A combined FE-hybrid MCDM framework for improving the performance of the conical stem tibial design for TAR with the addition of pegs.
The conical stemmed design of the tibial component for total ankle replacement (TAR) (example Mobility design) uses a single intramedullary stem for primary fixation. Tibial component loosening is a common mode of failure for TAR. Primary causes of loosening are lack of bone ingrowth due to excessive micromotion at the implant-bone interface and bone resorption due to stress shielding after implantation. The fixation feature of the conical stemmed design can be modified with the addition of small pegs to avoid loosening. The aim of the study is to select the improved design for conical stemmed TAR using a combined Finite Element (FE) hybrid Multi-Criteria Decision-Making (MCDM) framework. The geometry and material properties of the bone for FE modeling were extracted from the CT data. Thirty-two design alternatives with varying pegs in number (one, two, four, eight), location (anterior, posterior, medial, lateral, anterior-posterior, medial-lateral, equally spaced), and height (5 mm, 4 mm, 3 mm, 2 mm) were prepared. All models were analyzed for dorsiflexion, neutral, and plantarflexion loading. The proximal part of the tibia was fixed. The implant-bone interface coefficient of friction was taken as 0.5. The implant-bone micromotion, stress shielding, volume of bone resection, and surgical simplicity were the important criteria considered for evaluating the performance of TAR. The designs were compared using a hybrid MCDM method of WASPAS, TOPSIS, EDAS, and VIKOR. The weight calculations were based on fuzzy AHP and the final ranks on the Degree of Membership method. The addition of pegs decreased the mean implant-bone micromotions and increased stress shielding. There was a marginal decrease in micromotion and a marginal increase in stress shielding when the peg heights were increased. The results of hybrid MCDM indicated that the most preferable alternative designs were two pegs of 4 mm height in the AP direction to the main stem, two pegs of 4 mm height in the ML direction, and one peg of 3 mm height in the A direction. Outcomes of this study suggest that the addition of pegs can reduce the implant-bone micromotions. Modified three designs would be useful by considering implant-bone micromotions, stress shielding, volume of bone resection, and surgical simplicity.


Ex vivo gene transfer of endothelial nitric oxide synthase to atherosclerotic rabbit aortic rings improves relaxations to acetylcholine.
Cholesterol feeding results in impaired endothelium dependent vasorelaxation. The role of nitric oxide in this process is unclear. The aim of this study was to evaluate the role of nitric oxide in cholesterol-induced vasomotor dysfunction by examining the effect of overexpression of eNOS in the hypercholesterolemic rabbit aorta on vascular reactivity. Vascular rings from the thoracic aorta of hypercholesterolemic rabbits were exposed ex vivo either to an adenoviral vector encoding endothelial nitric oxide synthase (AdeNOS) or Escherichia coli beta Galactosidase (AdbetaGal). Transgene expression was examined by histochemistry for beta galactosidase, immunohistochemistry for eNOS and cyclic GMP measurements and vasomotor studies were performed. Transgene expression was found to localize to the endothelium and adventitia. cGMP levels were significantly greater in AdeNOS compared to AdbetaGal transduced rings. Acetylcholine mediated relaxation was significantly impaired in cholesterol fed rabbits and was markedly improved by overexpression of eNOS. These results suggest that reduced NO bioavailability observed in cholesterol-induced vascular dysfunction can be partially overcome by eNOS gene transfer.


Does primary immunisation status predict MMR uptake?
To investigate the relationship between primary immunisation status and MMR uptake. Nationally representative Millennium Cohort Study. Children born in the UK, 2000-2002. 14,578 children with immunisation data. MMR status at 3 years, defined as immunised with MMR, immunised with at least one single antigen vaccine or unimmunised. 88.6% of children had been immunised with MMR, 5.2% had received at least one of the single antigen vaccines and 6.1% were unimmunised against measles, mumps and rubella at age 3 years. Children who were unimmunised with the primary vaccines at ages 9 months (1.2%, n = 168) and 3 years (0.4%, n = 67) were 13 (95% CI 10.8 to 14.7) and 17 (95% CI 14.6 to 19.7) times more likely to be unimmunised against measles, mumps and rubella compared with children who were fully immunised. They were also more likely to be immunised with at least one of the single antigen vaccines with risk ratios of 2.8 (95% 1.2 to 6.1) and 4.3 (95% CI 1.8 to 10.1). Similar but smaller associations were observed if children were partially immunised with the primary vaccines at 9 months (3.4%, n = 502) and 3 years (3.6%, n = 522) with risk ratios of 4.0 (95% 3.2 to 4.9) and 5.2 (95% 4.2 to 6.1) for no MMR immunisation, and 2.0 (95% C 1.1 to 3.6) and 1.6 (95% CI 1.1 to 2.5) for single antigen vaccine use. Children who remain unimmunised with primary vaccines are also more likely not to receive MMR. More work is needed to determine how best to target this group.


Efficacy of malononitrilamide FK778 in a preclinical model of small bowel transplantation.
In a swine model of orthotopic small bowel transplantation, we assessed the efficacy of combined immunosuppressive therapy with low-dose tacrolimus plus FK778, compared with high-dose tacrolimus monotherapy. The small bowel was replaced in 23 piglets: group 1 (n = 5), no immunosuppression; group 2 (n = 12), oral tacrolimus to maintain whole blood trough levels between 15 and 25 ng/mL; and group 3 (n = 6), oral FK778 4 mg/kg/d, plus oral tacrolimus to maintain whole blood trough levels between 5 and 15 ng/mL. Follow-up time was limited to 60 days. Overall survival rates at 30 and 60 days were 0% and 0% in group 1, 30% and 0% in group 2, and 66% and 66% in group 3, respectively. The median survival time was 11 days in group 1, 28 days in group 2, and more than 60 days in group 3. The differences between groups 3 and 1 and between groups 3 and 2 were statistically significant. The numbers of major bacterial infections were 19 in group 2 (1.9 episodes per animal) and 3 in group 3 (0.75 episodes per animal). The infectious-related mortality rate was 70% in group 2 (7 cases) and 0% in group 3 (P < .05). Acute cellular rejection was absent or mild in 85% of group 2 stomal biopsy specimens and in 100% of group 3 biopsy specimens. In conclusion, combination therapy of low-dose tacrolimus is potentiated by FK778 to prevent acute cellular rejection and prolong small bowel transplant survival in pigs.


Solar light photocatalytic transformation of heptachlorobiphenyl (PCB 180) using g-C3N4 based magnetic porous photocatalyst.
A novel porous core-shell magnetic β-cyclodextrin/graphitic carbon nitride photocatalyst (Mβ-CD/GCN) was synthesized and employed in a solar light driven catalytic system for the degradation of polychlorinated biphenyls (PCBs). The Mβ-CD/GCN display superior photocatalytic performance on account of porous structure and ultrathin GCN nanosheets design, the former improves the utilization of visible light by multiple scattering and reflection of incident light, and the latter accelerates electron transfer. The ultrahigh specific surface area (1255 m2 g-1) of Mβ-CD/GCN provided a large number of active sites for adsorption and degradation of the target pollution. The pseudo-first order reaction rate constant (kobs) for the degradation of PCB180 by Mβ-CD/GCN was 0.021 min-1, which improved 3.23 times than the bulk GCN. Additionally, the effects of various reaction parameters and water matrices were studied on the degradation of PCB180. Three possible degradation pathways and mechanism of PCB180 were speculated according to the identification of reaction intermediates and detection of reactive species. The solar light driven Mβ-CD/GCN catalytic technology is a promising method not only for the control of persistent organic pollutants (POPs), but also the catalyst could be recovered and reused through simple magnetic separation.


The influence of very preterm birth on adolescent EEG connectivity, network organization and long-term outcome.
The aim of this study was to explore differences in functional connectivity and network organization between very preterm born adolescents and term born controls and to investigate if these differences might explain the relation between preterm birth and adverse long-term outcome. Forty-seven very preterm born adolescents (53% males) and 54 controls (54% males) with matching age, sex and parental educational levels underwent high-density electroencephalography (EEG) at 13 years of age. Long-term outcome was assessed by Intelligence Quotient (IQ), motor, attentional functioning and academic performance. Two minutes of EEG data were analysed within delta, theta, lower alpha, upper alpha and beta frequency bands. Within each frequency band, connectivity was assessed using the Phase Lag Index (PLI) and Amplitude Envelope Correlation, corrected for volume conduction (AEC-c). Brain networks were constructed using the minimum spanning tree method. Very preterm born adolescents had stronger beta PLI connectivity and less differentiated network organization. Beta AEC-c and differentiation of AEC-c based networks were negatively associated with long-term outcomes. EEG measures did not mediate the relation between preterm birth and outcomes. This study shows that very preterm born adolescents may have altered functional connectivity and brain network organization in the beta frequency band. Alterations in measures of functional connectivity and network topologies, especially its differentiating characteristics, were associated with neurodevelopmental functioning. The findings indicate that EEG connectivity and network analysis is a promising tool for investigating underlying mechanisms of impaired functioning.


Myasthenia gravis: overlap with 'polyendocrine' autoimmunity.
81 patients with spontaneously acquired myasthenia gravis (MG) were investigated for the presence of autoimmune (AI) diseases and their sera were tested for a range of organ-specific autoantibodies. 77 of the patients were HLA-phenotyped. Antibody titres to acetylcholine receptors (AChR) were higher in non-thymomatous patients who possessed HLA-B8 (p less than 0.05) and/or -DR3 (p less than 0.05) as compared to patients lacking these HLA antigens. 3 out of 20 (15%) patients with ocular MG, 7/23 (30%) with generalized MG of early onset, 11/23 (48%) generalized MG of late onset and 5/14 (35%) patients with thymoma had either overt AI diseases or significant titres of organ-specific autoantibodies suggesting subclinical AI disease. In ocular MG, low titres and an infrequent finding of antibodies to AChR (32%) as well as the low prevalence of associated autoantibodies and AI diseases indicate that this subgroup of MG consists of patients with restricted AI reactivity. HLA-B8 and -DR3 were present in all the patients with associated AI disorders in the young onset group but in none of the patients with old age of onset. In the young group, 6 out of 7 patients with associated AI conditions were women whereas the sex ratio was about equal in the older cases in both, patients with and without associated AI diseases or autoantibodies. We conclude from these observations that ageing provides conditions that allow the breakdown of self tolerance. The simultaneous presence of HLA B8, DR3 and female sex provide important additional factors for early expression of MG.


