine learning model and the best performing logistic regression model was negligible (0.014; 95% CI: 0.013-0.015). Machine learning algorithms were not inferior to logistic regression models for prediction of prehospital delay after stroke. All models provided good discrimination, thereby creating valuable diagnostic programs for prehospital delay prediction.


Saponin-Rich Extracts and Their Acid Hydrolysates Differentially Target Colorectal Cancer Metabolism in the Frame of Precision Nutrition.
Saponins or their aglycone form, sapogenin, have recently gained interest as bioactive agents due to their biological activities, their antitumoral effects being among them. Metabolic reprogramming has been recognized as a hallmark of cancer and, together with the increased aerobic glycolysis and glutaminolysis, the altered lipid metabolism is considered crucial to support cancer initiation and progression. The purpose of this study was to assess and compare the inhibitory effects on colorectal cancer cell lines of saponin-rich extracts from fenugreek and quinoa (FE and QE, respectively) and their hydrolyzed extracts as sapogenin-rich extracts (HFE and HQE, respectively). By mean of the latest technology in the analysis of cell bioenergetics, we demonstrate that FE and HFE diminished mitochondrial oxidative phosphorylation and aerobic glycolysis; meanwhile, quinoa extracts did not show relevant activities. Distinct molecular mechanisms were identified for fenugreek: FE inhibited the expression of TYMS1 and TK1, synergizing with the chemotherapeutic drug 5-fluorouracil (5-FU); meanwhile, HFE inhibited lipid metabolism targets, leading to diminished intracellular lipid content. The relevance of considering the coexisting compounds of the extracts or their hydrolysis transformation as innovative strategies to augment the therapeutic potential of the extracts, and the specific subgroup of patients where each extract would be more beneficial, are discussed in the frame of precision nutrition.


Early endosomal rerouting of major histocompatibility class I conformers.
Major histocompatibility class I (MHC-I) molecules are present at the cell surface both as fully conformed trimolecular complexes composed of heavy chain (HC), beta-2-microglobulin (β2m) and peptide, and various open forms, devoid of peptide and/or β2m (open MHC-I conformers). Fully conformed MHC-I complexes and open MHC-I conformers can be distinguished by well characterized monoclonal antibody reagents that recognize their conformational difference in the extracellular domain. In the present study, we used these tools in order to test whether conformational difference in the extracellular domain determines endocytic and endosomal route of plasma membrane (PM) proteins. We analyzed PM localization, internalization, endosomal trafficking, and recycling of human and murine MHC-I proteins on various cell lines. We have shown that fully conformed MHC-I and open MHC-I conformers segregate at the PM and during endosomal trafficking resulting in the exclusion of open MHC-I conformers from the recycling route. This segregation is associated with their partitioning into the membranes of different compositions. As a result, the open MHC-I conformers internalized with higher rate than fully conformed counterparts. Thus, our data suggest the existence of conformation-based protein sorting mechanism in the endosomal system.


Mycobacterium smegmatis fatty acid synthetase. Polysaccharide stimulation of the rate-limiting step.
An initial activity burst lasting 5 to 10 s is observed for both de novo synthesis with acetyl-CoA as primer and for elongation of palmitoyl-CoA catalyzed by the multienzyme complex fatty acid synthetase from Mycobacterium smegmatis. After the initial burst, synthetase activity slows at least 6-fold to the steady state rate. The size of the initial burst is proportional to the amount of synthetase protein and corresponds to the synthesis of a small number C three to five) of C24 or C26 acyl chains per mol of enzyme. During the initial burst, C24, C26 acyl enzyme is formed and can be isolated by ammonium sulfate precipitation. On incubation with CoA, enzyme-bound acyl chains undergo transacylation to form the corresponding CoA derivatives. Diffusion of C24-CoA and C26-CoA from the enzyme is slow and rate-limiting for overall fatty acid synthesis. Mycobacterial polysaccharides markedly accelerate this rate-determining step but bovine serum albumin does not. This facilitation of product diffusion accounts for the large stimulation of de novo synthesis and of elongation of mycobacterial polysaccharide. It is also shown that the high apparent Km for acetyl-CoA (approximately 400 micrometer) in the steady state reflects the substrate concentration required to shift the product pattern in favor of shorter chain fatty acids (C16,C18). These conditions circumvent the slow, rate-limiting diffusion of C24-CoA and C26-CoA.


