Organic solution versus aqueous dispersion of Eudragit RS in preparation of sustained release microparticles of theophylline using spray drying.
The aim of this study was to compare aqueous dispersion and organic solution of Eudragit RS in preparation of sustained release theophylline microparticles using spray drying technique. Spray dried samples (SD) with drug:polymer (D:P) ratios of 1:1, 1:2, 1:3 were prepared using aqueous dispersion (SDaq) or organic solutions of Eudragit RS in ethanol (SDor). Properties of spray dried samples including yield, particle morphology, size distribution and drug dissolution were examined. Differential scanning calorimetry (DSC) and FTIR studies were performed to track any polymorphic changes in drug and/or drug- polymer interaction respectively. The SD samples were compacted and the crushing strengths and release profiles of tablets were determined. The yields of samples were in the range of 33-74%. The yield was higher for SDaq samples, being higher at higher D:P ratios. The SDor samples were smaller in size. SEM images confirmed the formation of spherical particles with somehow different structures for SDaq or SDor samples. Tablets prepared from SDor samples exhibited the highest crushing strengths. In study on release profiles for uncompacted samples, SDor samples exhibited superior sustained release properties. The same results were observed for compacted SD samples. DSC studies showed no polymorphism in SD samples and FTIR analysis showed that there was not any interaction between drug and polymer. In conclusion spray dried samples prepared from organic solution of Eudragit RS had superior sustained release properties and have more potential for application in sustained release formulation of theophylline than aqueous dispersion of the polymer.


Evaluation of a staff manual for improving work performance of retarded clients in sheltered workshops.
A self-instruction manual to develop a production supervisory strategy (PSS) was studied as an aid for staff responsible for supervising production of 80 retarded persons working on contract assembly tasks in sheltered work settings. The manual was introduced in a multiple-baseline across three groups of staff and clients. Subsequently, at the request of the first author, the PSS developed via the manual was withdrawn in a multiple-baseline across the three groups. Average hourly production increased for 77 of the 80 clients under the PSS as compared to the mean production during baseline, with an average percentage increase for all clients of 68%. The error rates were not affected by the changes in production rates. Mean production rates decreased when the PSS was withdrawn. A preference test showed that all of the clients were in favor of the PSS. A staff questionnaire indicated that all the staff recommended the use of the PSS for the benefit of the clients and as a personal preference for work conditions. Following the completion of data collection, staff in all settings voluntarily reintroduced the PSS. Many components of the PSS were still in effect with all three groups at an 11-month follow-up, and with two of the groups at a 20-month follow-up. Failure to maintain the PSS in a group coincided with complete staff turnover for that group. It was concluded that the PSS can be effectively implemented by workshop staff on the basis of a self-help manual.


Caregiving in U.S. Gulf States During Natural Disasters and COVID-19.
To ascertain common experiences and needs of a diverse group of caregivers challenged by hurricanes/floods and COVID-19. In-depth interviews with unpaid caregivers in U.S. Southeast/Gulf Coast states who had experienced caregiving during a natural disaster and during COVID-19. Caregivers report challenges including daily living disruption, altered social supports, complicated health management, additional disaster planning, and emotional/financial impacts. Caregivers suggested helpful resources, policy options, and preparatory tools at individual, local, and health system levels to mediate discontinuity. Our data describe combined caregiver experiences of hurricanes/floods and the pandemic. Caregivers experience unique burdens related to care recipient diagnosis, location, and veteran status. Access to community supports varies as they manage the tasks required for care recipients' health and safety. Our findings indicate the need for public health reinforcement of caregiving though caregiver pre-planning and targeted support. Bolstering understanding of communities' caregiving capacity though first responder trainings and caregiver registries may enhance health and safety.


Gold-Catalyzed Addition-N-Boc Cleavage-Cyclization of N,O-Acetal with Ynamides for Construction of 6-(tert-Butyldimethylsilyl)oxy-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-ones.
A highly efficient gold-catalyzed approach between N,O-acetals and ynamides for the construction of 6-(tert-butyldimethylsilyl)oxy-tetrahydropyrrolo[1,2-c][1,3]oxazin-1-ones was developed. This reaction tolerated a wide range of substituted N,O-acetals and TsN-substituted ynamides, leading to novel heterocycles in moderate to good yields and with excellent diastereoselectivities (dr > 99:1).


Structural basis for the SUMO protease activity of the atypical ubiquitin-specific protease USPL1.
Post-translational protein modifications by ubiquitin and ubiquitin-like modifiers regulate many major pathways in the cell. These modifications can be reversed by de-ubiquitinating enzymes such as ubiquitin-specific proteases (USPs). Proteolytic activity towards ubiquitin-modified substrates is common to all USP family members except for USPL1, which shows a unique preference for the ubiquitin-like modifier SUMO. Here, we present the crystal structure of USPL1 bound to SUMO2, defining the key structural elements for the unusual deSUMOylase activity of USPL1. We identify specific contacts between SUMO2 and the USPL1 subdomains, including a unique hydrogen bond network of the SUMO2 C-terminal tail. In addition, we find that USPL1 lacks major structural elements present in all canonical USPs members such as the so-called blocking loops, which facilitates SUMO binding. Our data give insight into how a structural protein scaffold designed to bind ubiquitin has evolved to bind SUMO, providing an example of divergent evolution in the USP family.


Up-to-date tools for risk assessment before allogeneic hematopoietic cell transplantation.
Cure of malignant and non-malignant hematological diseases is potentially possible after allogeneic hematopoietic stem cell transplantation (HCT). Accurate evaluation of the risk-benefit ratio for an individual patient could improve the decision-making process about transplant, which ultimately would increase the likelihood of success. Several transplant-related models were designed in an effort to optimize decision-making about suitable candidates for allogeneic HCT. In 1998, The European Society for Blood and Marrow Transplantation (EBMT) developed a five-component pretransplantation risk scoring system for patients with CML. The EBMT score was later tested in patients with various hematological disorders, and it was shown to stratify risks of mortality after allogeneic HCT. More recent research efforts focused on models that assess health status before HCT. A HCT-specific comorbidity index was designed to assign weights to 17 relevant comorbidities that were shown to independently predict non-relapse mortality. Performance status scales and comprehensive geriatric assessment tools might uncover additional overall health limitations that affect long-term survival among older recipients of allogeneic HCT. Other models include the pretransplantation assessment of mortality score that summarizes the impacts of eight different pretransplantation patient- and disease-specific variables into a 50-point model that predicts survival. The disease-risk index captures the impact of primary diagnoses and disease status on relapse and survival following allogeneic HCT. The values and limitations of each model are discussed herein. We also provide insight on how to use these models in the clinic to decide about offering allogeneic HCT with the most suitable conditioning regimen intensity.


Production of low-expressing recombinant cationic biopolymers with high purity.
The growing complexity of recombinant biopolymers for delivery of bioactive agents requires the ability to control the biomaterial structure with high degree of precision. Genetic engineering techniques have provided this opportunity to synthesize biomaterials in an organism such as E. coli with full control over their lengths and sequences. One class of such biopolymers is recombinant cationic biopolymers with applications in gene delivery, regenerative medicine and variety of other biomedical applications. Unfortunately, due to their highly cationic nature and complex structure, their production in E. coli expression system is marred by low expression yield which in turn complicates the possibility of obtaining pure biopolymer. SlyD and ArnA endogenous E. coli proteins are considered the major culprits that copurify with the low-expressing biopolymers during the metal affinity chromatography. Here, we compared the impact of different parameters such as the choice of expression hosts as well as metal affinity columns in order to identify the most effective approach in obtaining highly pure recombinant cationic biopolymers with acceptable yield. The results of this study showed that by using E. coli BL21(DE3) LOBSTR strain and in combination with our developed stringent expression and Ni-NTA purification protocols highly pure products in one purification step (>99% purity) can be obtained. This approach could be applied to the production of other complex and potentially toxic biopolymers with wide range of applications in biomedicine.


Clear aligner mandibular advancement in growing patients with Class II malocclusion.
Treatment effects occurring during Class II malocclusion treatment with the clear aligner mandibular advancement protocol were evaluated in two growing patients: one male (12 years, 3 months) and one female (11 years, 9 months). Both patients presented with full cusp Class II molar and canine relationships. Intraoral scans and cone-beam computed tomography were acquired before treatment and after mandibular advancement. Three-dimensional skeletal and dental long-axis changes were quantified, in which the dental long axis was determined by registering the dental crowns obtained from intraoral scans to the root canals in cone-beam computed tomography scans obtained at the same time points. Class II correction was achieved by a combination of mandibular skeletal and dental changes. A similar direction of skeletal and dental changes was observed in both patients, with downward and forward displacement of the mandible resulting from the growth of the mandibular condyle and ramus. Dental changes in both patients included mesialization of the mandibular posterior teeth with flaring of mandibular anterior teeth. In these two patients, clear aligner mandibular advancement was an effective treatment modality for Class II malocclusion correction with skeletal and dental effects and facial profile improvement.


Ceramide-induced activation of cytosolic NADH/cytochrome c electron transport pathway: An additional source of energy for apoptosis.
We have investigated whether increase in the oxidation rate of exogenous cytochrome c (cyto-c), induced by long-chain ceramides, might be due to an increased rate of cytosolic NADH/cyto-c electron transport pathway. This process was identified in isolated liver mitochondria and has been studied in our laboratory for many years. Data from highly specific test of sulfite oxidase prove that exogenous cyto-c both in the absence and presence of ceramide cannot permeate through the mitochondrial outer membrane. However, the oxidation of added NADH, mediated by exogenous cyto-c and coupled to the generation of a membrane potential supporting the ATP synthesis, can also be stimulated by ceramide. The results obtained suggest that ceramide molecules, by increasing mitochondrial permeability, with the generation of either raft-like platforms or channels, may have a dual function. They can promote the release of endogenous cyto-c and activate, with an energy conserving process, the oxidation of cytosolic NADH either inducing the formation of new respiratory contact sites or increasing the frequency of the pre-existing porin contact sites. In agreement with the data in the literature, an increase of mitochondrial ceramide molecules level may represent an efficient strategy to activate and support the correct execution of apoptotic program.