Subunit interactions at the V1-Vo interface in yeast vacuolar ATPase.
Eukaryotic vacuolar ATPase (V-ATPase) is regulated by a reversible dissociation mechanism that involves breaking and reforming of protein-protein interactions at the interface of the V(1)-ATPase and V(o)-proton channel domains. We found previously that the head domain of the single copy C subunit (C(head)) binds one subunit EG heterodimer with high affinity (Oot, R.A. and Wilkens, S. (2010) J. Biol. Chem. 285, 24654-24664). Here we generated a water-soluble construct of the N-terminal domain of the V(o) "a" subunit composed of amino acid residues 104-372 (a(NT(104-372))). Analytical gel filtration chromatography and sedimentation velocity analysis revealed that a(NT(104-372)) undergoes reversible dimerization in a concentration-dependent manner. A low-resolution molecular envelope was calculated for the a(NT(104-372)) dimer using small angle x-ray scattering data. Isothermal titration calorimetry experiments revealed that a(NT(104-372)) binds the C(foot) and EG heterodimer with dissociation constants of 22 and 33 μM, respectively. We speculate that the spatial closeness of the a(NT), C(foot), and EG binding sites in the intact V-ATPase results in a high-avidity interaction that is able to resist the torque of rotational catalysis, and that reversible enzyme dissociation is initiated by breaking either the a(NT(104-372))-C(foot) or a(NT(104-372))-EG interaction by an as-yet unknown signaling mechanism.


Topical perioperative antibiotic prophylaxis for minor clean inguinal surgery.
In minor clean procedures, such as inguinal hernia repair and varicocelectomy, the efficacy of systemic perioperative antibiotic prophylaxis is not well established. To determine the efficacy of topical antibiotic prophylaxis alone in preventing postoperative wound infection in a minor urologic clean procedure, we retrospectively reviewed the medical records of 1,654 patients who had undergone microsurgical varicocelectomy. From September 1985 until December 2000, 1,654 men underwent 2,554 microsurgical varicocelectomies (900 bilateral) by a single surgeon (MG). The skin was shaved and then prepped with standard Betadine gel (Purdue Frederick) that was wiped away with 70% ethanol. No systemic antibiotics were used. The wound was irrigated with 1% neomycin at the moment the incision was made, and then every few minutes until the completion of the procedure, which averaged 45 minutes per side. No postoperative antibiotics were used. No wound infections occurred. No patient developed an adverse reaction to topical application of neomycin. One can conclude that the infection rate in this study is no higher than 0.2% with 95% confidence. Our review of a large series of consecutive clean urologic procedures indicates that by combining a skin preparation of Betadine gel and 70% ethanol with perioperative topical neomycin irrigation at the moment of skin incision, the risk of postoperative wound infection when performing microsurgical varicocelectomy can be effectively reduced to less than 0.2%.


Synthesis and characterization of a silver nanoparticle-containing polymer composite with antimicrobial abilities for application in prosthetic and orthotic devices.
The presence of skin problems in patients using external lower limb prosthesis is recurrent. This has generated the need to develop interfaces for prosthesis with the ability to control microbial growth. Silver nanoparticles (AgNPs) have been implemented in the development of biomaterials because of their high antimicrobial activity. This article discusses the development of an AgNP-containing polymer composite with antimicrobial activity for developing prosthetic liners. AgNPs were synthesized using a photochemical method and certain physicochemical properties were characterized. Furthermore, the antimicrobial activity of AgNPs against Staphylococcus aureus ATCC 25923 and methicillin-resistant Staphylococcus aureus (MRSA), was assessed on the basis of their minimum inhibitory concentrations (MICs). AgNPs were incorporated into a silicon elastomer to assess certain physicomechanical properties, antimicrobial activity and cytotoxic effect of the material. The maximum antimicrobial activity of the material against Staphylococcus aureus ATCC 25923 and MRSA was 41.58% ±2.97% at AgNP concentration of 32.98 μg/mL and 14.85% ±5.94% at AgNP concentration of 16.49 μg/mL, respectively. Additionally, the material exhibited tensile yield strength, rupture tensile strength, and tensile modulus of elasticity of 0.70 - 1.10 MPa, 0.71-1.06 MPa, and 0.20 - 0.30 MPa, respectively. The mechanical characteristics of the material were within the acceptable range for use in external lower limb prosthetic and orthotic interfaces. It was possible to incorporate the AgNPs in a silicone elastomer, finding that the composite developed presented antimicrobial activity against Staphylococcus aureus ATCC 25923 and MRSA when compared to non-AgNP material samples.


Endodermal sinus (yolk sac) tumor of oral cavity originating from gingiva.
Endodermal sinus tumor is a malignant germ cell tumor which usually arises in gonads. Extragonadal endodermal sinus tumors in the head and neck are very rare. Here a gingival endodermal sinus tumor is reported. The lesion demonstrated typical microscopic features of the endodermal sinus tumors of gonads. The tumor cells showed alpha-fetoprotein immunoreactivity in immunohistochemical evaluation. The serum alpha-fetoprotein level was high. This is the first gingival case in the related literature.


Model processes and cavitation indicators for a quantitative description of an ultrasonic cleaning vessel: Part I: experimental results.
In this paper, four sensor types are presented for quantitative measurements in an ultrasonic cleaning vessel: (1) a hydrophone to measure spectral components of the sound field; (2) an aluminium foil technique as a model process for erosion; (3) a test tube filled with a solution of luminol to measure the emission of light; and (4) a test tube filled with potassium iodide solution to measure the oxidation of iodide. Thus a broad range of diverse cavitation effects is covered. The quantities were measured in dependence on three parameters: the electrical input power of the transducers, the temperature and the O(2) concentration of the water. To ensure constant environmental conditions, a flow system was built up which continuously exchanges the water in the vessel. The comparability of the data measured in subsequent measurement cycles is discussed and the influence of the different sensor types on the cavitation field is considered. Dependences on the three parameters are shown. A quantitative analysis of correlations between the data is carried out in the second part of the study (Koch and Jüschke, 2012 [1]).


Gastric emptying cycles in the human fetus.
Fetal swallowing contributes greatly to amniotic fluid homeostasis and fetal somatic development. Despite the absorption and recirculation of significant volumes of amniotic fluid, little is known about the rates of fetal gastric emptying or gastrointestinal absorption. We sought to determine the patterns of human fetal gastric emptying cycles across gestation. The gastric emptying cycle of 80 normal human fetuses at 12 to 39 weeks of gestation was studied. Real-time ultrasound examination of the fetal stomach (defined as the largest gastric area inclusive of the pylorus) was recorded continuously for a minimum of 1 hour (60-112 minutes). Images were replayed with measurements of gastric size every minute. The gastric area ratio was defined as the ratio of the fetal gastric area divided by the area of the fetal abdominal transverse section. The changes in gastric area ratio of all subjects were analyzed with the discrete Fourier transform method. The calculable maximum cycle was 60 or 112 minutes, and the minimum cycle was 2 minutes. The highest and second highest peaks of all power spectrum were recorded, and each cycle was converted from frequency of each peak. The gastric emptying cycles of the highest peak before 24 weeks of gestation were scattered between 30 and 100 minutes with low power. At 32 to 35 weeks of gestation, cycles were focused at approximately 40 minutes with increased power. At term, the cycles increased to >80 minutes. The gastric emptying cycles of the second highest peak were constant at 20 minutes, with stronger power after 24 weeks of gestation. Fetal gastric emptying cycles normalize during the early third trimester. The near-term evidence of delayed emptying may contribute to newborn infant feeding satiation.


Racial Differences in Val122Ile-Associated Transthyretin Cardiac Amyloidosis.
The valine-to-isoleucine substitution (Val122Ile) is the most common variant of transthyretin (TTR) amyloidosis in the United States, affecting primarily individuals of African descent. This variant has been identified recently in a cluster of white individuals in Italy. Clinical phenotype and chamber performance of Black and white individuals with Val122Ile TTR cardiac amyloidosis (ATTR-CA) were compared. Compared to white patients (n = 17), Black individuals (n = 53) had lower systolic blood pressures (110 vs 131 mmHg, <0.001), reduced pulse pressures (41 vs 58 mmHg; P < 0.001), and impaired renal function (eGFR 46 vs 67 mL/min/1.73m2; P < 0.001) at presentation. Systolic properties and arterial elastance were similar. Black patients had end-diastolic pressure-volume relationships that were shifted upward and leftward relative to those of white patients, indicating reduced left ventricular chamber capacitance. Pressure-volume area at a left ventricular end-diastolic pressure of 30 mmHg was lower in Black than in white individuals (8055 mmHg/mL vs 11,538 mmHg/mL; P = 0.008). Despite presenting at ages similar to those of white patients, Black individuals with Val122Ile-associated ATTR-CA had a greater degree of cardiac chamber dysfunction at the time of diagnosis due to impaired ventricular capacitance. Whether these differences are attributable to amyloidosis or other cardiovascular disease requires further study.


Youth cannabis use in Canada post-legalization: service providers' perceptions, practices, and recommendations.
In 2018, Canada legalized recreational cannabis use with the purpose of protecting youth and restricting access. However, concerns have been raised that this objective has not been met as rates of cannabis use among youth aged 16-24 have not declined. Youth cannabis use is associated with various adverse effects including psychosis, anxiety, depression, suicidality, respiratory distress, cannabinoid hyperemesis syndrome, and intoxications. Service providers play a crucial role in addressing youth cannabis use. This study aimed to understand Ontario service providers' perceptions, practices, and recommendations on youth cannabis use. This mixed method study included a survey and two focus groups. The survey was distributed to mental health service providers serving youth aged 16-24 across Ontario who were given the option to participate in a focus group. The survey included closed and open-ended questions regarding perceptions, practices, and recommendations, while the focus groups explored these categories in greater depth. Descriptive statistics were used to analyze close-ended questions and interpretative content analysis was applied for open-ended questions. Focus group data were analyzed using thematic analysis. The survey was completed by 160 service providers and 12 participated in two focus groups. Regarding perceptions, 60% of survey participants agreed with legalization, 26% had a strong understanding of medical versus recreational cannabis, 84% believed that cannabis has physical and mental health risks, and 49% perceived stigmatization. Less than half of the survey participants reported screening or assessing cannabis use, 16% stated they are highly familiar with treating cannabis use, and 67% reported that they rarely work with families. Subthemes identified in the focus groups under perceptions included normalization and stigmatization, harms for youth, and stigma, racism, and discrimination. Subthemes under practice included cannabis not being the primary focus, challenges with screening, assessment, and intervention, and referral to specialized services. Both the survey and focus group participants recommended increasing public education, enhancing service provider training, improving regulation and policies, reducing stigma and minimization, improving service access, and providing more culturally responsive services. Youth cannabis use in Canada remains a significant public health concern, necessitating a more comprehensive plan to protect Ontario youth and reduce associated harms.