Areas for safe percutaneous nephrocentesis--a study of practical anatomy.
The safest percutaneous nephrocentesis route is through the posterolateral aspect of the kidney. From study of 160 kidneys from adults at autopsy, we conclude that the most favorable nephrocentesis area is the lower major renal calyx and its minor calyces or the upper minor calyces. We believe that the lateral aspect of the middle calyces may be an area for safe nephrocentesis.


Hi-plex deep amplicon sequencing for identification, high-resolution genotyping and multidrug resistance prediction of Mycobacterium leprae directly from patient biopsies by using Deeplex Myc-Lep.
Expansion of antimicrobial resistance monitoring and epidemiological surveillance are key components of the WHO strategy towards zero leprosy. The inability to grow Mycobacterium leprae in vitro precludes routine phenotypic drug susceptibility testing, and only limited molecular tests are available. We evaluated a culture-free targeted deep sequencing assay, for mycobacterial identification, genotyping based on 18 canonical SNPs and 11 core variable-number tandem-repeat (VNTR) markers, and detection of rifampicin, dapsone and fluoroquinolone resistance-associated mutations in rpoB/ctpC/ctpI, folP1, gyrA/gyrB, respectively, and hypermutation-associated mutations in nth. The limit of detection (LOD) was determined using DNA of M. leprae reference strains and from 246 skin biopsies and 74 slit skin smears of leprosy patients, with genome copies quantified by RLEP qPCR. Sequencing results were evaluated versus whole genome sequencing (WGS) data of 14 strains, and versus VNTR-fragment length analysis (FLA) results of 89 clinical specimens. The LOD for sequencing success ranged between 80 and 3000 genome copies, depending on the sample type. The LOD for minority variants was 10%. All SNPs detected in targets by WGS were identified except in a clinical sample where WGS revealed two dapsone resistance-conferring mutations instead of one by Deeplex Myc-Lep, due to partial duplication of the sulfamide-binding domain in folP1. SNPs detected uniquely by Deeplex Myc-Lep were missed by WGS due to insufficient coverage. Concordance with VNTR-FLA results was 99.4% (926/932 alleles). Deeplex Myc-Lep may help improve the diagnosis and surveillance of leprosy. Gene domain duplication is an original putative drug resistance-related genetic adaptation in M. leprae. EDCTP2 programme supported by the European Union (grant number RIA2017NIM-1847 -PEOPLE). EDCTP, R2Stop: Effect:Hope, The Mission To End Leprosy, the Flemish Fonds Wetenschappelijk Onderzoek.


The effects of vertebral artery injections of an enkephalin analogue, (D-Met2,Pro5)-enkephalinamide, on somatosympathetic reflexes.
The present study was initiated to test the effects of intravertebral arterial injection of an enkephalin analogue (D-Met2,Pro5)-enkephalinamide on somatosympathetic responses to myelinated A afferent and to unmyelinated C afferent stimulation (A- and C-reflex, respectively). In anesthetized cats, 0.5 mg/kg administered directly into the vertebral artery, the artery supplying most of the cat brain stem and upper cervical spinal cord, depressed both the A- and C-reflex (to 66 and 64% of control, respectively) while intravenous or carotid arterial injections did not have any effect on these reflexes. It is suggested that intravertebral arterial administration may be a useful method of restricting the effective sites of delivery of biologically active compounds to areas of the brain supplied by this artery.


Cellulose or chitin nanofibril-stabilized latex for medical adhesion via tailoring colloidal interactions.
The objective of this research is to develop a functional medical adhesive from natural nanofibril-stabilized latex through an aqueous process. Surface charged cellulose or chitin nanofibrils are used to form Pickering emulsions of acrylic monomers, followed by in situ polymerization. Charged initiators are selected to tailor the interactions between them and nanofibrils, and it is found that the repulsive electrostatic interactions play a key role in stabilizing the heterogeneous system. As a result, poly(2-ethylhexyl acrylate-co-methyl methacrylate) latexes are successfully prepared for surfactant-free adhesives with a high shear strength of 72.0 ± 6.5 kPa. In addition, drug can be easily incorporated in the nanopaper substrate or adhesive layer to form a medical tape, exhibiting long-term drug release and antibacterial behaviors. We managed developing a facile method to integrate green synthesis, versatile functionalities and excellent adhesion into one adhesive, which remains a great challenge.