Triamcinolone acetonide aqueous nasal spray improves nocturnal rhinitis-related quality of life in patients treated in a primary care setting: the Quality of Sleep in Allergic Rhinitis study.
Sleep disturbances due to allergic rhinitis can contribute to daytime fatigue, impair mood, and decrease daytime functioning. To measure allergic rhinitis patients' nocturnal rhinitis-related quality of life using a new, validated disease-specific instrument, the Nocturnal Rhinoconjunctivitis Quality of Life Questionnaire (NRQLQ). This open-label study was conducted in a primary care setting. Adult patients with seasonal or perennial allergic rhinitis rated nocturnal rhinitis-related quality of life using the NRQLQ and sleep disturbances using the Pittsburgh Sleep Quality Index (PSQI) at baseline and after 3 weeks of treatment with triamcinolone acetonide aqueous nasal spray (TAA AQ), 220 microg/d. Changes from baseline in overall and individual domain scores for both the NRQLQ and PSQI were evaluated using t tests for paired differences. The majority of the patients (N = 651) were female (58%), were white (85%), and shared a bed with a partner (63%). Mean +/- SD patient age was 45.7 +/- 15.5 years. TAA AQ treatment was associated with significant improvements in overall NRQLQ score (mean +/- SD change, -1.5 +/- 1.3; P < .001) and in individual domain scores (P < .001 for sleep problems, symptoms during sleep, symptoms upon waking in morning, and practical problems). Similarly, overall and individual PSQI domain scores were statistically significantly improved (P < .001). There were strong correlations between NRQLQ and PSQI scores (all comparisons P < .001). Treatment with TAA AQ for 3 weeks resulted in statistically significant improvements in nocturnal rhinitis-related quality of life and sleep quality in allergic rhinitis patients treated in a primary care setting.


DNA encapsidation as a target for anti-herpesvirus drug therapy.
The current repertoire of approved anti-herpesviral drugs consists primarily of nucleoside analogues that inhibit viral replication by targeting the virus-encoded DNA polymerase. This class of agents has been critical in controlling infections by herpes simplex, varicella zoster, and cytomegalovirus. However, because nucleoside analogues share a similar mechanism of action, treatment options are limited once resistance develops. This becomes an important medical issue with respect to the treatment of disease caused by resistant viral strains, particularly in immunocompromised individuals. Furthermore, several of the currently available therapies can result in mild to severe side effects making the discovery of less toxic drugs desirable. Efforts over the last decade have focused on the identification and development of improved therapies including less toxic compounds with novel mechanisms of action. Here we review the progress that has been made in targeting the DNA packaging and encapsidation process as a novel target for chemotherapy. Several recently identified compounds may warrant further development as a medically important group of herpesviral encapsidation inhibitors.


Impacts of electrical parameters on the electroformation of giant vesicles on ITO glass chips.
A "sandwich" structure device consisted of ITO electrodes and PDMS spacer was designed and used to explore the impact of different electrical parameters (intensity and frequency) on the electroformation of GUVs (giant unilamellar vesicles). Theoretical analysis of the dielectrophoretic effect (DEPE) and the electrohydrodynamic effect (EHE) on the electroformation process indicated that the characteristic frequency of the system could maximize the mutual effect of the both, which might benefit the formation of GUVs. The calculated value of the characteristic frequency (13.3 kHz) was very close to the experimental one (11 kHz). We demonstrated that for a given electroformation system, large amount of well-distributed GUVs can be obtained by optimizing the electrical parameters. In this paper, when choosing the optimal electrical parameters (11 kHz frequency and 5V/mm intensity), the amount of GUVs could reach 65/mm(2), and the diameters of most GUVs (>70%) were 50-70 μm.


Mitogenic lectins bind to the antigen receptor on human lymphocytes.
The specificity of interactions between mitogenic and non-mitogenic lectins and disulfide-linked cell surface receptors on human lymphocytes was explored. Lysates (Nonidet-P40) of surface-radioiodinated tonsil lymphocytes and T lymphoblastoid cells (HPB-ALL) were absorbed with lectin-agarose derivatives (or bovine serum albumin, BSA-agarose) or immunoprecipitated with appropriate monoclonal antibodies (mAb). Lectin eluates and solubilized immunoprecipitates were analyzed by two-dimensional (nonreduced/reduced) sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Radiolabeled polypeptides were visualized by autoradiography. Among the various lectin-binding polypeptides, two disulfide-linked heterodimers (II and III) and two apparent homodimers (I and IV) are bound by pea lectin, concanavalin A and lentil lectin on tonsil lymphocytes; II, III and IV are bound both leukoagglutinating (L)- and erythroagglutinating (E)-phytohemagglutinins from Phaseolus vulgaris (PHA). Pokeweed mitogen recognizes only II and III. These molecules are weakly bound by peanut agglutinin, soybean agglutinin, Ulex europaeus agglutinin-I, Dolichos biflorus agglutinin, Vicia villosa agglutinin and Sophora japonica agglutinin, but are not bound by Helix pomatia agglutinin or BSA-agarose. Heterodimer II (82-88 kDa), comprised of 50-55-kDa and 40-43-kDa subunits, probably represents the alpha/beta T cell antigen receptor (TcR alpha/beta). Heterodimer III (64-72 kDa), comprised of 41-kDa and 37-kDa subunits, may represent TcR gamma. The homodimers, I (120-130 kDa) and IV (55-61 kDa), comprised of 55-60-kDa and 30-kDa polypeptides, respectively, have apparently not been previously described. Evidence that H1-2D4, a mAb directed against the antigen receptor on HPB-ALL cells, and E-PHA interact with a common molecule includes: (a) immunoprecipitation of TcR with H1-2D4 from the glycopeptide fraction specifically eluted from insolubilized lectin with N-acetylgalactosamine; and (b) adsorption of TcR from a solubilized H1-2D4 immunoprecipitate by E-PHA-agarose. Recognition of CD3 by E-PHA is indicated by immunoprecipitation of CD3 protein by UCHT1 from the glycopeptide fraction specifically eluted from E-PHA. The results are consistent with the view that mitogenic lectins interact with certain disulfide-linked molecules on human lymphocytes, including the TcR alpha/beta and perhaps TcR gamma; while some nonmitogenic lectins also recognize these receptors, the interaction is of low affinity.


A phase-contrast and immunofluorescence study of adrenal medullary chromaffin cells in culture: neurite formation, actin and chromaffin granule distribution.
Immunofluorescence studies of bovine chromaffin cells in culture with specific antibodies against dopamine-beta-hydroxylase gave a distinct punctate pattern of labelling, reflecting the distribution of chromaffin granules. There was strong staining of cell extensions and growth ones. Linear arrays of fluorescent dots were observed, suggesting an association of granules with a filamentous cytoskeleton. Labelling of neuritic processes was periodic, perhaps indicative of a packaging of secretory granules. Chromaffin cells stained strongly with specific anti-actin antisera. Fine filament bundles were observed, and also diffuse staining, some punctate labelling and staining of the plasma membrane or sub-membranous cytoplasm. Growth cones and non-terminal cytoplasmic varicosities contained significant amounts of actin. Colchicine (5 X 10(-5) M) caused retraction of neuritic extensions and formation of lateral growth cones. Cytochalasin (10 microgram/ml) caused ballooning of terminal growth cones and non-terminal cytoplasmic varicosities. Phalloidin (10(-4) M) stimulated microspike formation. The results are discussed in terms of the role of the cytoskeleton in growth cone formation, cell-substratum contacts and the transport of chromaffin granules.


Mechanism of trophoblast cell-derived microparticles mediated immunocontraceptive response.
Immunomodulation profoundly affects the process of human implantation. Trophoblast cell-derived microparticles (Tr-MPs) may activate specific T cells to attack trophoblast cells, thus potentially acting as an immunocontraceptive vaccine. The safety and persistence of Tr-MP vaccine are needed to address. Flow cytometry and confocal fluorescent microscopy were conducted to detect cellular absorptivity and localization of Tr-MPs in bone marrow-derived dendritic cells (BMDCs). The phenotype and cytokine secretion of BMDC and T cells were performed by flow cytometry and enzyme-linked immuno sorbent assay (ELISA). The constructed vaccine female moused model were used to observe the infertile effect and safety of Tr-MPs. As compared with non-irradiation exposure groups, the number of MPs released by trophoblast cells in ultraviolet immunized groups significantly increased. The phagocytosis of Tr-MPs led to the maturation of dendritic cells (DCs), which, in turn, activate T cells. Then cytotoxic T cells attacking trophoblast cells. In mouse model, female mice were infertile after receiving Tr-MPs, and the effect of contraception is transient and safety. Using Tr-MPs to initiate an adaptive immune response against alloantigens in trophoblast cells. Tr-MPs may be a new candidate for the development of contraceptive vaccines due to its effectiveness, safety, and reversibility.


Orbital rehabilitation: surgical and prosthetic.
Restoration of facial symmetry is the goal in rehabilitation of an orbit disfigured by trauma or tumor extirpation. Successful rehabilitation may require replacement of repositioning of the orbital walls and/or construction of a complex orbital prosthesis. Preoperative communication among the head and neck surgeon, ophthalmologist, and maxillofacial prosthodontist is essential.


CD28 costimulation enhances the sensitivity of the ELISPOT assay for detection of antigen-specific memory effector CD4 and CD8 cell populations in human diseases.
The frequencies of antigen-specific memory cells are often low in chronic disease states related to infection and autoimmunity, making detection of such populations difficult, even with high sensitivity assays such as the cytokine enzyme-linked immunospot (ELISPOT). The spectrum and function of antigen presenting cells (APC) in the peripheral compartment can differ considerably from the inflamed target organ. In order to approximate the costimulatory environment of the target organ, we measured T cell responses with and without the addition of agonistic anti-CD28 antibody in the ELISPOT assay. CD4 and CD8 IFN-gamma responses to viral (hepatitis C) and autoimmune antigens (islet cell) were tested in 10 hepatitis C and 8 type 1 diabetic as well as healthy control subjects. IFN-gamma responses to tetanus toxoid, mumps and cytomegalovirus (CMV) protein antigen, as well as Epstein-Barr virus and CMV peptides were also measured in healthy control subjects. We found higher frequencies of T cells reactive to protein and peptide antigens when anti-CD28 antibody was present, often detecting responses only in the presence of anti-CD28 antibody. These results demonstrate that anti-CD28 antibody signal enhanced ELISPOT assays can facilitate the identification of low precursor frequency T cells in chronic infectious and autoimmune disease states where suboptimal costimulatory environment may exist in the periphery. The use of such costimulation may also enable a more quantitative assessment of circulating memory effector T cell frequency.