The Role of Psychotherapy in the Management of Treatment-Resistant Depression.
This article reviews the role of psychotherapy in management of treatment-resistant depression (TRD). Meta-analyses of randomized trials show that psychotherapy has a positive therapeutic benefit in TRD. There is less evidence that one type of psychotherapy approach is superior to another. However, more trials have examined cognitive-based therapies than other forms of psychotherapy. Also reviewed is the potential combination of psychotherapy modalities and medication/somatic therapies as an approach to TRD. There is significant interest in ways that psychotherapy modalities could be combined with medication/somatic therapies to harness a state of enhanced neural plasticity and improve longer-term outcomes in mood disorders.


Antimicrobial susceptibility of Streptococcus pneumoniae isolates from vaccinated and non-vaccinated patients with a clinically confirmed diagnosis of community-acquired pneumonia in Belgium.
We assessed the in vitro susceptibility of Streptococcus pneumoniae isolates from patients with confirmed community-acquired pneumonia (CAP) to β-lactams, macrolides and fluoroquinolones and the association of non-susceptibility and resistance with serotypes/serogroups (STs/SGs), patient's risk factors and vaccination status. Samples (blood or lower respiratory tract) were obtained in 2007-2009 from 249 patients (from seven hospitals in Belgium) with a clinical and radiological diagnosis of CAP [median age 61 years (11.6% aged <5 years); 85% without previous antibiotic therapy; 86% adults with level II Niederman's severity score]. MIC determination (EUCAST breakpoints) showed for: (i) amoxicillin, 6% non-susceptible; cefuroxime (oral), 6.8% resistant; (ii) macrolides: 24.9% erythromycin-resistant [93.5% erm(B)-positive] but 98.4% telithromycin-susceptible; and (iii) levofloxacin and moxifloxacin, all susceptible. Amongst SGs: ST14, all resistant to macrolides and most intermediate to β-lactams; SG19 (>94% ST19A), 73.5% resistant to macrolides and 18-21% intermediate to β-lactams; and SG6, 33% resistant to clarithromycin. Apparent vaccine failures: 3/17 for 7-valent vaccine (children; ST6B, 23F); 16/29 for 23-valent vaccine (adults ST3, 7F, 12F, 14, 19A, 22F, 23F, 33F). Isolates from nursing home residents, hospitalised patients and patients with non-respiratory co-morbidities showed increased MICs for amoxicillin, all β-lactams, and β-lactams and macrolides, respectively. Regarding antibiotic susceptibilities: (i) amoxicillin is still useful for empirical therapy but with a high daily dose; (ii) cefuroxime axetil and macrolides (but not telithromycin) are inappropriate for empirical therapy; and (iii) moxifloxacin and levofloxacin are the next 'best empirical choice' (no resistant isolates) but levofloxacin will require 500 mg twice-daily dosing for effective coverage.


Enhanced two-photon biosensing with double-clad photonic crystal fibers.
A double-clad photonic crystal fiber was used to improve detection efficiency over a standard single-mode fiber in a two-photon fluorescence detection scheme in which the dye was excited and the fluorescence was detected back through the same fiber.


Is ascorbate Dr Jekyll or Mr Hyde in the Cu(Aβ) mediated oxidative stress linked to Alzheimer's disease?
Evaluation of the pro versus antioxidant activity of ascorbate regarding Cu(Aβ) induced reactive oxygen species production in the context of Alzheimer's disease shows that a protective activity can only be observed at high ascorbate concentration for exogenous molecules but not for the amyloid-β peptide itself.


Somatization and Somatic Symptom Disorder and its overlap with dimensionally measured personality pathology: A systematic review.
Difficulties in the assessments of Somatoform Disorders (SD) and Personality Disorders (PD) regarding operationalization, arbitrary thresholds, and reliability led to a shift from categorical to dimensional models in the DSM-5. Empirical research data postulates a continuous level of severity in both groups of diseases. The aim of this systematic review was to investigate the overlap between somatization and personality pathology. Until July 2020, we conducted a systematic literature search with PubMed, Web of Science and SCOPUS. We specifically reviewed current empirical data on the Alternative Model of Personality Disorders (AMPD) and Somatic Symptom Disorder (SSD) and SD. Data was drawn out using predefined data panels. Results were reflected in the context of the Hierarchical Taxonomy of Psychopathology (HiTOP) model. Risk of bias was assessed due to blinding, randomization, selective reporting, incomplete data, and attribution bias. A total of eight studies (N = 2979) met the inclusion criteria. Whereas categorical measures revealed mixed results, positive correlations between SD/SSD and dimensionally measured personality functioning were present in four studies (N = 1741). In three studies (N = 2025) correlations between SD/SSD and neuroticism/negative affectivity (d = 0.22-1.041) were present. Moreover, harm avoidant (d = 0.526 - 0.826) and self-defeating traits (d = 0.892) revealed significant associations with somatization. Dimensional personality assessments are highly neglected in patients with SSD and warrant further research. However, in line with the HiTOP model, there is tentative evidence that somatization can be described as an independent personality trait, which shows most striking overlaps with self-pathologies (Criterion A) and the trait of negative affectivity (Criterion B).


Characterization and health risk assessment of organophosphate esters in indoor dust from urban and rural domestic house and college dormitory in Nanjing, China.
Indoor dust is an important route of exposure for organophosphate esters (OPEs), which are associated with adverse health effects. In the present study, the pollution occurrence and potential health risks of 13 OPEs in indoor dust from urban homes, college dormitories, and rural homes in Nanjing were investigated. Most OPEs were detected in the tested samples. College dormitories dust samples showed significantly higher OPEs concentrations (132.31-1.61 × 103 ng/g), followed by that in urban homes (31.42-49.84 ng/g) and rural homes (51.19-309.75 ng/g). The Mann-Whitney U test found no significant difference in the total concentrations of OPEs except for some individual OPEs between urban and rural homes. Tris (2-chloroisopropyl) phosphate (TCPP) was the most abundant compound in all tested areas. Spearman correlation coefficients and principal component analysis indicated that OPEs might originate from different sources in three microenvironments. Estimated exposures for adults and children in all indoor dust were below the relevant reference doses. Additionally, TCPP was the primary contributors to the non-carcinogenic risk, ranging from 1.07 × 10-6 to 2.20 × 10-5. Tris (2,3-dibromopropyl) phosphate was the dominant carcinogenic risk contributor in indoor dust, with a range of 1.33 × 10-11 to 8.74 × 10-10. These results suggested that the health risk of OPEs was within acceptable limits in the tested areas.


Fibril growth kinetics reveal a region of beta2-microglobulin important for nucleation and elongation of aggregation.
Amyloid is a highly ordered form of aggregate comprising long, straight and unbranched proteinaceous fibrils that are formed with characteristic nucleation-dependent kinetics in vitro. Currently, the structural molecular mechanism of fibril nucleation and elongation is poorly understood. Here, we investigate the role of the sequence and structure of the initial monomeric precursor in determining the rates of nucleation and elongation of human beta(2)-microglobulin (beta(2)m). We describe the kinetics of seeded and spontaneous (unseeded) fibril growth of wild-type beta(2)m and 12 variants at pH 2.5, targeting specifically an aromatic-rich region of the polypeptide chain (residues 62-70) that has been predicted to be highly amyloidogenic. The results reveal the importance of aromatic residues in this part of the beta(2)m sequence in fibril formation under the conditions explored and show that this region of the polypeptide chain is involved in both the nucleation and the elongation phases of fibril formation. Structural analysis of the conformational properties of the unfolded monomer for each variant using NMR relaxation methods revealed that all variants contain significant non-random structure involving two hydrophobic clusters comprising regions 29-51 and 58-79, the extent of which is critically dependent on the sequence. No direct correlation was observed, however, between the extent of non-random structure in the unfolded state and the rates of fibril nucleation and elongation, suggesting that the early stages of aggregation involve significant conformational changes from the initial unfolded state. Together, the data suggest a model for beta(2)m amyloid formation in which structurally specific interactions involving the highly hydrophobic and aromatic-rich region comprising residues 62-70 provide a complementary interface that is key to the generation of amyloid fibrils for this protein at acidic pH.


Detection of hepatitis C virus in paraffin-embedded liver biopsies of patients negative for viral RNA in serum.
The diagnosis of hepatitis C is based on serological testing for antibodies against various epitopes of the hepatitis C virus (HCV) and detection of HCV RNA in serum, because anti-HCV antibodies alone cannot discriminate patients who are infectious from those who have resolved the infection. If HCV RNA is not detected, which is the case in at least 20% of enzyme immunoassay (EIA)-positive patients, diagnosis remains unclear in a state of disease possibly well suited for therapeutic intervention. Therefore, we investigated if detection of HCV antigens or HCV RNA in routinely processed, formalin-fixed and paraffin-embedded (ffpe) liver biopsy specimens of patients positive for anti-HCV, but negative for HCV RNA in serum, could confirm diagnosis in this serological constellation. We detected HCV RNA by reverse-transcription polymerase chain reaction (RT-PCR) in 27 (61%) of 44 ffpe liver biopsies from EIA-positive, but HCV-RNA-seronegative, patients. Testing of 18 of these biopsies by a panel of polyclonal antibodies against structural and nonstructural HCV proteins revealed positive immunostaining in 6 cases (33%), which were also positive by RT-PCR. Most biopsies showed necroinflammation compatible with chronic hepatitis C, and the detection of tissue HCV RNA correlated significantly with a higher grade of inflammatory activity. Detectability of HCV RNA did not correlate with HCV subtype. In conclusion, the search for HCV RNA by RT-PCR within the liver biopsy specimen can establish rapid and unequivocal diagnosis of hepatitis C in at least 60% of anti-HCV antibody-positive patients who are seronegative for HCV RNA, and thus may help to avoid repeated testing and delayed therapy. Tissue RT-PCR may also be more efficient than serological testing for surveillance of interferon therapy response, because ongoing chronic active hepatitis C is clearly demonstrated in the absence of detectable serum HCV RNA.