Inherent constraints on a polyfunctional tissue lead to a reproduction-immunity tradeoff.
Single tissues can have multiple functions, which can result in constraints, impaired function, and tradeoffs. The insect fat body performs remarkably diverse functions including metabolic control, reproductive provisioning, and systemic immune responses. How polyfunctional tissues simultaneously execute multiple distinct physiological functions is generally unknown. Immunity and reproduction are observed to trade off in many organisms but the mechanistic basis for this tradeoff is also typically not known. Here we investigate constraints and trade-offs in the polyfunctional insect fat body. Using single-nucleus sequencing, we determined that the Drosophila melanogaster fat body executes diverse basal functions with heterogenous cellular subpopulations. The size and identity of these subpopulations are remarkably stable between virgin and mated flies, as well as before and after infection. However, as an emergency function, the immune response engages the entire tissue and all cellular subpopulations produce induce expression of defense genes. We found that reproductively active females who were given bacterial infection exhibited signatures of ER stress and impaired capacity to synthesize new protein in response to infection, including decreased capacity to produce antimicrobial peptides. Transient provision of a reversible translation inhibitor to mated females prior to infection rescued general protein synthesis, specific production of antimicrobial peptides, and survival of infection. The commonly observed tradeoff between reproduction and immunity appears to be driven, in D. melanogaster, by a failure of the fat body to be able to handle simultaneous protein translation demands of reproductive provisioning and immune defense. We suggest that inherent cellular limitations in tissues that perform multiple functions may provide a general explanation for the wide prevalence of physiological and evolutionary tradeoffs.


Tarantulas do not shoot silk from their legs: experimental evidence in four species of New World tarantulas.
Theraphosid tarantulas, like all other spiders, secrete silk from spigots on the abdominal spinnerets. A few years ago, it was proposed that the large tarantula Aphonopelma seemanni could extrude silk from specialized spigots on the tarsi to help adhesion to vertical surfaces. This suggestion was later questioned because silk was not observed after the spinnerets had been sealed. Recently, experiments with the tarantula Grammostola rosea again suggested tarsal silk secretion. All observations of the supposed tarsal silk were made in spiders with functional spinnerets, thus contamination with silk coming from the spinnerets could not be excluded. Recent morphological arguments also questioned putative tarsal spigots and proposed that they are actually contact chemoreceptors. We here test the supposed tarsal silk secretion in Aphonopelma seemanni, Avicularia avicularia, Brachypelma vagans and Grammostola mollicoma using similar experimental conditions as the previous authors, but with sealed spinnerets. Our results clearly demonstrate that when spinnerets are sealed, tarantulas do not show any tarsal silk secretion. We reinterpret those putative tarsal spigots and discuss possible evolutionary implications of these findings.


Pulmonary artery catheter placement with two-dimensional echocardiographic guidance: a technique applicable in critically ill neonates.
In nine critically ill neonates with persistent fetal circulation, femoral venous catheters were inserted at the bedside to initiate treatment and provide venous access. After femoral vein puncture or cutdown, a 5-F sheath was placed in the inferior vena cava through the femoral vein. With use of two-dimensional echocardiographic guidance, a 5-F balloon angiographic catheter was advanced through the inferior vena cava into the right atrium and subsequently manipulated through the tricuspid valve and into the main pulmonary artery. No major complications were attributable to the procedure. When performed by a pediatric cardiologist, this technique is as safe as umbilical catheter placement.


Rapid differentiation of PEDV wild-type strains and classical attenuated vaccine strains by fluorescent probe-based reverse transcription recombinase polymerase amplification assay.
Porcine epidemic diarrhea virus (PEDV), an intestinal coronavirus that causes acute diarrhea and high mortality in suckling piglets, can result in high economic losses in the swine industry. In recent years, despite the use of China's current vaccine immunization strategy, multiple types of PEDV strains were still found in immunized swine herds. Our research aims to explore a new rapid differentiation method to distinguish the different types of PEDV strains and assess the safety evaluation of classical attenuated vaccine strains in swine herds. In the study, a differential one-step quantitative real-time fluorescent reverse transcription recombinase polymerase amplification (real-time RT-RPA) method based on the PEDV universal real-time RT-RPA assay was established according to the ORF1 deletion sequences of three classical attenuated vaccine strains (PEDV attenuated vaccine KC189944, attenuated CV777 and DR13) and five Vero cell-adapted isolates (JS2008, SDM, SQ2014, SC1402, HLJBY), which could effectively differentiate PEDV classical attenuated vaccine strains from wild-type strains (PEDV classical wild strains and variant strains). The detection limits of PEDV RNA in the both PEDV real-time RT-RPA assays were 300 copies within 20 min at 39 °C, and the detection limits of classical attenuated vaccine strain CV777, Vero-cell-adapted isolate JS2008, and PEDV wild-type strain DX were 100.5 TCID50/100 μL, 101.1 TCID50/100 μL, and 101.2 TCID50/100 μL, respectively. Both assays were highly specific for PEDV, showing no cross-reactivity with other enteral viruses. This RPA method we developed is simple, time-effective, and safe and provides a reliable technical tool for the differential diagnosis and clinical epidemic surveillance of PEDV classical attenuated vaccine strains and wild-type strains.