A family of neuropeptides that inhibit juvenile hormone biosynthesis in the cricket, Gryllus bimaculatus.
Four nonapeptides that inhibit juvenile hormone synthesis have been isolated by four high performance liquid chromatographic steps from extracts of the brain of the field cricket, Gryllus bimaculatus. The primary structures of these peptides were assigned by Edman degradation and mass spectrometry as Gly-Trp-Gln-Asp-Leu-Asn-Gly-Gly-Trp-NH2 (Grb-AST B1), Gly-Trp-Arg-Asp-Leu-Asn-Gly-Gly-Trp-NH2 (Grb-AST B2), Ala-Trp-Arg-Asp-Leu-Ser-Gly-Gly-Trp-NH2 (Grb-AST B3), and Ala-Trp-Glu-Arg-Phe-His-Gly-Ser-Trp-NH2 (Grb-AST B4). Each of the peptides shows high sequence similarity to the locustamyoinhibiting peptide (Lom-MIP), but is structurally different from all the allatostatins so far identified. The synthetic allatostatins Grb-AST B1-4 are potent inhibitors (50% inhibition at 10(-8) to 7 x 10(-8) M) of juvenile hormone III biosynthesis by corpora allata from 3-day-old virgin females of G. bimaculatus using an in vitro bioassay. At 10(-7) M, Grb-AST B1 also strongly inhibits juvenile hormone III biosynthesis by corpora allata from 2-day-old adult males and 1-day-old (males and females) and 4-day-old (females) last instar larvae of G. bimaculatus. The inhibitory effect of Grb-AST B1 was also evident on corpora allata from a related species, Acheta domesticus. Inhibition of juvenile hormone synthesis by Grb-AST B1-4 is reversible.


HLA molecule expression on the surface of cells and microparticles in platelet concentrates.
Platelet (PLT) transfusions are an essential treatment for bleeding disorders. However, immunologic complications can occur, including alloantibody production against Class I HLA molecules. The principal source of HLA molecules in PLT concentrates (PCs) is the PLTs themselves. However, extracellular microparticles (MPs) present in PCs may express HLA molecules. We used nanoscale flow cytometry to explore the expression of HLA-A2, HLA-B7, and HLA-B57 on the surface of cells, PLT-derived MPs (PMPs), lymphocyte-derived MPs (LMPs), and monocyte-derived MPs (MMPs) present in PCs. Expression was studied during 7 days of storage. Platelets were not the only source of HLA molecules in PCs. HLA molecules were present on PMPs, LMPs, and MMPs. The level of HLA Class I molecule expression varied between haplotypes and MPs of different origins and during storage. Platelets or residual cells remaining after leukoreduction are not the only source of HLA Class I molecules in PCs, highlighting the contribution of MPs to alloimmunization mechanisms. These data may be relevant for the development of new transfusion guidelines.


West African rivers as biogeographic islands: species richness of fish communities.
Some factors influencing the species richness of West African fish communities were studied in a sample of 26 rivers using four habitat and hydrologic variables. Analysis of a larger sample of 39 rivers showed that species richness was positively related to area. A power function with an exponent of 0.32 gave the best fit. As the surface area used was that of the catchment area and not that (unknown) of the river, the biological significance of this relationship and the possibilities of comparison were limited. Ridge regression analysis and forward stepwise selection indicated that a model that explained ln(species richness) as a function of ln(mean annual discharge) and ln-(catchment surface area) was best, accounting for 90% of the variance of the dependent variable. The combination of surface area and discharge was presumed to act through the volume of water available for the fishes and habitat productivity. Habitat diversity, measured by the diversity of the terrestrial vegetation covering the catchment area, had no significant positive effect when surface area was used in the regression. Rivers ("islands") should have fewer species than tributaries of similar size since, for fishes within a river system ("continent"), there is free circulation between all its branches. The model derived from the river data underestimated the species richness of a sample of 11 tributaries. This was compatible with the hypothesis of higher population extinction rates in insular biotopes. The residuals of the linear model did not show random geographical distribution; the rivers in some areas had more species than expected. The possibility that historical factors, especially Quaternary climatic variations, might cause this distribution is discussed.


Development of a knowledge broker group to support evidence-informed policy: lessons learned from Myanmar.
Globally, policy-makers face challenges to using evidence in health decision-making, particularly lack of interaction between research and policy. Knowledge-brokering mechanisms can fill research-policy gaps and facilitate evidence-informed policy-making. In Myanmar, the need to promote evidence-informed policy is significant, and thus a mechanism was set up for this purpose. This paper discusses lessons learned from the development of the Knowledge Broker Group-Myanmar (KBG-M), supported by the Johns Hopkins Bloomberg School of Public Health's Applied Mental Health Research Group (JHU) and Community Partners International (CPI). Sixteen stakeholders were interviewed to explore challenges in formulating evidence-informed policy. Two workshops were held: the first to further understand the needs of policy-makers and discuss knowledge-brokering approaches, and the second to co-create the KBG-M structure and process. The KBG-M was then envisioned as an independent body, with former officials of the Ministry of Health and Sports (MoHS) and representatives from the nongovernmental sector actively engaging in the health sector, with an official collaboration with the MoHS. A development task force that served as an advisory committee was established. Then, steps were taken to establish the KBG-M and obtain official recognition from the MoHS. Finally, when the technical agreement with the MoHS was nearly complete, the process stopped because of the military coup on 1 February 2021, and is now on hold indefinitely. Learning from this process may be helpful for future or current knowledge-brokering efforts, particularly in fragile, conflict-affected settings. Experienced and committed advisory committee members enhanced stakeholder relationships. Responsive coordination mechanisms allowed for adjustments to a changing bureaucratic landscape. Coordination with similar initiatives avoided overlap and identified areas needing technical support. Recommendations to continue the work of the KBG-M itself or similar platforms include the following: increase resilience to contextual changes by ensuring diverse partnerships, maintain advisory committee members experienced and influential in the policy-making process, ensure strong organizational and funding support for effective functioning and sustainability, have budget and timeline flexibility to allow sufficient time and resources for establishment, organize ongoing needs assessments to identify areas needing technical support and to develop responsive corrective approaches, and conduct information sharing and collaboration between stakeholders to ensure alignment.


Universal venous thromboembolism policy is effective but may not adequately protect hospitalized cancer patients with larger BMI.
Routine VTE prophylaxis is recommended for hospitalized patients, but its effectiveness and safety in cancer patients is unclear. By observation, larger patients seemed poorly covered by the prophylaxis policy. The effectiveness and safety of VTE prophylaxis policy in the hospitalized patients, their potential risk factors such as BMI were examined. A retrospective chart review was conducted to determine VTE incidences, risk factors for VTE and major bleeding events between 2007 and 2016 on the solid tumor units (STU). Patients were divided into pre-policy (Pre-2012) or post-policy implementation groups (Post-2012). Descriptive statistics were used to evaluate effectiveness and safety of prophylaxis, while propensity score matching (1:3, VTE:Non-VTE) was used to reduce selection bias. The VTE incidence per patient was 1.30% (57/4392) pre-policy and 0.56% (18/3210) post-policy (p value = 0.0013). After propensity score matching, a reduction (32.3%) of VTE cases was observed after policy implementation (OR = 0.677, p = 0.32). BMI was found to be a significant predictor of VTE (OR = 1.094, 95% CI 1.021-1.172, p = 0.011). Between July 2014 and July 2016, 1.7% (19/1091) patients who received anticoagulants had a documented bleeding event. The policy positively impacted VTE events on the STU. A significant predictor of VTE was BMI and patients with high BMI may pose a risk of breaking through standard VTE prophylaxis dosing. There was no reported major bleeding for patients who developed an VTE event despite receiving prophylaxis in either the pre-policy or post-policy phase of the study, although a low incidence of minor bleeding was documented in the post-phase.


Monitoring Treatment of Childhood Tuberculosis and the Role of Therapeutic Drug Monitoring.
Most children tolerate the first-line antibiotics used to treat Mycobacterium tuberculosis (TB) very well. The most common adverse effect is gastrointestinal distress unrelated to hepatotoxicity; the latter is seen in less than 1% of children. Despite the infrequency of hepatotoxicity, the potential long-term impact of hepatic insufficiency dictates that all children receiving antimycobacterial therapy should be evaluated periodically by symptom screening and physical examination. Routine measurement of transaminases in previously healthy, asymptomatic children is discouraged, as up to 40% of children will have transient, asymptomatic transaminase elevation that should not alter clinical management; measurement of serum liver enzymes is reserved for children who develop symptoms and those with existing liver disease or taking other potentially hepatotoxic drugs. Caregivers and personnel distributing directly-observed therapy need to be cognizant of potential drug toxicities and have a clear understanding of what to do if a child develops symptoms. There are substantial inter-patient variations in serum antibiotic concentrations when the same milligram per kilogram dose is given to different children of varying ages and sizes, reflecting differences in drug absorption and metabolism. While these variations may not impact the outcome of previously healthy children with mild disease, outcomes for children with human immunodeficiency virus infection or severe disease can be worse if sub-therapeutic drug concentrations are achieved. Therapeutic drug monitoring, wherein serum drug concentrations are used to optimize medication doses, should be considered for children with severe disease or if there is concern about alterations in drug absorption or metabolism.


Estimating the severity distribution of disease in South Korea using EQ-5D-3L: a cross-sectional study.
There is a paucity of data on the distribution of disease severity. In this study, we estimated disease severity distributions in South Korea using two EQ-5D-3L population surveys. A total of 110 health states for 35 diseases with 2-5 severity levels (e.g., mild, moderate, severe) were included in this study. A general population of 360 participants from the areas surrounding Seoul and Gyunggi evaluated these health states using EQ-5D-3L via face-to-face interviews and a paper questionnaire. The EQ-5D indices were used to measure the severity levels of health states and used as the cutoff points for the disease severity distributions. Finally, these cutoff points were applied to disease prevalence data with EQ-5D-3L, which were obtained from the Korean National Health and Nutrition Examination Surveys (KNHNES) and Korean Community Health Survey, in order to estimate the disease severity distributions. The severity distributions of 8 diseases were estimated, including asthma, angina, stroke, chronic obstructive pulmonary disease, major depressive disorder, musculoskeletal problems in the legs, anemia, and allergic rhinitis and conjunctivitis. For example, the EQ-5D indices for chronic obstructive pulmonary disease severity were 0.929, 0.742, and 0.620, and the cut-off points were 0.835 (between mild and moderate) and 0.681 (between moderate and severe). Using these cutoff points, the distributions of chronic obstructive pulmonary disease severity were 66.5 % (mild), 23.3 % (moderate), and 10.1 % (severe) according to KNHNES. The estimated severity distributions in this study can be used as a valid calculation of the disease burden in the general population.