Orthopedic tissue regeneration: cells, scaffolds, and small molecules.
Orthopedic tissue regeneration would benefit the aging population or patients with degenerative bone and cartilage diseases, especially osteoporosis and osteoarthritis. Despite progress in surgical and pharmacological interventions, new regenerative approaches are needed to meet the challenge of creating bone and articular cartilage tissues that are not only structurally sound but also functional, primarily to maintain mechanical integrity in their high load-bearing environments. In this review, we discuss new advances made in exploiting the three classes of materials in bone and cartilage regenerative medicine--cells, biomaterial-based scaffolds, and small molecules--and their successes and challenges reported in the clinic. In particular, the focus will be on the development of tissue-engineered bone and cartilage ex vivo by combining stem cells with biomaterials, providing appropriate structural, compositional, and mechanical cues to restore damaged tissue function. In addition, using small molecules to locally promote regeneration will be discussed, with potential approaches that combine bone and cartilage targeted therapeutics for the orthopedic-related disease, especially osteoporosis and osteoarthritis.


Quantitative assays of idiotype-bearing IgE antibodies.
The present report describes a method allowing quantitation of anti-arsonate IgE antibodies and the estimation of the fraction of such antibodies which expresses the recurring CRIA idiotypic determinant. This method permits an analysis of the regulation of this idiotype within IgE-type antibodies.


Cell type-dependent mechanisms for formin-mediated assembly of filopodia.
Filopodia are finger-like protrusions from the plasma membrane and are of fundamental importance to cellular physiology, but the mechanisms governing their assembly are still in question. One model, called convergent elongation, proposes that filopodia arise from Arp2/3 complex-nucleated dendritic actin networks, with factors such as formins elongating these filaments into filopodia. We test this model using constitutively active constructs of two formins, FMNL3 and mDia2. Surprisingly, filopodial assembly requirements differ between suspension and adherent cells. In suspension cells, Arp2/3 complex is required for filopodial assembly through either formin. In contrast, a subset of filopodia remains after Arp2/3 complex inhibition in adherent cells. In adherent cells only, mDia1 and VASP also contribute to filopodial assembly, and filopodia are disproportionately associated with focal adhesions. We propose an extension of the existing models for filopodial assembly in which any cluster of actin filament barbed ends in proximity to the plasma membrane, either Arp2/3 complex dependent or independent, can initiate filopodial assembly by specific formins.


What's new in bone forming tumours of the skeleton?
Bone tumours are difficult to diagnose and treat, as they are rare and over 60 different subtypes are recognised. The emergence of next-generation sequencing has partly elucidated the molecular mechanisms behind these tumours, including the group of bone forming tumours (osteoma, osteoid osteoma, osteoblastoma and osteosarcoma). Increased knowledge on the molecular mechanism could help to identify novel diagnostic markers and/or treatment options. Osteoid osteoma and osteoblastoma are bone forming tumours without malignant potential that have overlapping morphology. They were recently shown to carry FOS and-to a lesser extent-FOSB rearrangements suggesting that these tumours are closely related. The presence of these rearrangements could help discriminate these entities from other lesions with woven bone deposition. Osteosarcoma is a malignant bone forming tumour for which different histological subtypes are recognised. High-grade osteosarcoma is the prototype of a complex karyotype tumour, and extensive research exploring its molecular background has identified phenomena like chromothripsis and kataegis and some recurrent alterations. Due to lack of specificity, this has not led to a valuable novel diagnostic marker so far. Nevertheless, these studies have also pointed towards potential targetable drivers of which the therapeutic merit remains to be further explored.


Bovine WC1(-) gammadeltaT cells incubated with IL-15 express the natural cytotoxicity receptor CD335 (NKp46) and produce IFN-gamma in response to exogenous IL-12 and IL-18.
The gammadeltaT cells of ruminants are believed to participate in innate immunity and have been described with regulatory, inflammatory and cytotoxic functions. Here we describe a subset of CD3(+) TcR1(+) WC1(-)gammadeltaT cells expressing CD335 (NKp46), classically associated with CD3(-) natural killer (NK) cells, as a consequence of incubation with IL-15. This population, undetectable at the time of collection, developed after 2 week of IL-15 culture from splenic leukocytes (SPL) reaching greater than 50% of the total gammadeltaT cells. However, they did not grow well from peripheral blood leukocytes (PBL). Splenic gammadeltaT cells positively selected by magnetic separation prior to incubation with IL-15 and analyzed by flow cytometry, consistently yielded CD3(+) cells expressing CD335. These cells arose from the CD335(-)gammadeltaT cell population suggesting that the new population represents up-regulation of CD335 by gammadeltaT cells. CD335 mRNA expression from sorted IL-15-incubated SPL CD335(+)gammadeltaT cells or NK cells exceeded that of CD335(-)gammadeltaT cells. Incubation with IL-12 and IL-18 increased the number of CD335(+)gammadeltaT cells in both the PBL and SPL fractions as compared to controls or IL-12 or IL-18 alone. In addition, CD335(+)gammadeltaT cells demonstrated a robust ability to produce IFN-gamma in response to exogenous IL-12 and IL-18. Taken as a whole, we describe a new phenotypically distinct bovine gammadeltaT cell sub-population capable of participating in type 1 immune responses.


Effects of shoulder strapping in patients with stroke: A randomised control trial.
Disability post stroke remains a global problem, with upper limb involvement playing a key role. Shoulder strapping is one of the techniques used clinically to address this. To compare the effect of two shoulder strapping techniques in patients with stroke. A longitudinal randomised controlled trial included baseline, weeks one, two and six assessments of 56 participants with upper limb hemiplegia. The participants were assessed for shoulder subluxation, shoulder pain, upper limb motor function and muscle tone. They were randomised into control, longitudinal strapping or circumferential strapping groups. Longitudinal strapping had a non-significant decrease in shoulder subluxation and pain (p > 0.05). Circumferential strapping had no significant effect on any outcomes; however, it prevented the shoulder pain from worsening as much as in the control group (p > 0.05). General improvement in upper limb motor function was observed for all three groups. Trends in improvement showed that longitudinal strapping could be recommended because it positively influenced shoulder subluxation and pain. Even without significant changes, strapping creates awareness of the limb in patients and caregivers and could be of clinical benefit. Longitudinal strapping of the shoulder in patients with stroke seems to positively influence shoulder subluxation and pain.


Use of flow-cytometric analysis to optimize cell banking strategies for production of biopharmaceuticals from mammalian cells.
Production of biopharmaceuticals from mammalian cells requires generation of master, working and post-production cell banks of high quality under GMP conditions. An optimal cryopreservation strategy is needed for each new production cell line, particularly with regard to establishing production processes that are completely devoid of serum or even any animal components and to ensuring robust thaw performance for reliable production. Here, we describe a novel strategy employing flow-cytometric (FC) analysis of Annexin V-stained cells for high-throughput characterization of cell banks. Our data show that this method enables predictive evaluation of a cryopreservation strategy as early as 6h after thawing of cells. Furthermore, a broad study is presented characterizing various factors that may influence the quality of serum-free production cell banks from NSO and CHO cell lines. These results demonstrate how FC-based analysis can be used for development of future state-of-the-art cryopreservation strategies.


Perioperative Dexamethasone Does Not Reduce Postoperative Opioid Use Following Anterior Cervical Discectomy and Fusion.
To determine if dexamethasone administration reduced narcotic consumption during hospitalization and to evaluate if patients who received dexamethasone refilled fewer opioid prescriptions postoperatively. All adult patients who underwent primary elective 1- to 4-level anterior cervical discectomy and fusion at a single center were retrospectively identified. Prescription opioid use was collected from governmental online prescription drug monitoring programs, and in-hospital opioid use was collected from each patient's medication administration record and recorded as morphine milligram equivalents (MMEs). Patients were categorized by whether or not intravenous dexamethasone was administered perioperatively. Dexamethasone protocols were considered high dose if weight-based dosing was >0.20 mg/kg and low dose if <0.20 mg/kg. Multivariable linear regression was conducted to assess the relationship between dexamethasone administration and MMEs prescribed at each time point while accounting for confounders. Of 249 included patients, 167 (67%) were administered dexamethasone. Patients in both groups used a similar quantity of opioids while hospitalized (no dexamethasone: 56.7 MMEs/day vs. dexamethasone: 39.4 MMEs/day, P = 0.350). Patients in both groups refilled a similar quantity of opioids in all postoperative time periods: 0-3 weeks (3.38 vs. 4.07 MMEs/day, P = 0.528), 3-6 weeks (0.36 vs. 0.75 MMEs/day, P = 0.198), 6-12 weeks (0.53 vs. 0.75 MMEs/day, P = 0.900), and 3 months to 1 year (0.28 vs. 0.43 MMEs/day, P = 0.531). On multivariable linear regression, dexamethasone was not associated with a reduction in opioid volume at any time point (all P > 0.05). Administration of perioperative dexamethasone does not reduce in-hospital or home opioid usage regardless of weight-based dose. Analgesia should not be the primary driver of dexamethasone administration for anterior cervical discectomy and fusion.


Large Isospin Asymmetry in ^{22}Si/^{22}O Mirror Gamow-Teller Transitions Reveals the Halo Structure of ^{22}Al.
β-delayed one-proton emissions of ^{22}Si, the lightest nucleus with an isospin projection T_{z}=-3, are studied with a silicon array surrounded by high-purity germanium detectors. Properties of β-decay branches and the reduced transition probabilities for the transitions to the low-lying states of ^{22}Al are determined. Compared to the mirror β decay of ^{22}O, the largest value of mirror asymmetry in low-lying states by far, with δ=209(96), is found in the transition to the first 1^{+} excited state. Shell-model calculation with isospin-nonconserving forces, including the T=1, J=2, 3 interaction related to the s_{1/2} orbit that introduces explicitly the isospin-symmetry breaking force and describes the loosely bound nature of the wave functions of the s_{1/2} orbit, can reproduce the observed data well and consistently explain the observation that a large δ value occurs for the first but not for the second 1^{+} excited state of ^{22}Al. Our results, while supporting the proton-halo structure in ^{22}Al, might provide another means to identify halo nuclei.


Serum levels of soluble form of receptor for advanced glycation end products (sRAGE) are positively associated with circulating AGEs and soluble form of VCAM-1 in patients with type 2 diabetes.
We have recently found that soluble form of receptor for advanced glycation end products (sRAGE) levels are positively associated with inflammatory biomarkers and the presence of coronary artery disease (CAD) in type 2 diabetic patients. Since advanced glycation end products (AGEs) up-regulate RAGE expression and endogenous sRAGE could be generated from the cleavage of cell surface RAGE, it is conceivable that sRAGE is positively associated with circulating AGEs levels in diabetes. In this study, we examined whether sRAGE were correlated to circulating levels of AGEs and soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in patients with type 2 diabetes. Eighty-two Japanese type 2 diabetic patients underwent a complete history and physical examination, determination of blood chemistries, sRAGE, AGEs, sVCAM-1 and sICAM-1. Multiple regression analysis revealed that serum levels of AGEs and sVCAM-1 were independently correlated with sRAGE. This study demonstrated that serum levels of sRAGE were positively associated with circulating AGEs and sVCAM-1 levels in type 2 diabetic patients. Our present observations suggest sRAGE level may be elevated in response to circulating AGEs, thus being a novel marker of vascular injury in patients with type 2 diabetes.