Toxicity profile of antibody-drug conjugates in breast cancer: practical considerations.
Antibody-drug conjugates (ADCs) represent a novel and evolving class of antineoplastic agents, constituted by monoclonal antibody linked to biologically active drugs, delivering cytotoxic compounds at the tumor site, reducing the likelihood of systemic exposure and toxicity. They are generally well tolerated, nevertheless some predictable adverse reactions need careful monitoring and timely approach. These include neutropenia, nausea and vomiting, alopecia, diarrhea, left ventricular dysfunction, ILD/pneumonitis. The mechanisms leading to drug-associated toxicities are summarized, and prophylaxis protocols and appropriate management strategies are proposed, based on current literature. This review aims to collect the most updated evidence on toxicities potentially occurring during breast cancer treatment with approved or under clinical investigation (advanced stage) ADCs. A focus is dedicated to monitoring protocols and clinical management, aimed at preventing and/or promptly address relevant problems, in order to avoid premature discontinuation or improper dose reduction.


Bleeding Complications in Vancomycin-Induced Thrombocytopenia: A Real-world Postmarketing Pharmacovigilance Analysis.
Vancomycin and linezolid are first-line drugs used for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Vancomycin is well known as the best alternative drug when linezolid-induced thrombocytopenia occurs. However, several cases with vancomycin-induced thrombocytopenia, especially with bleeding complications, have been reported recently, which has attracted attention. The objective of this study is to assess the potential relevance between vancomycin and bleeding complications in thrombocytopenia. This is a real-world pharmacovigilance study conducted in October 2022 using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. We performed a disproportional analysis to assess the risk of bleeding complications in vancomycin-induced thrombocytopenia by calculating reporting odds ratios (RORs) and information components (ICs), with a weak signal defined as a lower limit of the IC 95% CI of 0 to 1.5, a middle signal defined as a lower limit of the IC 95% CI of 1.5 to 3.0, and a strong signal defined as a lower limit of the IC 95% CI of >3.0. There were 21,854 cases in the FAERS database that listed vancomycin as a suspected drug from quarter 1 of 2004 to quarter 2 of 2022. There were 800 cases of vancomycin-induced thrombocytopenia and 125 cases of bleeding complications in vancomycin-induced thrombocytopenia. Teicoplanin, tigecycline, and vancomycin (3 middle signals) were sequentially less associated with thrombocytopenia than linezolid (strong signal). However, bleeding complications in thrombocytopenia were significant associated with vancomycin (ROR = 9.641; 95% CI, 8.105-11.468; IC = 3.184; 95% CI, 2.929-3.440 [middle signal]), followed by linezolid (ROR = 9.350; 95% CI, 7.318-11.947; IC = 3.106; 95% CI, 2.745-3.466 [middle signal]), teicoplanin (ROR = 6.399; 95% CI, 2.869-14.272; IC = 2.059; 95% CI, 0.881-3.283 [weak signal]), and daptomycin (ROR = 2.784; 95% CI, 1.496-5.180; IC = 1.287; 95% CI, 0.374-2.201 [weak signal]). Tigecycline and daptomycin were the least likely anti-MRSA drug to cause thrombocytopenia (middle signal and weak signal, respectively) and bleeding complications in thrombocytopenia (no signal and weak signal, respectively). Middle signals of bleeding complication in vancomycin-induced thrombocytopenia were found in all group except those <45 to ≥80 years of age (weak signal). Bleeding complications in thrombocytopenia were significantly associated with vancomycin use, and the risk was highest among all the anti-MRSA drugs. Physicians should be aware of this possible serious adverse reaction.