Retracted: Novel Decision-Making Techniques in Tripolar Fuzzy Environment with Application: A Case Study of ERP Systems.
[This retracts the article DOI: 10.1155/2022/4488576.].


Effect of chilling on the development of in vitro produced bovine embryos at various cleavage stages.
Bovine embryos and zygotes are known to be sensitive to "temperature shock" when cooled to temperatures near 0 degrees Celsius. The effect of chilling on in vitro derived embryos at various cleavage stages was investigated. Cumulus-oocyte-complexes (COCs) were matured in IVM medium with serum. Presumptive zygotes were cultured in serum free in vitro culture (IVC) medium. Embryos were used as chilled or control samples at the 2-cell, 4-cell, 8-cell, morula, and blastocyst stages. Embryos in 0.2 mL PBS in plastic straws were cooled rapidly in ethanol baths at 0 degrees Celsius for 30 min. Embryo viability was assessed by in vitro development. The percentage of control embryos that hatched as blastocysts increased the later stage at which they were selected. Relative proportion of embryos increased from 28% to 48% to 68% when chilled at the 8-cell, morula or blastocyst stages. IVF-produced embryos are differentially susceptible to cooling injury. Cell counts made of those blastocysts formed from chilled embryos indicated subtle effects of chilling.


Dermojet histopathological artifacts.
The Dermojet has recently become popular as a new tool in dermatology. The injection of local anesthetic agents or of steroid preparations into the skin by pressure is a convenience for the physician and protects the patient from the psychological and physical trauma of a needle.


Neuronal migration prevents spatial competition in retinal morphogenesis.
The concomitant occurrence of tissue growth and organization is a hallmark of organismal development1-3. This often means that proliferating and differentiating cells are found at the same time in a continuously changing tissue environment. How cells adapt to architectural changes to prevent spatial interference remains unclear. Here, to understand how cell movements that are key for growth and organization are orchestrated, we study the emergence of photoreceptor neurons that occur during the peak of retinal growth, using zebrafish, human tissue and human organoids. Quantitative imaging reveals that successful retinal morphogenesis depends on the active bidirectional translocation of photoreceptors, leading to a transient transfer of the entire cell population away from the apical proliferative zone. This pattern of migration is driven by cytoskeletal machineries that differ depending on the direction: microtubules are exclusively required for basal translocation, whereas actomyosin is involved in apical movement. Blocking the basal translocation of photoreceptors induces apical congestion, which hampers the apical divisions of progenitor cells and leads to secondary defects in lamination. Thus, photoreceptor migration is crucial to prevent competition for space, and to allow concurrent tissue growth and lamination. This shows that neuronal migration, in addition to its canonical role in cell positioning4, can be involved in coordinating morphogenesis.


Polystyrene microplastics cause granulosa cells apoptosis and fibrosis in ovary through oxidative stress in rats.
Microplastics (MPs) are receiving increased attention as a harmful environmental pollutant. Studies have investigated that MPs have reproductive toxicity, but the mechanism is little known. Here, we aimed to investigate the effects of polystyrene microplastics (PS-MPs) on ovary in rats and the underlying molecular mechanisms. in vivo, thirty-two female Wistar rats were exposed to 0.5 μm PS-MPs at different concentrations (0, 0.015, 0.15 and 1.5 mg/d) for 90 days. And then, all animals were sacrificed, ovaries and blood were collected for testing. in vitro, granulosa cells (GCs) were separated from rat ovary and treated with 0、1、5、25 μg/mL PS-MPs and reactive oxygen species (ROS) inhibitor N-Acetyl-l-cysteine (NAC) respectively. Our results showed that PS-MPs could enter into GCs and result in the reducing of growing follicles number. And the Enzyme-linked immunosorbent assay (ELISA) manifested that PS-MPs could obviously decrease the level of anti-Müllerian hormone (AMH). In addition, PS-MPs induced oxidative stress, apoptosis of GCs and ovary fibrosis evidenced by assay kits, flow cytometry, immunohistochemistry, Masson's trichrome and Sirius red staining. Moreover, the western blot assay manifested that PS-MPs exposure significantly increased the expression levels of Wnt/β-Catenin signaling pathways-related proteins (Wnt, β-catenin, p-β-catenin) and the main fibrosis markers (transforming growth factor-β (TGF-β), fibronectin, α-smooth muscle actin (α-SMA). Additionally, the expression levels of Wnt and p-β-catenin, apoptosis of GCs decreased after NAC treatment. In summary, polystyrene microplastics cause fibrosis via Wnt/β-Catenin signaling pathway activation and granulosa cells apoptosis of ovary through oxidative stress in rats, both of which ultimately resulted in decrease of ovarian reserve capacity.


[Specialist training situation in rheumatology from a trainer's perspective].
This article focuses on the training situation of rheumatologists from the perspective of trainers regarding the existing and potentially increasing deficits of specialists for internal medicine and rheumatology. According to the new regulations defining the rheumatologist training, a substantial part of the training schedule is required to be completed in a hospital setting in order to become a specialist rheumatologist. In this context, the increased training capacity necessitates additional hospital training positions. In addition, the rheumatology residents desire a structured training program. Significantly, the work-life balance is an important factor to make working as a specialist for internal medicine and rheumatology more attractive.


Enhancing Expression of 3-Ketosteroid-9α-Hydroxylase Oxygenase, an Enzyme with Broad Substrate Range and High Hydroxylation Ability, in Mycobacterium sp. LY-1.
3-Ketosteroid-9α-hydroxylase (KSH) consists of two protein systems, KshA and KshB, and is a key enzyme in microbial degradation pathway of natural sterols. 9α-Hydroxy-4-androstene-3,17-dione (9α-OH-AD) is a valuable steroid pharmaceutical intermediate. The expression of a 3-ketosteroid-9α-hydroxylase oxygenase (KshA1) with a broad substrate range and high hydroxylation ability was enhanced in Mycobacterium sp. LY-1 to improve the yield of 9α-OH-AD. Through whole-genome sequence mining and homologous comparison, the putative genes (kshA1 and kshB) in wild strain LY-1 were firstly identified. Then they were heterogeneously co-expressed in Escherichia coli BL21. The transformation results of recombinant BL21-KshA1/B demonstrated KshA1/B had high hydroxylation ability to AD. Moreover, substrate preference analysis suggested that KshA1LY-1 had a broad substrate range. After enhancing expression of kshA1 and kshB in the strain LY-1, the maximum productivity of 9α-OH-AD in recombinant LY-1-KshA1/B reached 0.064 g/L/h in a 5-L stirred fermenter.


Epibulbar allergic granulomatous nodules in a human immunodeficiency virus-positive patient.
To report an unusual epibulbar inflammatory process in a patient with human immunodeficiency virus (HIV). Case report. A 32-year-old man developed fleshy epibulbar nodules on his right conjunctiva and cornea after being treated for conjunctivitis. A biopsy of the lesions was done, and the specimen was processed for histopathologic examination. The biopsy specimen contained inflammatory cells, including an eosinophilic abscess. The diagnosis was allergic granulomatous nodules. This case illustrates the occurrence of epibulbar allergic granulomatous nodules in an HIV-positive patient.


Approaches to Psychosocial Care Within Tertiary Diabetes Care Centres in Canada: An Environmental Scan.
Patients with diabetes facing psychosocial challenges often struggle with diabetes self-management, and thereby are at risk of complications arising from hyperglycemia and hypoglycemia. Despite the Diabetes Canada Clinical Practice Guidelines' recommendations for diabetes centres to offer psychosocial services for the screening and support of patients with psychosocial barriers, the extent to which these recommendations have been implemented in centres across Canada is unknown. Tertiary adult diabetes centres affiliated with academic institutions were invited to participate in our quantitative survey (n=40). At each centre, a structured telephone interview was administered to a manager, as well as a social worker and psychologist (if employed at the centre), to inquire regarding the psychosocial services offered. Thirty diabetes centres (75%) completed at least one questionnaire. Participating diabetes centres varied considerably in capacity, employing from 3 to more than 50 diabetes educators and from 0 to 20 endocrinologists. Approximately 80% of centres reported providing patients with access to psychosocial services, but only about 50% had a dedicated, internal psychosocial team. Stratified results showed centres that are the main centres affiliated with academic teaching hospitals were more likely to have embedded psychosocial services and to make referrals for psychosocial concerns when compared with satellite centres. The majority of managers reported that their staffing and funding model provided inadequate psychosocial support and that increased funding for psychosocial care was either somewhat of a priority or a high priority. Diabetes centres across Canada struggle to offer adequate psychosocial services; greater funding and training for staff is required to uphold the Diabetes Canada Clinical Practice Guidelines.


Familial predisposition for otitis media in Apache Indians at Canyon Day, Arizona.
The familial occurrence of otitis media was studied in White Mountain Apache Indians at Canyon Day, Arizona. Of the 760 residents, 366 persons were seen during a village survey for otitis media. There were 133 first-degree relatives involving 113 first-degree relative pairs. Of these, there were 38 children involving 19 separate sibling pairs, for whom age- and sex-matched controls could be assigned. Tympanic membrane scarring was assumed to be a marker of prior otitis media. The findings suggested (P less than .01 for the nonindependent first-degree relative pairs, and P less than .05 for the independent sibling pairs) a familial predisposition. With the additional assumption that the severity of tympanic membrane scarring can be ranked, no association of severity of otitis media was apparent in the first-degree relatives.


Pseudo-intracellular collagen tangles in human spinal ganglia.
A new structure was found in the spinal ganglia of 6 out of 215 human autopsy cases with various disorders. It was composed of ballooned cells fully packed with fibrillar structures showing the same staining properties as collagen. Ultrastructurally the fibrillar structures were bundles of collagen fibres with a striation of about 70nm periodicity, and they were enclosed by the cell membrane invaginated in a very complex manner into the cytoplasm. This structure, which we named 'pseudo-intracellular collagen tangle', was considered to result from a disturbance in the releasing process of collagen fibre from fibroblasts. The aetiology of the structure is unknown, but it might represent one of regressive or senile changes in human spinal ganglia.