Kaolin-activated thromboelastography and standard coagulation assays in cyanotic and acyanotic infants undergoing complex cardiac surgery: a prospective cohort study.
Several studies report the use of thromboelatography (TEG) to monitor coagulation in pediatric cardiac surgery. The aim of this study was to compare baseline and intraoperative TEG, TEG-functional fibrinogen, and standard coagulation assays in children with cyanotic and acyanotic congenital heart disease (CHD) undergoing cardiac surgery. This is a prospective observational study of 63 children aged <24 months undergoing cardiac surgery with cardiopulmonary bypass (CPB). Exclusion criteria included preoperative anticoagulant therapy and hepatic failure. We collected blood at anesthesia induction (T1), at lowest temperature after CPB start (T2), and after heparin neutralization (T3). Coagulation was evaluated by TEG (reaction time [R]), k, alpha-angle, maximum amplitude (MA), MA-fibrinogen (MA-fib), and by standard coagulation assays (prothrombin time, activated partial thromboplastin time, fibrinogen level, platelet [PLT] count). Sixty-three patients were enrolled (38 cyanotic and 25 acyanotic). Median age was 4 [IQR 2-6] months and median weight was 5 [IQR 3.7-6.5] kg. Most common surgeries were: ventricular septal defect repair (n = 13), Fallot correction (n = 11), and arterial switch operation (n = 10). Cyanotic and acyanotic children were well matched: R, k, MA, and MA-fib at T1, T2, and T3 were not significantly different between cyanotic and acyanotic children. At T2, significant correlations were showed between MA and PLT count (r = 0.4; P = 0.0008) and k and plasma fibrinogen level (r = -0.54; P < 0.0001). At T3, significant correlations were showed between MA and PLT count (r = 0.5; P < 0.0001), G and PLT count (r = 0.6; P < 0.0001), and MA-fib and plasma fibrinogen level (r = 0.5; P = 0.002). According to our findings, cyanosis does not affect TEG parameters in children with CHD. PLT count and plasma fibrinogen significantly correlated (are significantly associated) with MA and MA-fib respectively, suggesting that use of TEG after protamine administration may be prompted for improved hemostatic monitoring in the perioperative phase.


Solar-Driven Overproduction of Biofuels in Microorganisms.
Microbial cell factories reinvigorate current industries by producing complex fine chemicals at low costs. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is the main reducing power to drive the biosynthetic pathways in microorganisms. However, insufficient intrinsic NADPH limits the productivity of microorganisms. Here, we report that supplying microorganisms with long-lived electrons from persistent phosphor mesoporous Al2 O3 (meso-Al2 O3 ) can elevate the NADPH level to facilitate efficient fine chemical production. The defects in meso-Al2 O3 were demonstrated to be highly efficient in prolonging electrons' lifetime. The long-lived electrons in meso-Al2 O3 can pass the material-microorganism interface and power the biosynthetic pathways of E. coli to produce jet fuel farnesene. This work represents a reliable strategy to design photo-biosynthesis systems to improve the productivity of microorganisms with solar energy.


Floral structure of Cardiopteris (Cardiopteridaceae) with special emphasis on the gynoecium: systematic and evolutionary implications.
Cardiopteris, a small herbaceous genus, had long been placed in its own family, Cardiopteridaceae. However, the family was recently broadly circumscribed to include more genera in Aquifoliales. To better understand the morphological relationships of the genus and the family, I studied the floral anatomy and development of Cardiopteris using C. quinqueloba. As has been previously described, flowers are 5-merous with a unilocular gynoecium. I confirmed that the gynoecium is bicarpellate, possessing two dissimilar styles. An analysis of the development, structure, and vasculature of the gynoecium showed that it is pseudomonomerous, consisting of one fertile adaxial carpel and one solid sterile abaxial carpel. The adaxial carpel forms a thin style with a capitate stigma, whereas the abaxial carpel has a thick style, which develops into a freshy fruit appendage. Comparisons with flowers of other genera (Citronella, Gonocaryum, and Leptaulus) of Cardiopteridaceae as well as the other families (Aquifoliaceae, Helwingiaceae, Phyllonomaceae, and Stemonuraceae) of Aquifoliales showed that the pseudomonomerous gynoecium is very likely a synapomorphy to support the sister-group relationship between Cardiopteridaceae and Stemonuraceae. Moreover, contrary to all previous descriptions, Cardiopteris flowers were found to have an annular nectariferous disk at the base of the gynoecium.


Subchronic treatment of rats with oxytocin results in improved adipocyte differentiation and increased gene expression of factors involved in adipogenesis.
Treatment with thiazolidinediones, insulin-sensitizing drugs, enhances adipogenesis, which may result in unwanted increase in adiposity. Based on the suggested metabolic effects of oxytocin, the aims of the present study were to: (i) determine whether chronic treatment with oxytocin exerts positive effects on white adipose tissue growth without increasing adiposity; (ii) investigate possible mechanisms of action of oxytocin by measuring the level of gene expression of adipogenic factors; and (iii) test the hypothesis that oxytocin's effect on adipose tissue involves specific activation of eukaryotic elongation factor 2 (eEF2). Adult rats were subcutaneously treated with oxytocin (3.6 µg·100 g⁻¹ body weight day⁻¹) via osmotic minipumps for 2 weeks. Adipocytes from epididymal adipose tissue were isolated and their size evaluated by light microscopy. Gene expression of adipogenic and angiogenic factors was determined by real-time PCR and dephosphorylation of eEF2 by immunoblotting. Oxytocin treatment decreased the diameter of adipocytes and increased the epididymal adipose tissue protein content without changing the adipose tissue mass. Increases in fatty acid binding protein, peroxisome proliferator-activated receptor γ, insulin-sensitive glucose transporter 4, leptin and CD31 mRNA levels were noted in the epididymal and/or retroperitoneal fat tissue of oxytocin-treated rats. Oxytocin enhanced the dephosphorylation of eEF2 in the epididymal adipose tissue. The present results demonstrate that subchronic treatment with oxytocin induces adipogenic and angiogenic effects and that the eEF2 signalling pathway is involved in these effects of oxytocin on adipose tissue in vivo. These findings are likely to motivate further research and indicate new approaches for modulating adipose tissue morphology and metabolism.


Expression and localization of galectin 4 in rat stomach during postnatal development.
Galectins are lectins implicated in cell-cell or cell-matrix adhesion, cell growth, the cell cycle, transcription processes, and apoptosis, and some of them are differentially regulated during pre- or post-natal development. The purpose of the present study was to determine whether the expression of galectin 4 is relevant to developmental processes during postnatal development in the rat stomach. Galectin 4 expression in the rat gastric mucosa, between birth and adulthood, was studied at the protein and mRNA levels by western and northern blotting, respectively. This lectin was localized precisely by immunoelectron microscopy. In the gastric mucosa, galectin 4 protein was present at lower levels in suckling than in weaned rats, but mRNA levels did not change significantly during postnatal development. This suggests possible differences in mRNA stability or in the translation regulation. Immunocytochemical examination of galectin 4 confirmed more highly elevated levels of the protein in endocrine, parietal, and chief cells in weaned rats than in suckling rats. Galectin 4 was more strongly localized in weaned rats than in suckling rats in the nuclei of all cell types and in or over secretory granules in endocrine and chief cells, suggesting that galectin 4 is implicated in nuclear events and perhaps in secretory processes.


Human Naive Embryonic Stem Cells: How Full Is the Glass?
Human naive embryonic stem cells in the ground state of pluripotency provide a new opportunity to study human developmental biology and potential clinical applications. Two studies now report related work in human naive stem cell derivation and DNA methylation analysis, with one reporting some differences from oocyte and blastocyst profiles.


Identification of a cis-regulatory element for delta 12-prostaglandin J2-induced expression of the rat heme oxygenase gene.
We recently reported that delta 12-prostaglandin (PG) J2 caused various cells to synthesize heme oxygenase, HO-1 (Koizumi, T., Negishi, M., and Ichikawa, A. (1992) Prostaglandins 43, 121-131). Here we examined the molecular mechanism underlying the delta 12-PGJ2-induced HO-1 synthesis. delta 12-PGJ2 markedly stimulated the promoter activity of the 5'-flanking region of the rat HO-1 gene from -810 to +101 in rat basophilic leukemia cells. From functional analysis of various deletion mutant genes we found that the delta 12-PGJ2-responsive element was localized in a region from -690 to -660, containing an E-box motif, which was essential for the delta 12-PGJ2-stimulated promoter activity. When the region containing the delta 12-PGJ2-responsive element was combined with a heterologous promoter, SV40 promoter, in the sense and antisense direction, the element showed an enhancer activity in response to delta 12-PGJ2. Gel mobility shift assays demonstrated that delta 12-PGJ2 specifically stimulated the binding of two nuclear proteins to the E-box motif of this region. These results indicate that delta 12-PGJ2 induces the expression of the rat HO-1 gene through nuclear protein binding to a specific element having an E-box motif.


A comparative investigation of catalytic mechanism and domain between catechol-O-methyltransferase isoforms by isomeric shikonin and alkannin.
The differences in catalytic mechanism and domain between the soluble (S-COMT) and membrane-bound catechol-O-methyltransferase (MB-COMT) are poorly documented due to the unavailable crystal structure of MB-COMT. Considering the enzymatic nature of S-COMT and MB-COMT, the challenge could be solvable by probing the interactions between the enzymes with the ligands with minor differences in structures. Herein, isomeric shikonin and alkannin bearing a R/S -OH group in side chain at the C2 position were used for domain profiling of COMTs. Human and rat liver-derived COMTs showed the differences in inhibitory response (human's IC50 and Ki values for S-COMT < rat's, 5.80-19.56 vs. 19.56-37.47 μM; human's IC50 and Ki values for MB-COMT > rat's) and mechanism (uncompetition vs. noncompetition) towards the two isomers. The inhibition of the two isomers against human and rat S-COMTs was stronger than those for MB-COMTs (S-COMT's IC50 and Ki values < MB-COMT's, 5.80-37.47 vs. 40.01-111.8 μM). Additionally, the inhibition response of alkannin was higher than those of shikonin in no matter human and rat COMTs. Molecular docking stimulation was used for analysis. The inhibitory effects observed in in vitro and in silico tests were confirmed in vivo. These findings would facilitate further COMT-associated basic and applied research.