The impact of metformin with or without lifestyle modification versus placebo on polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials.
Available evidence has shown that metformin improves insulin sensitivity and weight management in polycystic ovary syndrome (PCOS). Nevertheless, key knowledge gaps remain regarding its efficacy and the specific outcomes in this population. This review evaluates the effectiveness of metformin and lifestyle modification compared with placebo in the management of PCOS and will inform the forthcoming, 2023 evidence-based PCOS guidelines. Systematic review and meta-analysis of the literature. A search was performed in MEDLINE, EMBASE, PsycINFO, All EBM, and CINAHL. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and included randomized controlled trials published in English through July 2022. Moderate certainty of evidence showed a larger reduction of body mass index (BMI) (mean difference [MD] -0.53, 95% confidence interval [CI] -0.95 to -0.12 kg/m2), homeostatic model assessment for insulin resistance (MD -0.50, 95% CI -0.91 to -0.09) (critical outcomes), and fasting glucose (MD -0.13, 95% CI -0.19 to -0.07 mmol/L) with metformin compared to placebo with increased mild gastrointestinal adverse effects (odds ratio [OR] 7.67, 95% CI 2.74-21.46). Low certainty of evidence showed a larger reduction of waist-hip ratio (MD -0.02, 95% CI -0.03 to -0.00), total cholesterol (MD -0.24, 95% CI -0.43 to -0.05 mmol/L), low-density lipoprotein (MD -0.16, 95% CI -0.30 to -0.01 mmol/L), and triglycerides (MD -0.11, 95% CI -0.20 to -0.02 mmol/L) with metformin than placebo. Metformin should be considered an efficacious adjunct to lifestyle interventions in adults with PCOS, especially for those with a higher BMI, to improve weight loss, insulin resistance, and lipids.


Myelinated retinal nerve fibers associated with ipsilateral myopia, amblyopia, and strabismus.
Four patients had extensive unilateral myelinated nerve fibers associated with ipsilateral myopia, amblyopia, and strabismus. Their profound visual impairment, exotropia, and the early age onset of symptoms indicated that the amblyopia may have been organically caused. Prognosis is poor for even partial correction but good results have been obtained with intense therapy that includes full correction of the refractive error in each eye and extraocular muscle surgery if cosmetically necessary. In patients with axial myopia, images of a similar size will be produced by placing a lens of the correct power at the spectacle plane. In younger patients, a contact lens should not be used to correct the refractive error because it creates an undesirable anisometropia. Younger patients who have parafoveal fixation and no strabismus respond best to amblyopia therapy.


Efficacy and safety of thread embedding acupuncture for facial expression muscles atrophy after peripheral facial paralysis: study protocol for a randomized controlled trial.
Facial expression muscles atrophy is one kind of sequelae after peripheral facial paralysis. It causes critical problems in facial appearance of patient as well as social and psychological problems. This study aims to evaluate the efficacy and safety of Thread-embedding acupuncture (TEA) for the management of facial expression muscles atrophy after peripheral facial paralysis. This is a patient-assessor blinded, randomized, sham-controlled trial. A total of fifty-six eligible patients will be randomly divided into TEA (n=28) and sham TEA (STEA) (n=28) groups. Both groups will receive TEA or STEA treatment at the frontal muscle and the depressor anguli oris muscle, at one predefined points once a week for eight weeks. Additionally, both groups will receive traditional acupuncture treatment at ten acupoints (GB20, LI4, LR3, GB12, ST7, SI18, LI20, BL2, SJ23, ST4) twice a week for eight weeks as a concurrent treatment. B-mode ultrasonography will be used to assess the changes in facial expression muscle thickness ratio of the affected/healthy side at baseline and at 10 weeks after screening, as the primary outcome. House-Brackmann Grade and lip mobility score will be measured and analyzed at baseline and 4, 8, 10, and 12 weeks after screening, as secondary outcomes. The study will compare TEA with sham TEA to explore the feasibility for TEA in improving facial expression muscles atrophy after peripheral facial paralysis. Chinese Clinical Trial Registry, ChiCTR1900027170. Registered on 3 November 2019, http://www.chictr.org.cn/edit.aspx?pid=45173&htm=4.


Identification of dual PPARα/γ agonists and their effects on lipid metabolism.
The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARα, PPARγ and PPARδ, play central roles in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists, which stimulate both PPARα and PPARγ isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPARα and PPARγ agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPARα/γ agonist lead compounds (9-13 and 16-20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5%±3.5 and 54.1%±3.7 at 50μM and 100μM, respectively. In support of their potential as dual PPARα/γ agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPARα and PPARγ agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid β-oxidation in HuH7 hepatocytes.