Bioactivity-guided isolation of antiproliferative compounds from Centaurea jacea L.
Bioassay-guided fractionation of the chloroform extract of Centaurea jacea L. afforded the isolation of cirsiliol, apigenin, hispidulin, eupatorin, isokaempferide, axillarin, centaureidin, 6-methoxykaempferol 3-methyl ether, trachelogenin, cnicin, 4'-acetylcnicin and three aliphatic glucose diesters, including the new natural product 1β-isobutanoyl-2-angeloyl-glucose. The structures of the compounds were established on the basis of spectroscopic analyses (UV, MS and NMR). All compounds were isolated for the first time from this species. The compounds were evaluated for their tumour cell growth inhibitory activities on HeLa, MCF-7 and A431 cells. Different types of secondary metabolites (flavonoids, sesquiterpenes) were found to be responsible for the antitumour effects of the extracts; the highest activity was exerted by centaureidin, in addition to moderately active compounds (cirsiliol, isokaempferide, apigenin, hispidulin, cnicin and 4'-acetylcnicin).


Insulin Resistance in Human iPS Cells Reduces Mitochondrial Size and Function.
Insulin resistance, a critical component of type 2 diabetes (T2D), precedes and predicts T2D onset. T2D is also associated with mitochondrial dysfunction. To define the cause-effect relationship between insulin resistance and mitochondrial dysfunction, we compared mitochondrial metabolism in induced pluripotent stem cells (iPSC) from 5 healthy individuals and 4 patients with genetic insulin resistance due to insulin receptor mutations. Insulin-resistant iPSC had increased mitochondrial number and decreased mitochondrial size. Mitochondrial oxidative function was impaired, with decreased citrate synthase activity and spare respiratory capacity. Simultaneously, expression of multiple glycolytic enzymes was decreased, while lactate production increased 80%. These perturbations were accompanied by an increase in ADP/ATP ratio and 3-fold increase in AMPK activity, indicating energetic stress. Insulin-resistant iPSC also showed reduced catalase activity and increased susceptibility to oxidative stress. Thus, insulin resistance can lead to mitochondrial dysfunction with reduced mitochondrial size, oxidative activity, and energy production.


[Mycetoma and their treatment].
Mycetoma are chronic subcutaneous infections, endemic in dry tropical regions. It can be caused either by actinomycetes or by fungi, presenting as filamentous grains in vivo. The foot is the most common localization. The main complication is osseous involvement. Patients are rural workers living in areas situated far from medical centers. Too often, they reach well-equipped hospitals with advanced mutilating lesions. Early case detection is the first condition for good therapeutic results. Clinical presentations of actinomycetoma and eumycetoma are similar, only biological diagnosis can distinguish the two etiological forms. This distinction is essential as medical therapy for each is radically different. Precise identification of the causal agent is required for targeted treatment but it can only be realized in rare specialized laboratories. For actinomycetoma, standard therapy is trimethoprim-sulphamethoxazole (STX). Duration of treatment period is one-year minimum. In case of poor response to STX or high risk of dissemination, a combination with amikacin gave high cure rate. Other options as amoxicillin-clavulanate are available. Medical cure of actinomycetoma is generally obtained with antibiotic treatments and surgical indications are exceptional. Disappointing results were observed using antifungal in the treatment of eumycetoma and medical therapy must be completed with surgical excision. Itraconazole is now the most used drug, new triazoles are on evaluation.


Delta-endotoxins form cation-selective channels in planar lipid bilayers.
Delta-endotoxins CryIA(c) and CryIIIA, two members of a large family of toxic proteins from Bacillus thuringiensis, were each allowed to interact with planar lipid bilayers and were analyzed for their ability to form ion-conducting channels. Both of these toxins made clearly resolved channels in the membranes and exhibited several conductance states, which ranged from 200 pS to about 4000 pS (in 300 mM KCl). The channels formed by both toxins were highly cation-selective, but not ideally so. The permeability ratio of K+ to Cl- was about 25 for both channels. The ability of these proteins to form such channels may account for their toxic action on sensitive cells, and suggests that this family of toxins may act by a common mechanism.


Population trends in smoking, alcohol use and primary prevention variables among adolescents in Iceland, 1997-2014.
To estimate linear time-trends in substance use and primary prevention variables in adolescents in Iceland from 1997 to 2014. Repeated, cross-sectional population-based school surveys with seven waves of pooled data. Iceland. All accessible students enrolled in the 9th and 10th grades in the national Icelandic school system during the spring of 1997, 2000, 2003, 2006, 2009, 2012 and 2014 (n = 50 412, boys = 50%). Response rates ranged between 81 and 90% of the population. Measures on substance use included smoking and alcohol use. Primary prevention measures included parental monitoring, parental social involvement, participation in organized sports and reduced participation in a party life-style. Substance use decreased consistently during the study period. For example, 30-day drunkenness declined from 29.6 in 1997 to 3.6% in 2014 (linear trend: χ(2) (1) = 2846.8, P < 0.001), and daily smoking during the last 30 days declined from 17.0 to 1.6% during the same period (linear trend: χ(2) (1) = 1614.3, P < 0.001). Primary prevention factors strengthened over time. For example, the mean score for parents knowing where their children are in the evenings rose from 2.44 in 1997 to 3.08 in 2014 (Ftrend(1, 42635) , 2538.3, P < 0.001), and mean scores for participation in party life-style declined from 2.23 in 1997 to 1.71 in 2014 (Ftrend(1, 38773) , 2033.1, P < .001). Substance use among adolescents in Iceland has declined steadily from 1997 to 2014, while primary prevention factors for substance use have increased in strength during the same time-period.


Validity of a New 3-D Motion Analysis Tool for the Assessment of Knee, Hip and Spine Joint Angles during the Single Leg Squat.
Study concurrent validity of a new sensor-based 3D motion capture (MoCap) tool to register knee, hip and spine joint angles during the single leg squat. Cross-sectional. University laboratory. Forty-four physically active (Tegner ≥ 5) subjects (age 22.8 (±3.3)) Main outcome measures: Sagittal and frontal plane trunk, hip and knee angles at peak knee flexion. The sensor-based system consisted of 4 active (triaxial accelerometric, gyroscopic and geomagnetic) sensors wirelessly connected with an iPad. A conventional passive tracking 3D MoCap (OptiTrack) system served as gold standard. All sagittal plane measurement correlations observed were very strong for the knee and hip (r = 0.929-0.988, p < 0.001). For sagittal plane spine assessment, the correlations were moderate (r = 0.708-0.728, p < 0.001). Frontal plane measurement correlations were moderate in size for the hip (ρ = 0.646-0.818, p < 0.001) and spine (ρ = 0.613-0.827, p < 0.001). The 3-D MoCap tool has good to excellent criterion validity for sagittal and frontal plane angles occurring in the knee, hip and spine during the single leg squat. This allows bringing this type of easily accessible MoCap technology outside laboratory settings.


Ras/ERK1 pathway regulation of p27KIP1-mediated G1-phase cell-cycle arrest in cordycepin-induced inhibition of the proliferation of vascular smooth muscle cells.
Cordycepin, the main constituent of Cordyceps militaris, demonstrated an anti-atherogenic effect in experimental animals. However, the effects of cordycepin on cell-cycle regulation and the signaling pathway in vascular smooth muscle cells (VSMC) remain largely unknown; therefore, unexpected roles of cordycepin-induced inhibition in VSMC growth were investigated. Mechanisms in cordycepin-treated VSMC were examined via an MTT assay, a thymidine uptake experiment, FACS analysis, immunoblot analysis, kinase assay, immunoprecipitation assay, and transient transfection assays. Cordycepin inhibited cell growth, induced G1-phase cell-cycle arrest, down-regulated cyclins and cyclin-dependent kinase (CDK) expression, and up-regulated p27KIP1 expression in VSMC. Cordycepin induced activation of JNK, p38MAPK and ERK1/2. Blocking of the ERK function using either ERK1/2-specific inhibitor U0126 or a small interfering RNA (si-ERK1) reversed p27KIP1 expression, inhibition of cell growth, and decreased cell-cycle proteins in cordycepin-treated VSMC. Ras activation was increased by cordycepin. Transfection of cells with dominant negative Ras (RasN17) mutant genes rescued cordycepin-induced ERK1/2 activity, increased p27KIP1 expression, inhibited cell proliferation, and reduced cell cycle proteins. In conclusion, our findings indicate that Ras/ERK1 pathways participate in p27KIP1-mediated G1-phase cell-cycle arrest induced by cordycepin via a decrease in cyclin/CDK complexes in VSMC.


Gestational exposure to hydroxyprogesterone caproate suppresses reproductive potential in male rats.
Hydroxyprogesterone caproate was administered to pregnant rats at a dose level of 10 and 25 mg/kg body weight on 1st, 7th and 14th gestational day and the male pups (F1 generation) were allowed to grow for 90 days. The effect of gestational exposure to hydroxyprogesterone caproate on fertility was assessed by breeding F1 male rats with control female rats besides analyzing sperm quality and quantity in F1 male rats. The number of implantation sites and viable fetuses was significantly reduced in females mated with F1 males that were exposed to hydroxyprogesterone caproate during embryonic development. The decrease in sperm function was associated with a decrease in sperm motility, sperm viability and sperm count in F1 rats. The study clearly indicates that in utero exposure to hydroxyprogesterone caproate affects fertility in male rats.


Immunoscanning electron microscopy of antigenic determinants of T/t-complex (tw18) mouse embryos.
tw18 antigen(s) have been localized by immunoscanning electron microscopy in 7.5-day mutant embryos using a primary antiserum to tw18 made and defined on male germ cells and a secondary rabbit anti-mouse Ig antibody coupled to hemocyanin. Homozygotes (tw18/tw18) diagnosed on morphological grounds are more densely labeled primarily on those cell types affected by genetically caused dysfunction. Eight-celled tw18 embryos are not labeled. This finding of embryonic cell type specificity, together with the available evidence for stage specificity, implicate a function for t-antigens in embryonic development.


Tetanus immunity status among adult trauma patients in an ED.
Tetanus is a vaccine-preventable infectious disease. It is caused by the bacterium Clostridium tetani. The aim of this study was to investigate tetanus immunity among adult trauma patients. This study was performed with 267 trauma patients who were admitted to the emergency department of Tepecik Training and Research Hospital in Izmir City, Turkey over a six month period. After obtaining a written informed consent from each patient, a questionnaire concerning demographic information and tetanus vaccination history was filled in by the physician. Patients' blood samples (4-5 cc) were drawn into a test tube while creating an intravenous (IV) access prior to making any attempt for therapy. And the tetanus antibody level (IgG) was measured using the enzyme-linked immunosorbent assay method. Tetanus antibody levels ≥0.1 IU/mL were considered protective. Among 267 patients, 192 and 75 of the cases (71.9% and 28.1%) were male and female, respectively. The median age of the patients was 39 (IQRs = 28-52). Seventy-five percent of the patients (n = 201) had protective immunity rates for tetanus. In our study, which was conducted among adults, it was found that the protective ratio of tetanus immunity decreased with age with an additional, significant decline in elderly patients.