Intestine-specific ablation of the Hepatocyte Nuclear Factor 4a (Hnf4a) gene in mice has minimal impact on serum lipids and ileum gene expression profile due to upregulation of its paralog Hnf4g.
Ablation of the gene encoding the nuclear receptor Hepatocyte Nuclear Factor 4a (Hnf4a) in the liver strongly affects HDL concentration, structure and functionality but the role of this receptor in the intestine, the second organ contributing to serum HDL levels, has been overlooked. In the present study we show that mice with intestine-specific ablation of Hnf4a (H4IntKO) had undetectable levels of ΗΝF4A in ileum, proximal and distal colon but normal expression in liver. H4IntKO mice presented normal serum lipid levels, HDL-C and particle size (α1-α3). The expression of the major HDL biogenesis genes Apoa1, Abca1, Lcat was not affected but there was significant increase in Apoc3 as well as in Hnf4g, a paralog of Hnf4a. RNA-sequencing identified metabolic pathways significantly affected by Hnf4a ablation such as type II diabetes, glycolysis, gluconeogenesis and p53 signaling. Chromatin immunoprecipitation assays showed that HNF4G bound to various apolipoprotein gene promoters in control mice but its binding affinity was reduced in the ileum of H4IntKO mice suggesting a redundancy but also a cooperation between the two factors. In the distal colon of H4IntKO mice, where both HNF4A and HNF4G are absent and in a mouse model of DSS-induced colitis presenting decreased levels of HNF4A, most lipoprotein genes were strongly downregulated. In conclusion, Hnf4a ablation in mice does not significantly affect serum lipid levels or lipoprotein gene expression in ileum possibly due to compensatory effects by its paralog Hnf4g in this tissue.


Three-dimensional visualization and evaluation of hilar cholangiocarcinoma resectability and proposal of a new classification.
As digital medicine has exerted profound influences upon diagnosis and treatment of hepatobiliary diseases, our study aims to investigate the accuracy of three-dimensional visualization and evaluation (3DVE) system in assessing the resectability of hilar cholangiocarcinoma (hCCA), and explores its potential clinical value. The discovery cohort, containing 111 patients from April 2013 to December 2019, was retrospectively included to determine resectability according to revised criteria for unresectability of hCCA. 3D visualization models were reconstructed to evaluate resectability parameters including biliary infiltration, vascular involvement, hepatic atrophy and metastasis. Evaluation accuracy were compared between contrast-enhanced CT and 3DVE. Logistic analysis was performed to identify independent risk factors of R0 resection. A new comprehensive 3DVE classification of hCCA based on factors influencing resectability was proposed to investigate its role in predicting R0 resection and prognosis. The main outcomes were also analyzed in cohort validation, including 34 patients from January 2020 to August 2022. 3DVE showed an accuracy rate of 91% (95%CI 83.6-95.4%) in preoperatively evaluating hCCA resectability, significantly higher than 81% (95%CI 72.8-87.7%) of that of CT (p = 0.03). By multivariable analysis, hepatic artery involvement in 3DVE was identified an independent risk factor for R1 or R2 resection (OR = 3.5, 95%CI 1.4,8.8, P < 0.01). New 3DVE hCCA classification was valuable in predicting patients' R0 resection rate (p < 0.001) and prognosis (p < 0.0001). The main outcomes were internally validated. 3DVE exhibited a better efficacy in evaluating hCCA resectability, compared with contrast-enhanced CT. Preoperative 3DVE demonstrated hepatic artery involvement was an independent risk factor for the absence of R0 margin. 3DVE classification of hCCA was valuable in clinical practice.


Impact of a clinical pharmacist-led guidance team on cancer pain therapy in China: a prospective multicenter cohort study.
Cancer treatment capacity in China is severely limited relative to the enormous size of the population; and many aspects of treatment, such as opioid protocols for pain control, are not standardized. To improve the quality of drug treatment, clinical pharmacists are taking a more active role in patient care. This study compared the effectiveness of opioid treatment between cancer patients receiving interventions from Clinical Pharmacist-Led Guidance Teams (CPGTs) and a comparable control group. This was a prospective, multicenter, double-arm, controlled study conducted in China. Multidisciplinary guidance teams were established and led by clinical pharmacists with expertise in cancer pain therapy. The CPGTs provided pre-therapy consultation and drug education to physicians, monitored prescriptions during treatment, and conducted patient follow-up. The process and outcome parameters of therapy were collected and analyzed with overall statistics and logistic regression. A total of 542 patients were enrolled, 269 in the CPGT intervention group (CPGT group) and 273 controls. Standardization of opioid administration was improved significantly in the CPGT group, including more frequent pain evaluation (P<0.001), more standardized dosing titration (P<0.001), and less frequent meperidine prescriptions (P<0.001). The pain scores in the CPGT group were significantly improved compared with the control group (P<0.05). The incidences of gastrointestinal adverse events were significantly lower in the CPGT group (constipation: P=0.041; nausea: P=0.028; vomiting: P=0.035), and overall quality of life was improved (P=0.032). No opioid addiction was encountered in the CPGT group. Risk analysis revealed that patient follow-up by pharmacists and the controlled dosing of opioids were the major factors in improving treatment efficacy. The CPGTs significantly improved standardization, efficiency, and efficacy of cancer pain therapy in China. In a country where clinical pharmacy is still developing, this is a valuable service model that may enhance cancer treatment capacity and efficacy while promoting recognition of the clinical pharmacy profession.


An unusual response to 5-azacitidine by a patient with chronic myelomonocytic leukemia.
Hypomethylating agents may be useful in some but not all cases of myelodysplastic syndromes. In some versions of these conditions, this treatment may yield deleterious results. Chronic myelomonocytic leukemia (CMML) is considered to be a heterogeneous group of hematopoietic neoplasms. Usually it shares the features of myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) and is known as MDS/MPN. It occurs mostly in the elderly and has an inherent tendency to transform to acute myeloid leukemia. FDA has approved hypomethylating agents (HMAs) such as 5-azacitidine (AZA) and decitabine (DEC) for the treatment of this disorder. The extent of response rate to AZA varies considerably among patients. Our report describes a patient with CMML who not only did not respond to a conventional dose of intravenous (IV) therapy with AZA, but showed marked progression of the disease with the leucocyte count rising exponentially while undergoing the aforesaid treatment. We believe this is the first such case reported in the currently extant literature.


Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder.
Pharmacotherapeutics for treatment of psychostimulant use disorder are still an unmet medical goal. Recently, off label use of modafinil (MOD), an approved medication for treatment of sleep disturbances, has been tested as a therapeutic for cocaine and methamphetamine use disorder. Positive results have been found in subjects dependent on psychostimulants without concurrent abuse of other substances. Novel structural analogs of MOD have been synthesized in the search for compounds with potentially broader therapeutic efficacy than the parent drug. In the present report we review their potential efficacy as treatments for psychostimulant abuse and dependence assessed in preclinical tests. Results from these preclinical proof of concept studies reveal that some modafinil analogs do not possess typical cocaine-like neurochemical and behavioral effects. Further, they might blunt the reinforcing effects of psychostimulants in animal models, suggesting their potential efficacy as pharmacotherapeutics for treatment of psychostimulant use disorders.


Multiple flexor tendon ruptures following Colles' fracture: a case report.
Flexor tendon ruptures are a very rare complication of Colles' fracture. Only ten cases have been previously reported in the literature. We describe a case of multiple sequential flexor tendon rupture as a delayed consequence of a malunited Colles' fracture.


A Comparison Study of Communication Skills Between General Surgery and General Practice Residents on First-time Patient Visits.
There is little published research about differences in doctor-patient communication of different specialties. Accordingly, we compared doctor-patient communication skills in two different specialties, general surgery (GS) and general practice (GP). Twenty residents from the Bahrain Defence Force Hospital (10 men and 10 women; mean age 28 years; 10 GS and 10 GP) participated in 200 patient first visit consultations. The consultations were video-recorded and analysed by four trained observers using the MAAS Global scale. 1) Internal consistency reliability of the MAAS Global (> 0.91) and Ep(2) = 0.84 for raters was high, 2) GP residents spent more time (12 minutes) than GS residents (7 minutes), in the visits, 3) There were several differences on the MAAS Global items between GP and GS residents (GS > GP, p < 0.05 on history taking, diagnosis and medical aspects; GP > GS, p < 0.05 on information giving), and 4) The present participants performed well compared to normative samples as well as to criterion-referenced cut-off scores. The general level of communication skills in both specialties, however, was 'unsatisfactory' and 'doubtful', as it is for normative samples. Excellent doctor-patient communication is essential but does not appear to receive the amount of attention that it deserves in practice settings. There are some differences between specialties as well as unsatisfactory communication skills for both specialties, since residents from both programs spent less time than recommended on each consultation. Our findings emphasize the need to improve the communication skills of physicians and surgeons in general.


Separation of antiepileptogenic and antiseizure effects of levetiracetam in the spontaneously epileptic rat (SER).
The long-lasting antiseizure effects of levetiracetam (LEV) have been observed in the spontaneously epileptic rat (SER) that expresses both tonic and absence-like seizures. Furthermore, the antiepileptogenic effects of LEV in addition to antiseizure effects have been reported in the amygdala-kindling model in rats. This suggests that the long-lasting seizure protection of LEV may be at least partly due to its antiepileptogenic effects. Therefore this study aimed to differentiate the antiseizure and potential antiepileptogenic effects of LEV by administering LEV continuously to SERs before the appearance of any seizure expression. LEV was administered to the SERs at 80 mg/kg/day (i.p.) from postnatal weeks 5 to 8. The period of observation for tonic convulsions was from postnatal week 5 to 13. Absence-like seizures were recorded by using conventional EEG in weeks 12 and 13. After age 7-8 weeks, SERs exhibit spontaneous tonic convulsions. Development of tonic convulsions was significantly inhibited in the LEV group, compared with the control group, by the middle of week 9. A significant reduction of tonic convulsions also was observed in the LEV group until week 13 (5 weeks after termination of the administration). In week 12, the absence-like seizures were significantly lower in the LEV group, compared with the control group. This study demonstrates a significant inhibition of seizures after prolonged treatment with LEV before the developmental expression of seizure activity in SERs. This effect is suggested to be due to an antiepileptogenic effect and not an antiseizure effect of LEV, because the half-life of the drug in plasma is short (2-3 h in rats) after single and long-term administration. Furthermore, the inhibition of seizure expression in SERs was still apparent 5 weeks after termination of LEV treatment. These results further suggest that LEV possesses not only antiseizure effects but also antiepileptogenic properties.