High-fat diet-mediated dysbiosis exacerbates NSAID-induced small intestinal damage through the induction of interleukin-17A.
Non-steroidal anti-inflammatory drugs (NSAIDs) cause damage in the small intestine in a bacteria-dependent manner. As high-fat diet (HFD) is a potent inducer of gut dysbiosis, we investigated the effects of HFD on bacterial flora in the small intestine and NSAID-induced enteropathy. 16S rRNA gene analysis revealed that the population of Bifidobacterium spp. significantly decreased by fold change of individual operational taxonomic units in the small intestine of mice fed HFD for 8 weeks. HFD increased intestinal permeability, as indicated by fluorescein isothiocyanate-dextran absorption and serum lipopolysaccharide levels, accompanied by a decrease in the protein expressions of ZO-1 and occludin and elevated mRNA expression of interleukin (IL)-17A in the small intestine. HFD-fed mice exhibited increased susceptibility to indomethacin-induced damage in the small intestine; this phenotype was observed in normal diet-fed mice that received small intestinal microbiota from HFD-fed mice. Administration of neutralizing antibodies against IL-17A to HFD-fed mice reduced intestinal permeability and prevented exacerbation of indomethacin-induced damage. Thus, HFD-induced microbial dysbiosis in small intestine caused microinflammation through the induction of IL-17A and increase in intestinal permeability, resulting in the aggravation of NSAID-induced small intestinal damage.


Diffusion-weighted magnetic resonance for prediction of response after neoadjuvant chemoradiation therapy for locally advanced rectal cancer: preliminary results of a monoinstitutional prospective study.
To evaluate diffusion-weighted imaging (DWI) for assessment of treatment response in locally advanced rectal cancer (LARC) 8 weeks after neoadjuvant chemoradiotherapy (CRT). A total of 28 patients with LARC underwent magnetic resonance imaging (MRI) prior to and 8 weeks after CRT. Tumor volume (TV) was calculated on T2-weighted MRI scans as well as the apparent diffusion coefficient (ADC) was calculated using Echo-planar DWI-sequences. All data were correlated to surgical results and histopathologic tumor regression grade (TRG), according to Mandard's classification. Post-treatment difference ADC (%ΔADC) and TV (%ΔTV) changes at 8 weeks were compared complete response (CR; TRG1) and non-complete response tumors (non-CR; TRG2-5). The mean % ADC increase of CR group was significantly higher compared to non-CR group (77.2 ± 54.63% vs. 36.0 ± 29.44%; p = 0.05). Conversely, the mean % TV reduction did not significantly differ in CR group from non-CR group (73.7% vs. 63.77%; p = 0.21). Accordingly, the diagnostic accuracy of the mean % ADC increase to discriminate CR from non-CR group was significantly higher than that of the mean % TV reduction (0.913 vs. 0.658; p = 0.022). No correlation was found between mean % TV reduction and TRG (rho = 0.22; p = 0.3037), whereas a negative correlation between mean % ADC increase and TRG was recorded (r = -0.69; p = 0.006). The mean % ADC increase appears to be a reliable tool to differentiate CR from non-CR after CRT in patients with LARC.


Facile modification of silica substrates provides a platform for direct-writing surface click chemistry.
Please click here: a facile two-step functionalization strategy for silicon oxide-based substrates generates a stable platform for surface click chemistry via direct writing. The suitability of the obtained substrates is proven by patterning with two different direct-writing techniques and three different molecules.


Robust selection of sensory organ precursors by the Notch-Delta pathway.
The patterning of multicellular organisms is robust to environmental, genetic, or stochastic fluctuations. Mathematical modeling is instrumental in identifying mechanisms supporting this robustness. The principle of lateral inhibition, whereby a differentiating cell inhibits its neighbors from adopting the same fate, is frequently used for selecting a single cell out of a cluster of equipotent cells. For example, Sensory Organ Precursors (SOP) in the fruit-fly Drosophila implement lateral inhibition by activating the Notch-Delta pathway. We discuss parameters affecting the rate of errors in this process, and the mechanism (inhibitory cis interaction between Notch and Delta) predicted to reduce this error.


Influence of arrival weight, season and calf supplier on survival in Holstein beef calves on a calf ranch in California, USA.
On a yearly basis, large calf ranches rear thousands of neonatal cattle for replacement heifers, veal or dairy beef. Dairy beef ranches obtain bull-calves from multiple sources and with questionable colostrum intake histories. Such ranches accumulate large amounts of data that could be used to help them with calf purchasing and on-farm management practices to avoid losses. Our purpose was to describe some calf purchase factors associated with mortality in neonatal calves raised on a single large calf ranch. Computerized records describing 120,197 bull-calves purchased between January 1997 and November 1998 were used in a survival analysis. Risk factors for mortality within the first 4 weeks after arrival on the ranch included body weight on arrival, month of arrival, and the calf supplier. The strength of the effects was conditional on the week after arrival to the ranch.