Decreased lifespan in female "Munchkin" actors from the cast of the 1939 film version of The Wizard of Oz does not support the hypothesis linking hypopituitary dwarfism to longevity.
In laboratory mice, pituitary dwarfism caused by genetic reduction or elimination of the activity of growth hormone (GH) significantly extends lifespan. The effects of congenital pituitary dwarfism on human longevity are not well documented. To analyse the effects of untreated pituitary dwarfism on human lifespan, the longevity of a diverse group of widely known little people, the 124 adults who played "Munchkins" in the 1939 movie The Wizard of Oz was investigated. Survival of "Munchkin" actors with those of controls defined as cast members of The Wizard of Oz and those of other contemporary Academy Award winning Hollywood movies was compared. According to the Kaplan-Meier survival curves, survival of female and male "Munchkin" actors was shorter than cast controls and Hollywood controls of respective sexes. Cox regression analyses showed that female "Munchkin" actors had significantly higher risk ratios compared to both female cast controls (RR, 1.70; 95% CI, 1.05 to 2.77) and female Hollywood controls (RR, 1.52; 95% CI, 1.03 to 2.24). Similar trends were also discernible for men, albeit point estimates were not significant. The lack of lifespan extension in "Munchkin" actors does not support the hypothesis that hereditary GH deficiency regulates longevity in humans.


The role of tissue mast cells in exocrine secretion: studies in the submandibular gland of the cat.
Histamine was found to be stored in the submandibular gland of the cat mainly in the mast cells. The amine is released from mast cells by compound 48/80 and pilocarpine. This was demonstrated in the in vivo and in vitro experiments and by histological examination. During the physiological stimulation of the gland, via the electrical stimulation of the chorda tympani nerve, significant changes of histamine content were not found. This could be explained by the increased synthesis of histamine during physiological stimulation. The physiological role of histamine in salivary secretion was demonstrated. The similarity between the roles of histamine, mast cells and chromaffine-like cells in salivary and gastric secretion is discussed.


Changes in immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue syndrome.
The purpose of this study was to evaluate immune function through the assessment of lymphocyte subpopulations (total T cells, major histocompatibility complex [MHC] I- and II-restricted T cells, B cells, NK cells, MHC II-restricted T-cell-derived naive and memory cells, and several MHC I-restricted T-cell activation markers) and the measurement of cytokine gene expression (interleukin 2 [IL-2], IL-4, IL-6, IL-10, IL-12, gamma interferon [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]) from peripheral blood lymphocytes. Subjects included two groups of patients meeting published case definitions for chronic fatigue syndrome (CFS)-a group of veterans who developed their illness following their return home from participating in the Gulf War and a group of nonveterans who developed the illness sporadically. Case control comparison groups were comprised of healthy Gulf War veterans and nonveterans, respectively. We found no significant difference for any of the immune variables in the nonveteran population. In contrast, veterans with CFS had significantly more total T cells and MHC II+ T cells and a significantly higher percentage of these lymphocyte subpopulations, as well as a significantly lower percentage of NK cells, than the respective controls. In addition, veterans with CFS had significantly higher levels of IL-2, IL-10, IFN-gamma, and TNF-alpha than the controls. These data do not support the hypothesis of immune dysfunction in the genesis of CFS for sporadic cases of CFS but do suggest that service in the Persian Gulf is associated with an altered immune status in veterans who returned with severe fatiguing illness.


Regulation of neuronal type genes in congestive heart failure rats.
After myocardial infarction (MI), complex changes in the heart occur during progression into congestive heart failure (CHF). This study sought to identify regulated genes that could have a functional role in some of the changes seen in CHF. Myocardial infarction was induced by ligation of the left anterior descending coronary artery (LAD) in Wistar rats. Gene expression changes in 1- and 7-day MI left ventricular myocardium was analysed using complementary DNA (cDNA) filter arrays. Regulated genes were identified by repeated measurements and a ranked ratio analysis method. A total of 135 genes were identified as differentially expressed. A few genes were robustly regulated at 1-day MI. In 7-day CHF hearts, changes in the expression of neuronal type genes was prominent (32%, n = 28). Eleven of these genes with no described association with CHF were selected for validation. One gene failed the validation. In CHF hearts, the expression of the muscarinic m4 (Chrm4) and nicotinic alpha4 (Chrna4) acetylcholin receptors, the ATP receptor P2rx4, nerve growth factor receptor (Ngfr), discoidin domain receptor 1 (Ddr1), neuronal pentraxin receptor (Nptxr), peripheral myelin protein Pmp-22, leukocyte type 12-lipoxygenase (Alox15), cytochrome P450 4F5 (Cyp4F5) and cardiac Kcne1 were all increased (range 1.6-6.0-fold, P < 0.01 for all genes). The lack of significant regulation of these genes at 1-day post-MI, suggests that the induction of these genes at 7-day post-MI is not a short-term response induced by the infarct itself. These neuronal type genes may participate in underlying processes that affect contractility, intracardiac nerve function and development of arrhythmias in CHF hearts.


Cannabis and psychometrically-defined schizotypy: use, problems and treatment considerations.
Cannabis use is associated with onset of psychosis in individuals vulnerable for developing schizophrenia-spectrum disorders. The present study addressed three knowledge gaps pertaining to this issue: 1) clarifying the incidence of cannabis use in schizotypal individuals, 2) examining how cannabis use is related to psychosocial and physiological problems in schizotypy and interest in treatment, and 3) examining how cannabis use is associated with positive, negative and disorganization features of schizotypy. Scores from a measure of schizotypal traits were used to trichotomize 1665 young adults into schizotypy (top 5% of scorers), non-schizotypy (bottom 50% of scorers) and "unconventional" (scorers within the 50th to 85th percentile) groups. Nearly a quarter of the schizotypy group endorsed cannabis use at least weekly, a rate nearly two to four times that of the other groups. The schizotypy group also reported a much greater frequency of cannabis-related problems compared to the other groups. Despite this, interest in treatment for cannabis use in the schizotypy group was not elevated. Interestingly, 85% of individuals in the schizotypy group reported interest in psychological/psychiatric treatment more generally. Cannabis use was not associated with abnormal patterns of positive or disorganized schizotypy traits in the schizotypy group relative to the other groups. However, cannabis use was associated with lower severity of negative traits. Implications of these results are discussed.


A comparison of advanced semi-quantitative amyloid PET analysis methods.
To date, there is no consensus on how to semi-quantitatively assess brain amyloid PET. Some approaches use late acquisition alone (e.g., ELBA, based on radiomic features), others integrate the early scan (e.g., TDr, which targets the area of maximum perfusion) and structural imaging (e.g., WMR, that compares kinetic behaviour of white and grey matter, or SI based on the kinetic characteristics of the grey matter alone). In this study SUVr, ELBA, TDr, WMR, and SI were compared. The latter - the most complete one - provided the reference measure for amyloid burden allowing to assess the efficacy and feasibility in clinical setting of the other approaches. We used data from 85 patients (aged 44-87) who underwent dual time-point PET/MRI acquisitions. The correlations with SI were computed and the methods compared with the visual assessment. Assuming SUVr, ELBA, TDr, and WMR to be independent measures, we linearly combined them to obtain more robust indices. Finally, we investigated possible associations between each quantifier and age in amyloid-negative patients. Each quantifier exhibited excellent agreement with visual assessment and strong correlation with SI (average AUC = 0.99, ρ = 0.91). Exceptions to this were observed for subcortical regions with ELBA and WMR (ρELBA = 0.44, ρWMR = 0.70). The linear combinations showed better performances than the individual methods. Significant associations were observed between TDr, WMR, SI, and age in amyloid-negative patients (p < 0.05). Among the other methods, TDr came closest to the reference with less implementation complexity. Moreover, this study suggests that combining independent approaches gives better results than the individual procedure, so efforts should focus on multi-classifier systems for amyloid PET. Finally, the ability of techniques integrating blood perfusion to depict age-related variations in amyloid load in amyloid-negative subjects demonstrates the goodness of the estimate.


Two-Dimensional Electrophoresis and Identification by Mass Spectrometry.
Two-dimensional electrophoresis (2-DE) is a classical separation technique for complex protein mixtures based on a first-separation step by isoelectric point (pI) followed by SDS-PAGE. Due to its high resolving power (including protein isoforms) and the capability to display post-translational modifications, 2-DE has been the technique of choice in many studies focused in characterizing allergens. In this chapter, we describe a standard protocol which enables efficient protein separation and subsequent protein identification by tandem mass spectrometry (MALDI-MS/MS).


Rates of metastatic prostate cancer in newly diagnosed patients: Numbers needed to image according to risk level.
The numbers needed to image to identify pelvic lymph node and/or distant metastases in newly diagnosed prostate cancer (PCa) patients according to risk level are unknown. Relying on Surveillance, Epidemiology, and End Results (2010-2016), we tabulated rates and proportions of patients with (a) lymph node or (b) distant metastases according to National Comprehensive Cancer Network (NCCN) risk level and calculated the number needed to image (NNI) for both endpoints. Multivariable logistic regression analyses were performed. Of 145,939 newly diagnosed PCa patients assessable for analyses of pelvic lymph node metastases (cN1), 4559 (3.1%) harbored cN1 stage: 13 (0.02%), 18 (0.08%), 63 (0.3%), 512 (2.8%), and 3954 (14.9%) in low, intermediate favorable, intermediate unfavorable, high, and very high-risk levels. These resulted in NNI of 4619, 1182, 319, 35, and 7, respectively. Of 181,109 newly diagnosed PCa patients assessable for analyses of distant metastases (M1a-c ), 8920 (4.9%) harbored M1a-c stage: 50 (0.07%), 45 (0.1%), 161 (0.5%), 1290 (5.1%), and 7374 (22.0%) in low, intermediate favorable, intermediate unfavorable, high, and very high-risk. These resulted in NNI of 1347, 602, 174, 20, and 5, respectively. Our observations perfectly validated the NCCN recommendations for imaging in newly diagnosed high and very high-risk PCa patients. However, in unfavorable intermediate-risk PCa patients, in whom bone and soft tissue imaging is recommended, the NNI might be somewhat elevated to support routine imaging in clinical practice.


t(7;11)(p15;p15) Chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion.
We encountered a patient with Philadelphia-negative chronic myeloid leukaemia, with t(7;11)(p15;p15), in whom acute leukaemia phase (acute myeloid leukaemia-M2 morphology) developed within a short period. We detected a novel gene fusion between NUP98 and HOXA11 both in the chronic phase and in the acute leukaemia phase in this case. Although it is well known that a fusion of NUP98-HOXA9 in myeloid malignancies is created by the t(7;11)(p15;p15), this case suggests the possibility that HOXA11 might be another partner gene for NUP98 in t(7;11)(p15;p15) leukaemia.