Aptitude of Lymnaea palustris and L. stagnalis to Fasciola hepatica larval development through the infection of several successive generations of 4-mm-high snails.
Bimiracidial infections of Lymnaea palustris and Lymnaea stagnalis (shell height at exposure, 4 mm) with Fasciola hepatica were carried out during six successive snail generations to determine if prevalence and intensity of snail infection increased over time through descendants issuing from eggs laid by parents already exposed to this digenean. Controls were constituted by a French population of Galba truncatula (a single generation) infected according to the same protocol. In a first experiment performed with the F1 to F5 generations of L. palustris, the prevalence and intensity of F. hepatica infection in snails progressively increased. Immature rediae and a few cercariae-containing rediae of the digenean were observed in L. stagnalis from the F3 generation, but no free cercaria was noted in the bodies of this lymnaeid from the F4 to F6 generations. In another experiment carried out with the F6 generation of L. palustris, the prevalence of F. hepatica infection and the number of shed cercariae were significantly lower in L. palustris than in G. truncatula. This mode of snail infection suggests an explanation for cases of human fasciolosis occurring in central France after the collection of wild watercress from beds where L. palustris was the sole lymnaeid.


Increased expression of neuronal cyclooxygenase-2 in the hippocampus in amyotrophic lateral sclerosis both with and without dementia.
The pathophysiological basis of cognitive dysfunction, including frontotemporal dementia (FTD), in patients with amyotrophic lateral sclerosis (ALS) and ALS with dementia (ALSD) remains unclear. On the other hand, increased expression of cyclooxygenase-2 (COX-2) in the spinal cord is thought to play a pivotal role in motor neuron degeneration in ALS. In this study, to assess the relationship between the neuronal COX-2 expression in the cerebrum, the formation of tau- and alpha-synuclein-negative but ubiquitin-positive neuronal inclusions (UPIs), and dementia in motor neuron disease (MND), we examined neuronal COX-2 immunoreactivity in the frontal cortex and hippocampus of patients with non-demented ALS without UPIs ( n=11), ALSD with UPIs ( n=6), and normal controls ( n=24) using a quantitative immunohistochemical technique. Neuronal COX-2 expression in all CA1-4 in the hippocampus was significantly up-regulated in the ALSD group, and, to lesser degree but significantly, in the ALS group. Neuronal COX-2 expression in the frontal cortex was also significantly up-regulated in the ALSD group but not in the ALS group. These findings suggest that (1) the frontal cortex and hippocampus of MND are involved in the same pathogenic process associated with COX-2 induction that has been observed in spinal anterior horn cells, (2) COX-2 induction in the cerebrum is a pathogenic process that can occur even in the absence of UPI formation in MND, and (3) COX-2 expression in the cerebrum may be associated with cognitive dysfunction in MND.


The Association between Health Behaviours and Academic Performance in Canadian Elementary School Students: A Cross-Sectional Study.
Establishing early healthy eating and physical activity behaviours is critical in supporting children's long-term health and well-being. The objective of the current paper was to examine the association between health behaviours and academic performance in elementary school students in a school board in Nova Scotia, Canada. Our population-based study included students in grades 4-6 across 18 schools in a rural school board. Diet and physical activity were assessed through validated instruments. Academic performance measures were obtained from the school board for Mathematics and English Language Arts (ELA). Associations between health behaviours and academic performance were assessed using multilevel logistic regression. Students with unhealthy lifestyle behaviours were more likely to have poor academic performance for both ELA and Mathematics compared to students with healthy lifestyle behaviours; associations were statistically significant for diet quality, physical activity, sugar-sweetened beverage consumption for ELA; and breakfast skipping, not being physically active at morning recess, and not being physically active after school for Mathematics. The effects of diet and physical activity were independent of each other and there was no interaction between the two exposures. Our findings suggest that support for healthy behaviours may help to improve academic outcomes of students.


Genetic effects and repair of DNA photo-adducts induced by 8-methoxypsoralen and homopsoralen (pyranocoumarin) in diploid yeast.
The relationship between DNA mono- and di-adducts and genetic effects induced by the pyranocoumarin 8,8-desmethylxanthyletine (homopsoralen) HP and 365 nm radiation (UVA) was investigated in the diploid yeast strain D7 (Saccharomyces cerevisiae) taking 8-methoxypsoralen (8-MOP) as a reference compound. The number of DNA cross-links (CLs) induced was determined using alkaline step elution analysis. The induction and removal of total photo-adducts was followed using radioactively labelled compounds. HP showed the same photobinding capacity as 8-MOP. As a function of UVA dose, it was less effective than 8-MOP for the induction of CLs and genetic effects. However, as a function of CLs induced, HP was shown to be more effective for the induction of lethal effects and mitotic recombination than 8-MOP but equally effective for the induction of mutations. The results suggest that, although CLs are recognized as genetically effective lesions, at a given number of CLs, HP induced mono-adducts efficiently contribute to the induction of lethal effects and mitotic recombination but less to the induction of mutations. Using a re-irradiation protocol, HP was brought to yield the same relative amounts of CLs at the same number of total adducts as single UVA exposures with 8-MOP. In these conditions, mutation induction and the kinetics for the removal of photo-adducts were the same for both agents indicating that not only the removal of adducts but also mutation induction are highly dependent on the relative level of CLs induced.


Processing and function of undermethylated chicken embryo fibroblast mRNA.
Cycloleucine (1-aminocyclopentane-1-carboxylic acid) is a potent inhibitor of RNA methylation in B77 sarcoma virus-infected chicken embryo fibroblasts. Under conditions where 40 mM cycloleucine is present, internal N-6-methyladenosine and 5'-terminal cap 2'-O-ribose methylations of poly(A)+ RNA are inhibited greater than 90%. The methylation of the 5'-terminal 7-methylguanosine, however, does not appear to be significantly affected. The poly(A)+ RNA synthesized in cycloleucine-treated cells is transported from the nucleus to the cytoplasm and associates with polyribosomes at rates comparable to poly(A)+ RNA in untreated cells. On the other hand, the transport and utilization of newly synthesized ribosomal RNA in cycloleucine-treated cells is impaired, and the accumulation of mature 18 S and 28 S rRNA is reduced.


Effectiveness of bivalent mRNA vaccines against medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission among SARS-CoV-2-naive and previously infected individuals: a retrospective cohort study.
Emergence of the SARS-CoV-2 omicron (B.1.1.529) variant with high immune evasion has led to the development and roll-out of bivalent mRNA vaccines targeting original and omicron strains. However, real-world observational data on effectiveness of bivalent vaccines are scarce. We aimed to assess the relative effectiveness of a fourth vaccine dose with the BA.1-adapted or BA.4/BA.5-adapted bivalent vaccines against medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission among SARS-CoV-2-naive and previously infected individuals in Singapore. We conducted a retrospective cohort study among Singapore residents aged 18 years and older who had received three monovalent mRNA vaccine doses and were eligible for a fourth dose. Data were collected from official databases on COVID-19 cases and vaccinations maintained by the Singapore Ministry of Health. We analysed the incidence of medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission between Oct 14, 2022, and Jan 31, 2023, by previous infection status and type of fourth vaccine dose received. Inverse probability-weighted Cox regressions were used to estimate hazard ratios (HRs). 2 749 819 individuals were included in the analysis. For the SARS-CoV-2-naive group, a fourth monovalent vaccine dose did not confer additional protection over three monovalent doses against symptomatic infection (HR 1·09 [95% CI 1·07-1·11]), whereas the bivalent vaccine did provide additional protection (0·18 [0·17-0·19]). Among individuals with previous infection, the HR was 0·87 (95% CI 0·84-0·91) and 0·14 (0·13-0·15) with receipt of the fourth monovalent and bivalent doses, respectively. Against COVID-19-related hospital admission, the bivalent vaccine (HR 0·12 [95% CI 0·08-0·18] in SARS-CoV-2-naive participants and 0·04 [0·01-0·15] in previously infected participants) conferred greater benefit compared with the fourth monovalent dose (0·84 [0·77-0·91] in SARS-CoV-2-naive participants and 0·85 [0·69-1·04] in previously infected participants). A fourth dose with the bivalent vaccine was substantially more effective against medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission than four monovalent doses among both SARS-CoV-2-naive and previously infected individuals. Boosters with the bivalent vaccine might be preferred in this omicron-predominant pandemic, regardless of previous infection history. None.


Diagnosis of Acquired Uterine Arteriovenous Malformation by Doppler Ultrasound.
Acquired uterine arteriovenous malformation (AVM) is a rare cause of postpartum vaginal bleeding and can often be confused with retained products of conception (RPOC). Certain findings on ultrasound (US) increase the likelihood for AVM, such as hypoechoic areas in the myometrium and high velocity, multidirectional blood flow. Recognizing these changes on bedside US can cue the physician to send the patient for further studying and lead to the correct diagnosis. A 31-year-old, multigravida, multiparous female presented 5 weeks post-cesarean section with heavy, intermittent vaginal bleeding. Patient had multiple previous visits for similar bleeding, including an evaluation for RPOC. Upon current presentation, the patient underwent an US in the emergency department with color and pulse wave Doppler. US revealed a hypoechoic area within the myometrium, with high velocity, bidirectional blood flow, raising the clinical suspicion for uterine AVM. Following confirmatory studies, the patient underwent successful embolization of the AVM. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The proper diagnosis of AVM is crucial, because the primary treatment modality for the alternative diagnosis of RPOC (i.e., dilation and curettage) can worsen vaginal bleeding and lead to shock or death, and is therefore contraindicated for uterine AVM. US is a quick bedside tool that can be used for rapid diagnosis of uterine AVM.


Hereditary motor and sensory neuropathy type II (HMSN-II) and neurogenic muscle hypertrophy: a case report and literature review.
We present two siblings affected by hereditary motor and sensory type II neuropathy (HMSN-II) with neuromyotonia, and associated with muscle hypertrophy of the thighs and calves in one. We review the literature about the association between HMSN-II, neuromyotonia and muscle hypertrophy. Muscle enlargement in HMSN-II is rare and may be sporadic or under genetic control. In our patient, muscle hypertrophy was sporadic and probably due to neuromyotonia. The relationship between muscle hypertrophy and neuromyotonia can be deduced by the fact that both conditions were reduced after diphenylhydantoin treatment (200 mg/day).