Pharmacokinetics and safety of vitamin E δ-tocotrienol after single and multiple doses in healthy subjects with measurement of vitamin E metabolites.
Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects. Thirty-six subjects received from 100 to 1600 mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3 + 3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC. No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4-9.3 and 4.7-7.3 h, maximum concentration of 795.6-3742.6 and 493.3-3746 ng/mL, half-life of 1.7-5.9 and 2.3-6.9 h, and 0-12 h area under the curve of 4518.7-20,781.4 and 1987.7-22,171.2 ng h/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, δ-carboxyethyl hydroxychroman, and δ-carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30-60 times significantly higher than δ-tocotrienol levels. VEDT can be safely administered at doses up to 1600 mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed. Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.


Uncommon inflammatory/immune-related myelopathies.
The differential diagnosis for immune-mediated myelopathies is broad. Although clinical manifestations overlap, certain presentations are suggestive of a particular myelopathy etiology. Spine MRI lesion characteristics including the length and location, and the pattern of gadolinium enhancement, help narrow the differential diagnosis and exclude an extrinsic compressive cause. The discovery of specific antibodies that serve as biomarkers of myelitis such as aquaporin-4-IgG and myelin-oligodendrocyte -glycoprotein-IgG (MOG-IgG), has improved our understanding of myelitis pathophysiology and facilitated diagnosis. In this review we will focus on the pathophysiology, clinical presentation, imaging findings and treatment and outcomes of uncommon immune-mediated myelopathies.


Serology for Borrelia spp. in Northwest Italy: A Climate-Matched 10-Year Trend.
Ticks are hematophagous parasites that can transmit a variety of human pathogens, and their life cycle is dependent on several climatic factors for development and survival. We conducted a study in Piedmont and Aosta Valley, Italy, between 2009 and 2018. The study matched human sample serologies for Borrelia spp. with publicly available climatic and meteorological data. A total of 12,928 serological immunofluorescence assays (IFA) and Western blot (WB) tests were analysed. The median number of IFA and WB tests per year was 1236 (range 700-1997), with the highest demand in autumn 2018 (N = 289). In the study period, positive WB showed an increasing trend, peaking in 2018 for both IgM (N = 97) and IgG (N = 61). These results were consistent with a regional climatic variation trending towards an increase in both temperature and humidity. Our results suggest that coupling data from epidemiology and the environment, and the use of a "one health" approach, may provide a powerful tool in understanding disease transmission and strengthen collaboration between specialists in the era of climate instability.


Concurrent Chemoradiotherapy With Docetaxel, Cisplatin, and 5-Fluorouracil for T3 N0 Glottic Carcinoma Without Vocal Cord Fixation.
We retrospectively evaluated the efficacy and toxicity of concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin, and 5-fluorouracil (TPF) for T3 N0 glottic carcinoma without vocal cord fixation. Twenty-five patients underwent TPF-CCRT without elective nodal irradiaion (ENI). After the RT of 40 Gy, five patients (20%) without tumor regression underwent surgery. Others underwent RT with a median total dose of 66 Gy. Of the five patients who underwent surgery after the RT of 40 Gy, two showed residual carcinoma pathologically and the other three were confirmed to have complete pathological response to the treatment. The 5-year local control rate was 87%. No patients exhibited regional failure. No acute toxicities of grade 5 or late toxicities ≥grade 3 were observed. TPF-CCRT provides excellent tumor control with acceptable toxicities. CCRT while omitting ENI is a reasonable approach for T3 N0 glottic carcinoma without vocal cord fixation.