Employers' Perspectives on Accommodating and Retaining Employees with Newly Acquired Disabilities: An Exploratory Study.
Introduction Timely and appropriate accommodations can help employees who experience disabilities stay at work instead of exiting the labor force. Employers can play a critical role in connecting such workers with the accommodations they need. This qualitative study seeks to inform policy makers who want to improve workforce retention outcomes by uncovering factors that affect whether employers provide accommodations to, and ultimately retain, employees with disabilities. Methods We conducted semistructured interviews with a convenience sample of human resources professionals in 14 Arkansas-based employers, yielding detailed information on 50 cases in which an employee developed or disclosed a disability. We analyzed the interviews using a grounded theory approach and compared cases to identify key themes emerging across subgroups of cases. Results Two organization-level factors and four employee-level factors influenced employers' efforts to accommodate and retain employees with disabilities: employer resources; employers' communication with the employee and other stakeholders; employee tenure; employee work performance; active/sedentary nature of employee role; and the severity and type of employees' health conditions. Conclusions Consistent with prior literature, employers with greater access to resources and better ability to communicate generally made greater effort to accommodate and retain employees with disabilities. However, employers in the study did not deploy these resources and processes consistently when making decisions about whether and how to provide accommodations to workers with disabilities; employee-level characteristics affected their actions. Policy makers should consider intervention approaches that reach workers who may be overlooked by employers with scarce resources.


Exposure to low-dose ionizing radiation from cardiac imaging among patients with myocardial infarction.
Patients with first acute myocardial infarction (AMI) constitute a demographic that is exposed to significant amounts of low-dose ionizing radiation (LDIR) over a short period. The aim of this study was to describe cardiac LDIR exposure trends among patients with first AMI over a recent approximately 10-year period. Administrative databases were used to identify a cohort of 106,803 patients who had first AMIs in Quebec, Canada, from 1996 to 2004. These patients were followed through 2007, and the use over time of cardiac imaging procedures associated with LDIR was documented using a cumulative exposure variable. Exposure was documented in 2 periods: the acute phase (<1 month after AMI) and the chronic phase (1 month to 3 years after AMI). The mean dose of cardiac LDIR incurred in the acute post-AMI phase increased twofold during the study period, from 6.8 to 11.8 mSv/patient. However, the mean dose of cardiac LDIR incurred in the chronic post-AMI phase decreased, from 8.3 to 7.3 mSv/patient. Overall, there was a 26.4% increase in cumulative cardiac LDIR exposure, to a mean of 19.1 mSv/patient in the 2 years after AMI, which was driven primarily by an increase in percutaneous coronary interventions. When patients were stratified by cumulative LDIR exposure, several predictors of heavier LDIR exposure were identified among the strata of exposed patients, including younger age and the absence of acute and co-morbid conditions, and the heaviest exposed group subsequently had the lowest overall mortality. In conclusion, among patients experiencing first AMI in Canada, exposure to cardiac LDIR increased over a recent approximately 10-year period. However, the observed trend is toward increasing use of therapeutic procedures with proven mortality benefit undertaken earlier in the disease course and away from diagnostic procedures in the subsequent years after AMI.


Non-steady-state living polymerization: a new route to control cationic ring-opening polymerization (CROP) of oxetane via an activation chain end (ACE) mechanism at ambient temperature.
Well-defined polyoxetane with low polydispersivity has been synthesized via a novel living polymerisation process using 3-phenoxypropyl 1,4-dioxanium hexafluoroantimonate (3-PPD) as a model of a living "monomeric polyoxetane" initiator, in 1,4-dioxane at 35 degrees C.


SSC/ISTH classification of hemophilia A: can hemophilia center laboratories achieve the new criteria?
To assess the practicality of the recent Scientific and Standardization committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) recommendations in respect of the classification of hemophilia we distributed samples from three untreated subjects with hemophilia A to 91 UK hemophilia centers (HCs), comprising 20 comprehensive care centers (CCCs) and 71 HCs. Laboratories were requested to perform their routine factor (F)VIII:C assays and to classify the severity of hemophilia. Median values of < 1 U dL-1 were obtained on two samples. However, for each of the two, approximately 30% of laboratories obtained results in the range 1-29 U dL-1 and 1-33 U dL-1 respectively. For one of these samples 17 laboratories diagnosed severe hemophilia despite obtaining FVIII:C levels in the range 1-5 U dL-1. The median FVIII:C for the third sample was 5.8 U dL-1 with a range of 1.5-36 U dL-1. For this sample eight centers diagnosed severe hemophilia. Fifty-four laboratories obtained a result > 5 U dL-1; 21 of these diagnosed mild hemophilia, 31 moderate hemophilia and two severe hemophilia. Results from CCCs were more accurate and more precise than those from HCs. Our results indicate a need for improved standardization of FVIII assays. In the UK there remains a lack of consensus in respect of the laboratory diagnostic criteria for the classification of hemophilia A.


Involvement of B-aat1 and Cbs in regulating mantle pigmentation in the Pacific oyster (Crassostrea gigas).
Shell color formation is an important physiological process in bivalves, the molecular genetic basis has potential application in bivalve aquaculture, but there is still remaining unclear about this issue. The cystine/glutamate transporter (Slc7a11) and cystathionine beta-synthase (Cbs) are integral genes in pheomelanin synthesis pathway, which is vital to skin pigmentation. Here, the sequences of b (0, +) -type amino acid transporter 1 (B-aat1) and Cbs in Pacific oyster (Crassostrea gigas) (CgB-aat1, CgCbs) were characterized. Phylogenetically, the deduced amino acid sequences of CgB-aat1 and CgCbs both possessed conserved features. Genes were both ubiquitously expressed in six tested tissues with more abundant expression level in central mantle. Besides, the polyclonal antibodies of CgB-aat1, CgCbs, CgTyr, and CgTyrp2 were successfully prepared. Immunofluorescence analysis revealed that CgB-aat1 and CgCbs proteins were both expressed in gill rudiments of eyed-larvae and concentrated mainly in cytoplasm of epithelial cell and nerve axons in mantle. Additionally, after CgB-aat1 or CgCbs silencing, expressions at mRNA and protein levels of CgB-aat1 and CgCbs involved in pheomelanin synthesis were significantly suppressed, and CgTyr, CgTyrp1 and CgTyrp2 related to eumelanin synthesis were also down-regulated but no apparent differences, respectively. Moreover, micrographic examination found less brown-granules at mantle edge in CgB-aat1 interference group. These results implied that pheomelanin synthesis was possible induced by CgB-aat1-CgTyr-CgCbs axis, and it played an essential role on mantle pigmentation in the oysters. These findings provide the useful genetic knowledge and enrich the physiological information for the shell color formation in bivalve aquaculture.


Relationship between the nasal profile and craniofacial structures: does part of the nasal profile reflect some craniofacial structures?
This study aims to evaluate the relationship between the nasal profile and other craniofacial structures. Lateral cephalometric images of 124 adults were collected for this purpose. Statistical analyses such as regression analysis and canonical correlation analysis (CCA) were conducted on nasal and craniofacial anatomical parameters and their relationships. The regression analysis revealed that nasal length was related to maxillary height; nasal depth was related to the position of the maxilla and anterior cranial base length; and nasal base angle was related to upper dentoalveolar height. CCA revealed that nasal parameters (nasal length, depth, and hump) correlated more strongly with craniofacial parameters (maxillary height, anterior-posterior position of the maxilla, and maxillary length). Individuals with maxillary development curved anteriorly upwards had a straighter and smaller nasal profile, while those with maxillary development curved posteriorly downwards had a more arched and large nasal profile. The shape of the nasal dorsum was affected by the maxillomandibular rotation, while the increase in nasal base inclination was accompanied by an upward rotation of the maxillary plane, an increase in the upper dentoalveolar height, and an increase in the lower facial height. While it was observed that each nasal parameter was correlated with the underlying craniofacial structures to some extent, it was also observed that it would be more useful to evaluate the cumulative effects posed by craniofacial parameters. Various combinations of skeletal and dental structures are related to the nasal profile in varying forms and knowing these relationships will help reshape the face and provide aesthetic harmony.


Investigating the spatial and temporal modulation of visuotactile interactions in older adults.
Previous research has shown that spatially and temporally disparate multisensory events are more likely to interact for older adults. For visuotactile interactions, this suggests that the representation of peripersonal space is expanded and temporal perception within this space is less precise. Previously, visuotactile space has been found to expand horizontally into the opposite hemispace, and here we sought to replicate and extend this by exploring both horizontal and vertical space from the hand. Moreover, we investigated whether both spatial and temporal domains are affected for an individual, which have previously been measured using distinct tasks and different participants. We presented a modified cross-modal congruency task (Poole et al. in Multisens Res. doi: 10.1163/22134808-00002475 , 2015a) to thirty older participants (age range 65-85 years), with unisensory tactile performance equated for each individual. For the temporal manipulation, the timings of visual distractors and tactile targets were offset. For the spatial manipulation, visual distractors were presented from multiple positions in ipsilateral and contralateral hemispaces. Whilst the temporal modulation of visuotactile interactions for older adults was equivalent to that observed in young adults, spatial modulation was reduced; significant visuotactile interactions were observed for visual distractors presented in the same and opposite hemispace to the stimulated hand, in the lower visual field. This suggests an expanded representation of visuotactile space surrounding the hand in older adults, which occurs horizontally into the contralateral hemispace only, rather than expanding both vertically and horizontally. This is likely to have consequences for perception of space and goal-directed action in ageing.


FACT Disrupts Nucleosome Structure by Binding H2A-H2B with Conserved Peptide Motifs.
FACT, a heterodimer of Spt16 and Pob3, is an essential histone chaperone. We show that the H2A-H2B binding activity that is central to FACT function resides in short acidic regions near the C termini of each subunit. Mutations throughout these regions affect binding and cause correlated phenotypes that range from mild to lethal, with the largest individual contributions unexpectedly coming from an aromatic residue and a nearby carboxylate residue within each domain. Spt16 and Pob3 bind overlapping sites on H2A-H2B, and Spt16-Pob3 heterodimers simultaneously bind two H2A-H2B dimers, the same stoichiometry as the components of a nucleosome. An Spt16:H2A-H2B crystal structure explains the biochemical and genetic data, provides a model for Pob3 binding, and implies a mechanism for FACT reorganization that we confirm biochemically. Moreover, unexpected similarity to binding of ANP32E and Swr1 with H2A.Z-H2B reveals that diverse H2A-H2B chaperones use common mechanisms of histone binding and regulating nucleosome functions.