Antibody-based binding domain fused to TCRγ chain facilitates T cell cytotoxicity for potent anti-tumor response.
Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated potent clinical efficacy in the treatment of hematopoietic malignancies. However, the application of CAR-T in solid tumors has been limited due in part to the expression of inhibitory molecules in the tumor microenvironment, leading to T-cell exhaustion. To overcome this limitation, we have developed a synthetic T-cell receptor (TCR) that targets programmed death-ligand 1 (PD-L1), a molecule that is widely expressed in various solid tumors and plays a pivotal role in T-cell exhaustion. Our novel TCR platform is based on antibody-based binding domain, which is typically a single-chain variable fragment (scFv), fused to the γδ TCRs (TCRγδ). We have utilized the T-cell receptor alpha constant (TRAC) locus editing approach to express cell surface scFv of anti-PD-L1, which is fused to the constant region of the TCRγ or TCRδ chain in activated T cells derived from peripheral blood mononuclear cells (PBMCs). Our results indicate that these reconfigured receptors, both γ-TCRγδ and δ-TCRγδ, have the capability to transduce signals, produce inflammatory cytokines, degranulate and exert tumor killing activity upon engagement with PD-L1 antigen in vitro. Additionally, we have also shown that γ-TCRγδ exerted superior efficacy than δ-TCRγδ in in vivo xenograft model.


The Pharmacokinetics of Drugs Delivered to the Upper Nasal Space.
Pharmacokinetics (PK) includes how a drug is absorbed, distributed, metabolized and eliminated. The compartment providing this information is usually the plasma. This is as close to the tissue of interest that we can get, although biopsies may be obtained to give "tissue levels" of drugs. Ultimately, the goal of PK is to understand how long the drug is actually engaged with the target in the tissue of interest after a dose has been administered. Most drugs at some point in their development will have been administered intravenously (IV), which acts as the standard for 100% bioavailability. By comparing various routes of administration to IV, the percentage of drug delivered to the plasma, on a dose-normalized basis, can be calculated and is referred to as the "absolute bioavailability". As pharmacology has advanced and more drugs have become available, many older products have been reformulated to be given by routes other than those originally intended (often oral). As the drawbacks of oral (or IV) administration have become better appreciated, non-oral, non-IV formulations and methods of administration have become more popular. Nasal administration is one route that has historically been overlooked as an alternative to oral administration-particularly for products needing rapid and non-invasive access to the target tissue-mostly via the blood stream. But attention is now focused on nasal administration for direct access to the brain, as that has the potential to bypass the blood-brain-barrier (BBB), which not even IV administration can always achieve. Assessing PK for these drugs targeting the brain may require serial sampling of the cerebrospinal fluid (CSF), making PK assessments of CNS drugs more invasive and complex, but still possible in future product development. However, we are now seeing more drugs reformulated for nasal delivery to gain faster systemic levels than oral administration (especially in patients with known or suspected gastrointestinal dysmotility), while avoiding the use of needles. For example, in recent years several different formulations and delivery methods for an old drug, dihydroergotamine (DHE), have been developed and these show very different characteristics, suggesting that delivery to different parts of the nose may have very different PK profiles. This review summarizes the systemic PK of different nasal DHE options that have been, or are being, developed and suggests that delivery of drugs to the upper nasal space (UNS) may represent an optimal target. Further research is required to ascertain if this route could also be utilized for direct administration to the CNS (as an attractive alternative to intrathecal delivery) via the olfactory or trigeminal nerves-but already preclinical data (and some human data) suggest this is entirely possible.


Towards a new approach for managing pandemics: Hybrid resilience and bowtie modelling.
Pandemic viruses have historically caused tremendous damage to lives and livelihoods. The coronavirus, COVID-19, has proven to be a significant issue around the world. In this paper it is argued that systems of controlling similar types of disasters need to be improved through learning from past experience and from others, as well as through improved modelling for better decision making. In doing so, the focus will be on resilience modelling and learning from incidents. Therefore, in this paper, first the introduction deals with hybrid approaches in operational research highlighting the differences between hybrid modelling and hybrid models. Second, an introduction to mathematical modelling of epidemics is provided and how such modelling leads to certain types of public health modelling is demonstrated. Third, resilience modelling will be discussed as a complimentary type of modelling, where concepts related to robustness, redundancy, resourcefulness, and rapidity are introduced. Fourth, resilience modelling will be extended to new principles taking COVID-19 as an example for the analysis. Fifth, the analysis will then be used to compare degrees of resilience for different countries. Finally, other modelling approaches for managing - and learning from - pandemics, in terms of root cause analysis, bowtie modelling and safety barriers, are proposed.


Effects of parental and progeny rearing densities on locomotor activity of 1st-stadium nymphs in the migratory locust, Locusta migratoria: an analysis by long-term monitoring using an actograph.
The effects of parental and progeny rearing densities on locomotor activity in 1st-stadium nymphs of the migratory locust, Locusta migratoria, were observed over a 24- or 36-h period using an actograph. Newly hatched nymphs showed a small activity peak shortly after hatching and the peak level was significantly higher in offspring (gregarious nymphs) of crowd-reared adults than in those (solitarious nymphs) of isolated-reared adults. However, no significant difference was found between the two groups in maximum activity levels exhibited after the initial peak. Post-hatching crowding enhanced locomotor activity during 2-5h of measurements in 2-day-old nymphs. In this case, the parental density resulted in no significant influence on locomotor activity. However, the maximum activity level shown later in the observation period was higher in gregarious nymphs than in solitarious nymphs. Interestingly, this parental effect was more pronounced in nymphs reared in group than in those reared in isolation. The parental density appeared to affect the degree of response to crowding in the progeny. No evidence was found for the phase accumulation in terms of locomotor activity. The variation observed in locomotor activity among geographical populations did not correspond to their phylogenetic relationships.


A contemporary description of French newborns' growth using the Efemeris cohort.
Overweight and obesity in childhood are a major concern in developed countries. Reference growth curves are used in current practice to identify children at risk, especially at risk of overweight or obesity. National reference growth curves were published 35 years ago from children born in the 1950s to study growth from birth to adulthood. Additionally, more recent national curves exist to study birth weight and height according to gestational age. The primary objective was to describe anthropometric measurements of French children born in the 2000s and to compare them with the French references. The secondary objective was to describe overweight indicators during infancy. A total of 77,315 singletons live-born from 1 July 2004 to 31 December 2013 recorded in the Efemeris (a French cohort of women and their children) were included. The z-score means based on the French references for weight, height, and body mass index (BMI) at birth, 9 months, and 24 months were calculated. At birth, the weight and height of the cohort did not deviate from the recent French references taking into account gestational age. At 9 and 24 months, the cohort was between 0.12 and 0.39 standard deviations (SD) heavier and between 0.70 and 0.97 SD taller than the old French reference population. Between 0 and 2 years, 28.6% of the children underwent a rapid weight gain (change in SD scores>0.67). The prevalence of overweight at 2 years was between 5 and 6% using the International obesity task force (IOTF) references. The distributions of the height, weight, and BMI during early childhood differ from those of children in the national growth references. Contemporary children at 2 years are taller and heavier than children born in the 1950s. Approximately one in 20 children is overweight at 2 years.


In vivo 19F-NMR of 5-fluorouracil incorporation into RNA and metabolites in Escherichia coli cells.
19F resonances from RNA with 5-fluorouracil incorporated could be observed in intact Escherichia coli cells, as well as in tRNA isolated from the cells. 19F-NMR signals from the metabolic breakdown products of the fluorinated RNA were also detected in vivo. By observing the 19F-NMR spectrum, variations in the metabolic disposition of administered 5-fluorouracil could be monitored as a function of time and be compared when the cells were deprived of oxygen and other nutrients, subjected to ethidium bromide treatment, or grown in the presence of mitomycin C.


Survey of isoenzymes in the snail Cepaea nemoralis using different buffer/gel systems in polyacrylamide disc gel electrophoresis: validity of comparisons and effect of "nothing dehydrogenase" activity.
An investigation into isoenzymic analysis using four different buffer/gel systems was carried out. Fourteen different isoenzyme systems were surveyed on each buffer/gel system. It is shown that comparable results are not obtained between different systems. Previous workers in Cepaea nemoralis have used different buffer/gel systems from one another. Alkaline phosphatase and acid phosphatase and certain lactate and malate dehydrogenases are shown to behave similarly in three different systems. It is tentatively suggested that these isoenzymes may be genetically identical. "Nothing dehydrogenase" activity is demonstrated in gels stained for other dehydrogenases. It is suggested that nothing dehydrogenase activity may be attributable to glutamate or malate dehydrogenase.


Teleneurocritical Care for Patients with Large Vessel Occlusive Ischemic Stroke Treated by Thrombectomy.
Teleneurocritical care (TNCC) provides 24/7 virtual treatment of patients with neurological disease in the emergency department or intensive care unit. However, it is not known if TNCC is safe, effective, or associated with similar outcomes compared with in-person neurocritical care. We aim to determine the effect of daily inpatient consults from TNCC on the outcomes of patients with large vessel occlusive acute ischemic stroke treated by thrombectomy. A multicenter, retrospective cohort of consecutive patients ≥ 18 years old with acute ischemic stroke from a large vessel occlusion treated by thrombectomy were identified from 2018 to 2021 within a telehealth network of an integrated not-for-profit health care system in the United States. The primary end point was good functional outcome, i.e., modified Rankin Scale 0-3, at the time of hospital discharge in patients receiving in-person neurocritical care versus TNCC. A total of 437 patients met inclusion criteria, 226 at the in-person hospital (median age 67, 53% women) and 211 at the two TNCC hospitals (median age 74, 49% women). The rate of successful endovascular therapy (modified Thrombolysis in Cerebral Infarction score 2b-3) was not different among hospitals. Good functional outcome at discharge was similar between in-person neurocritical care and TNCC (in-person 31.4% vs. TNCC 33.5%, odds ratio 0.88, 95% confidence interval 0.6-1.3; p = 0.64). Only National Institutes of Health stroke scale and age were multivariable predictors of outcome. There were no differences in mortality (9.3% vs. 13.2%, p = 0.19), intensive care unit length of stay (2.1 vs. 1.9 days, p = 0.39), or rate of symptomatic intracerebral hemorrhage (6.8% vs. 6.6%, p = 0.47) between in-person neurocritical care and TNCC. Teleneurocritical care allows for equivalent favorable functional outcomes compared with in-person neurocritical care for patients with acute large vessel ischemic stroke receiving thrombectomy. The standardized protocols used by TNCC in this study, specifically the comprehensive 24/7 treatment of patients in the intensive care unit for the length of their stay, may be relevant for other health systems with limited in-person resources; however, additional study is required.