Translation, cultural adaptation, and validation of a screening test for cognitive and behavioural changes in amyotrophic lateral sclerosis.
To describe challenges of translating and culturally adapting the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis (ALS) Screen into Norwegian (ECAS-N), evaluate its content validity; provide age- and education-balanced norms for verbal fluency and cut-off values for abnormal performance. Translation to Norwegian and back-translation to English complied with standard methods. Patients and ALS experts evaluated the relevance, comprehensiveness and comprehensibility of the translated ECAS (ECAS-N). Content validity indexes at the item level (I-CVI), scale level (S-CVI) and inter-rater agreement were calculated. Performance of controls determined norms for written and spoken verbal fluency (n = 559) and cut-off scores for abnormal performance (n = 85). High levels of content validity was achieved for all items of the ECAS-N, I-CVI, S-CVI and inter-rater agreement was 87.5%. Age- and education-balanced norms for written and spoken verbal fluency were produced. Cut-off scores of abnormal performance were slightly lower than the original ECAS. The ECAS-N holds promise for detecting cognitive and behavioural impairment in Norwegian patients with ALS. Cut-off scores are situational and could slightly vary between different cultures. The ECAS-N can be used in international research, but researchers should be aware of the differences between the tests applied in the studies.Implications for rehabilitationThe ECAS-N, a Norwegian version of the English-language ECAS was produced for clinical use in Norway.Rigorous translation methods were used, and expert-judged modifications were made for Norwegian-specific culture and language nuances.Determination of ECAS-N cut-off scores for abnormal cognition was guided by a biostatistician, are slightly lower than the original ECAS, and are based on results from an objectively calculated number of healthy Norwegians.A nuanced picture of cognitive impairment in ALS drawn from a well-developed scale as the ECAS-N can contribute to a management process better tailored to patients'- and carers' individual needs.


[Attempts to demonstrate and identify avian adenoviruses by an immunofluorescence method].
A specific conjugate of a hyperimmune serum, obtained from rabbits with the use of the reference Phelps-CELO strain, was employed in a direct immunofluorescence method to investigate more than 320 lamelles with cell cultures infected with 4 field CELO virus strains and the reference Phelps-CELO strain. It is stated this method is specific and prompt for the early diagnosis and identification of adenoviruses (CELO viruses).


High intercorneal symmetry in corneal biomechanical metrics.
To evaluate the symmetry of corneal biomechanical metrics, measured using an ocular response analyzer (ORA) and self-built corneal inflation test platform, in bilateral rabbit corneas and to investigate their relationship with physical intraocular pressure (IOPp). Twenty fresh enucleated eyes from ten rabbits were used for ex vivo whole ocular globe inflation. IOP was increased from 7.5 to 37.5 mmHg with 7.5 mmHg steps and biomechanical metrics were acquired using the ORA. At least 3 examinations were performed at each pressure stage. Two biomechanical metrics, corneal hysteresis (CH) and corneal resistance factor (CRF) were recorded and analyzed as a function of IOPp. Corneal specimens were then excised from the intact ocular globe and tested under inflation conditions up to 45.7 mmHg posterior pressure. The experimental pressure-deformation data was analyzed using an inverse modeling procedure to derive the stress-strain behavior of the cornea. A comparison of corneal shape parameters showed no statistically significant difference (P > 0.05) between bilateral eyes. Similarly, there were no statistically significant differences in values of CH, CRF and corneal stiffness (as measured by the tangent modulus, Et) between bilateral eyes (CH: F = 0.94, P = 0.54; CRF: F = 4.42, P = 0.35; Et: F = 3.15, P = 0.12) at different pressure levels. IOPp was highly correlated with CRF while the relationship with CH was less pronounced. An obvious interocular symmetry in biomechanical metrics is found in this research. IOP has been shown to have important influences on the value of CRF provided by ORA.


Synthesis of 1-[11C]methylpiperidin-4-yl propionate ([11C]PMP) for in vivo measurements of acetylcholinesterase activity.
Synthesis of 1-[11C]methylpiperidin-4-yl propionate ([11C]PMP), an in vivo substrate for acetylcholinesterase, is reported. An improved preparation of 4-piperidinyl propionate (PHP), the immediate precursor for radiolabeling, was accomplished in three steps from 4-hydroxypiperidine by (a) protection of the amine as the benzyl carbamate, (b) acylation with propionyl chloride, and (c) deprotection of the carbamate by catalytic hydrogenation. The final product was obtained in an overall 82% yield. Reaction of the free base form of PHP with [11C]methyl trifluoromethanesulfonate at room temperature in N,N-dimethylformamide, followed by high performance liquid chromatography (HPLC) purification, provided [11C]PMP in 57% radiochemical yield, > 99% radiochemical purity, and > 1500 Ci/mmol at the end of synthesis. The total synthesis time from end-of-bombardment was 35 min. [11C]PMP can thus be reliably prepared for routine clinical studies of acetylcholinesterase in human brain using positron emission tomography.