Effects of doxazosin on exercise-induced angina pectoris, ST-segment depression, and insulin sensitivity in patients with syndrome X.
A significant proportion of patients with cardiac syndrome X have impaired coronary vasodilator capacity, which is thought to be caused by an increased sympathetic drive. The alpha1-adrenoceptor blocker, doxazosin, increases the coronary vasodilator reserve in patients with syndrome X. To study whether the augmentation is associated with clinical improvement in patients, we conducted a double-blind, placebo controlled, crossover study with doxazosin 1 to 4 mg once daily for 10 weeks in 16 patients with syndrome X (14 women and 2 men; mean +/- SD age 56+/-5 years). Time to angina, exercise duration, time to 0.1 mV ST-segment depression, and maximal ST-segment depression during bicycle exercise testing were compared after treatment with doxazosin 2 mg or placebo for 5 weeks and again after treatment with doxazosin 4 mg or placebo for 10 weeks. Insulin sensitivity was assessed by the minimal model after 10 weeks of doxazosin or placebo treatment. Twelve patients completed the protocol. Doxazosin 4 mg/day decreased systolic blood pressure at rest (109+/-16 vs 125+/-18 mm Hg, p <0.05) and increased basal heart rate (85+/-9 vs 76+/-11 beats/min, p <0.05), whereas hemodynamics were unaffected during exercise. Time to angina, exercise duration, time to 0.1 mV ST-segment depression, and maximal ST-segment depression were similar during treatment with doxazosin and placebo irrespective of the doxazosin dose. Insulin sensitivity was not different with doxazosin and placebo. In conclusion, alpha1 blockade does not significantly improve exercise duration, angina pectoris, and ST-segment depression despite a favorable vasodilator effect in patients with syndrome X. The absent clinical efficacy of doxazosin may challenge the use of the coronary vasodilator capacity as an appropriate method to subclassify patients with syndrome X.


The influence of regional profiles and senescence on the biomechanical properties of the temporalis muscle.
The present study focuses on the determination of the biomechanical properties for the human temporalis muscle. Eight pairs of temporalis muscles were collected from fresh cadavers and uniaxial traction tests were performed. Three specific regions were considered within the muscle: anterior, central and posterior. The results show that the central and posterior muscle regions are stiffer than the anterior ones. In order to interpret the different regional mechanical profiles observed in the temporalis muscle, a kinematic structural model for the muscle/joint system is proposed. Age influences the mechanical properties of the muscle, as older samples are apparently stiffer than younger ones.


Concurrent chemotherapy and reduced-dose cranial spinal irradiation followed by conformal posterior fossa tumor bed boost for average-risk medulloblastoma: efficacy and patterns of failure.
To review the efficacy and patterns of failure in average-risk medulloblastoma patients treated with concurrent chemotherapy and reduced-dose cranial spinal irradiation and a conformal tumor bed boost. Thirty-three patients with average risk (defined as < or =1.5 cm(2) of residual tumor after resection, age >3 years, and no involvement of the cerebrospinal fluid or spine [M0]) medulloblastoma were diagnosed at our institution between January 1994 and December 2001. They were enrolled in an institutional pilot protocol consisting of concurrent chemotherapy (vincristine), reduced-dose cranial spinal irradiation (2340 cGy), a conformal primary tumor bed boost (3240 cGy), followed by eight cycles of chemotherapy (vincristine, cisplatin, and lomustine or cyclophosphamide). The median age at diagnosis of the 33 patients was 7 years (range, 3-21 years). The male/female patient ratio was 2.4:1. The median follow-up of the entire group was 37 months (range, 6-96 months), and the median follow-up of the survivors was 44 months (range, 10-96 months). The 5-year estimated disease-free survival rate, as determined by Kaplan-Meier plots, was 86% (+/-12.6%, 95% confidence interval). The 5-year estimated disease-free posterior fossa control and primary tumor bed control rates were both 94% (+/-8.2%, 95% confidence interval). The patterns of failure included 2 patients with distant central nervous system failure only, 1 patient who developed local primary tumor bed failure, posterior fossa failure, and diffuse leptomeningeal spread simultaneously, and 1 patient with failure in the high-dose, primary tumor bed field. No patient experienced isolated posterior fossa failure outside the high-dose boost region. The treatment of average-risk medulloblastoma with chemotherapy, reduced-dose cranial spinal irradiation, and a conformal tumor bed boost results in survival rates and local control rates comparable to those in contemporary studies. A reduction in the amount of posterior fossa treated to the high dose is possible. These results need to be corroborated in a large, cooperative group study.


A composite prepared from BiOBr and gold nanoparticles with electron sink and hot-electron donor properties for photoelectrochemical aptasensing of tetracycline.
A photoelectrochemical (PEC) aptasensor is described for detecting tetracycline (TC). A gold nanoparticles/BiOBr (AuNPs/BiOBr) composite was prepared where the AuNPs play a key function in carrier transfer which is ascribed to the wavelength-dependent dual function as an electron sink and as a hot-electron donor. Due to this dual function, the composite exhibits a wide photo-response and high electron transfer efficiency. This results in enormously enhanced PEC response. The TC-aptamer was immobilized on an ITO modified with AuNPs/BiOBr via Au-S covalent bonding. The resulting PEC aptasensor possesses a wide linear range (1-104 ng L-1) and a low detection limit (0.35 ng L-1; at S/N = 3). Graphical abstractSchematic representation of a photoelectrochemical aptasensor for tetracycline based on the use of a AuNP/BiOBr composite with electron sink and hot-electron donor properties of the gold nanoparticles.


Upregulation of angiotensin converting enzyme by atrial natriuretic peptide and cyclic GMP in human endothelial cells.
To examine the role of atrial natriuretic peptide (ANP) and cyclic GMP in the regulation of angiotensin converting enzyme (ACE) in cultured human endothelial cells. Cultured endothelial cells from human umbilical veins (HUVEC) were treated with ANP (0.3-30 nM), 8-Br-cGMP (1-100 microM), Rp-8-Br-PET-cGMPS (1 microM), or the phosphodiesterase inhibitors, zaprinast (10-100 microM), dipyridamole (1-10 microM), or isobutyl methyl xanthine (IBMX, 0.1-0.5 mM). ACE amounts were measured by inhibitor binding assay and cellular cGMP levels by radioimmunoassay. ANP caused a dose dependent increase in ACE measured in intact endothelial cell culture. The stimulatory effect of ANP was blocked by Rp-8-Br-PET-cGMPS, a protein kinase G inhibitor. The cyclic GMP analog, 8-Br-cGMP and the cyclic GMP specific phosphodiesterase inhibitor, zaprinast, both increased ACE. Increase of ACE was also caused by nonspecific phosphodiesterase inhibitors, dipyridamole and IBMX. Intracellular cGMP levels were shown to increase by ANP, and phosphodiesterase inhibitors. These data suggest that cGMP is an intracellular mediator regulating ACE and that ANP induced increase of ACE is mediated via a cGMP dependent mechanism.


Public health events emergency management supervision strategy considering citizens' and new media's different ways of participation.
Public health events have done great harm. Emergency management requires the joint participation of multiple parties including government department, pharmaceutical enterprises, citizens and new media. Then, what are the effects of different strategy choices in participation of citizens and new media on emergency management? To answer the question, we construct a four-party evolutionary game model, considering the citizens' two participation ways consisted of true evaluation and false evaluation, and the new media's two participation ways consisted of report after verification and report without verification. This is of more practical significance than simply studying whether citizens and new media participate in emergency management or not because citizen and new media participation does not represent the completely positive behavior. Then, we conduct the evolutionary stability analysis, solve the stable equilibrium points using the Lyapunov first method and conduct the simulation analysis with MATLAB 2020b. The results show that, firstly, the greater the probability of citizens making true evaluation, the more inclined the government department is to strictly implement the emergency management system; secondly, when the probability of citizens making true evaluation decreases, new media are more inclined to report after verification, and when new media lose more pageview value or should be punished more for reporting without verification, the probability that they report without verification is smaller; thirdly, the greater the probability of citizens making false evaluation, the less enthusiasm of pharmaceutical enterprises to participate in emergency management, which indicates that false evaluation is detrimental to prompt pharmaceutical enterprises to participate; what's more, the greater the probability of new media reporting after verification, the greater the probability of pharmaceutical enterprises actively participating, which shows that new media's verification to citizens' evaluation is beneficial to emergency management.


The frequency of change in five-point scale score with a Bayesian penalised likelihood PET reconstruction algorithm on interim FDG PET-CT and its potential implications for therapy decisions in Hodgkin's lymphoma.
To assess the effect of a Bayesian penalised likelihood (BPL) reconstruction algorithm on the five-point scale (5-PS) score, response categorisation, and potential implications for therapy decisions after interim 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)-computed tomography (CT) (iPET-CT) to guide treatment in classical Hodgkin's lymphoma (HL). The present study included new patients with HL undergoing iPET-CT from 2014-2019 after two cycles of doxorubicin (Adriamycin), bleomycin, vincristine, and dacarbazine (ABVD). Two reporters categorised response using the 5-PS and measured maximum standardised uptake values (SUVmax) of the most avid tumour residuum, mediastinal blood pool, and normal liver with ordered subset expected maximisation (OSEM) and BPL reconstructions. Eighty-one iPET-CT examinations were reviewed. Compared with OSEM, BPL increased the 5-PS score by a single score in 18/81 (22.2%) patients. The frequency of potential treatment intensification by changing a score of 3-4 was 13.6% (11/81) and represented 25% (11/44) of patients with a score of 3 on OSEM. All 11 patients remained in remission without a change in therapy (mean 63 months) except one who required second-line treatment for refractory disease. Median SUVmax of tumour residuum was significantly higher with BPL compared with OSEM (2.7 versus 2.4, p<<0.0001), whilst liver SUVmax was significantly lower for both reporters (up to 6.6%, p<0.0001). BPL PET reconstruction increased the 5-PS score on iPET-CT in 22% of HL patients and can potentially result in unnecessary treatment escalation in over half of these patients.