Atrazine Resistance in Chenopodium album: Low and High Levels of Resistance to the Herbicide Are Related to the Same Chloroplast PSBA Gene Mutation.
In Chenopodium album two different levels of atrazine resistance have been found according to following criteria: lethal dose and leaf fluorescence curve. The intermediate (I) phenotype is represented by a low level of resistance and a typical I fluorescence curve. It arose at high frequency, within one generation, after self-pollination of particular plants displaying a susceptible (S) phenotype. The resistance phenotype (Ri) has a high level of resistance and presents a typical resistant fluorescence curve. It appeared after self-pollination of chemically treated I plants. The I, Ri, and also R (resistant plants found in atrazine treated fields) phenotypes contain a serine to glycine mutation at amino acid position 264 in the chloroplast psbA gene product. The steady state level of the psbA gene transcript is not modified between S, I, Ri, and R phenotypes.


ERS International Congress 2022: highlights from the Sleep Disordered Breathing Assembly.
During the European Respiratory Society (ERS) International Congress 2022 in Barcelona, Spain, the latest research and clinical topics in respiratory medicine were presented. The sleep medicine-focused presentations and symposia provided novel insights into the pathophysiology of sleep disordered breathing, its diagnostics, and new trends in translational research and clinical applications. The presented research trends focused mainly on the assessment of sleep disordered breathing-related intermittent hypoxia, inflammation and sleep fragmentation, and their implications, especially cardiovascular. The most promising methods for assessing these aspects encompass genomics, proteomics and cluster analysis. The currently available options include positive airway pressure and a combination of it and pharmacological agents (e.g. sulthiame). This article summarises the most relevant studies and topics on these subjects presented at the ERS International Congress 2022. Each section has been written by Early Career Members of the ERS Assembly 4.


The 5-year outcome of subjective quality of life in older schizophrenia patients.
Subjective quality of life (SQOL) is increasingly valued as an important outcome in schizophrenia treatment. The current study aims to gain insight into changes in SQOL during 5-year follow-up in older persons with schizophrenia spectrum disorders (SSD). The sample consisted of a catchment area-based group of 75 older Dutch patients (mean age 66.0 years) with schizophrenia or schizoaffective disorder. Factor analysis was used to identify subdomains of SQOL, measured with the Manchester Short Assessment of Quality of Life (MANSA). 5-Year course trajectories and putative predictors of changes in SQOL and subdomains were examined using multivariable regression analyses. 72% was stable in either a high or a low SQOL-status over time. When outcome was defined as change score, 36%, 20%, and 44% of participants, respectively, reported a clinically relevant improvement, deterioration, or no change of SQOL during follow-up. Three SQOL subdomains were identified with different course trajectories; 33% of participants reported an improvement in the subdomains satisfaction with 'daily life' and 'personal circumstances.' The largest number of declines (28%) was reported in the subdomain satisfaction with 'physical and mental health.' Predictors of positive total and subdomain SQOL-change scores were limited to a higher age of onset and higher baseline SQOL scores. In this cohort of older persons, it was demonstrated that SQOL might considerably change during 5-year follow-up. As course trajectories differed among subdomains, separate evaluation of these subdomains is clinically relevant. Improvement of SQOL is an attainable goal in older SSD patients despite deteriorating physical health.


Genome-wide screen of fission yeast mutants for sensitivity to 6-azauracil, an inhibitor of transcriptional elongation.
6-Azauracil (6 AU) inhibits enzymes in nucleoside synthesis and depletes the intracellular GTP/UTP pool. Mutations in transcriptional elongation machinery, as well as mutations in a variety of other pathways, exaggerate the growth defect of cells in the presence of 6 AU. Thus, identification of mutations that render cells sensitive to 6 AU will benefit study on the basis of 6 AU-sensitive phenotype. Here we performed a genome-wide screen of a fission yeast deletion library. Of 3235 single-gene deletions, 66 mutants displayed at least 50% drop of fitness in the presence of 6 AU and 60 mutants were reported for the first time; five deletions showed synthetic decrease of fitness when combined with deletion of set3(+) , which encodes a transcriptional regulator. Genes conferring tolerance to 6 AU were enriched in various processes, especially in chromosome segregation. Accordingly, genes encoding subunits of CLRC complex and spindle pole body were over-represented. Mutants were subjected to an in vivo transcript length-dependent reporter assay to assess the potential roles of deleted genes in transcriptional elongation. As with the deletions known to affect elongation, nab2Δ, nxt1Δ, rhp18Δ, SPAC24C9.08Δ, clr3Δ and ncs1Δset3Δ mutants exhibited defects in expressing long transcripts. New 6 AU-sensitive mutants identified here will help to elucidate the mechanism of action of 6 AU in the cells. Meanwhile, our study revealed novel genes potentially involved in transcriptional elongation and provided valuable targets for transcription study.


Contribution of facet joints to chronic low back pain in postlumbar laminectomy syndrome: a controlled comparative prevalence evaluation.
Postlumbar laminectomy syndrome, or pain following operative procedures of the lumbar spine, is increasingly a common entity in modern medicine. Multiple causes proposed for recurrence of pain after lumbar laminectomy are: epidural fibrosis, recurrent disc herniation, instability, and facet joints. Even though the prevalence of persistent low back pain secondary to the involvement of lumbosacral facet joints has been described in controlled studies from 15% to 45%, the prevalence of facet joint mediated pain in postlumbar laminectomy syndrome has not been studied. This prospective, randomized, controlled comparative evaluation was performed to determine the prevalence of facet joint mediated pain in persistent low back pain in postlumbar laminectomy patients with a comparative non-surgical group. One hundred patients with fifty patients in each group were randomly assigned with group I consisting of fifty patients without history of previous surgery and group II consisting of fifty patients with history of previous surgery. Results showed that the prevalence of facet joint mediated pain in non-surgical patients was 44% compared to 32% in post surgical patients determined by comparative controlled local anesthetic blocks utilizing lidocaine and bupivacaine. This study also showed a false positive rate of 36% in non-surgical group and 24% in post-surgical group. In conclusion, this study shows that facet joint mediated symptomatology in chronic low back pain is prevalent, both in non-surgical as well as post-surgical patients even though prevalence was somewhat higher in the non-surgical group compared to post-surgical group.


Ligand-induced regulation and localization of cannabinoid CB1 and dopamine D2L receptor heterodimers.
The cannabinoid CB(1) (CB(1)) and dopamine D(2) (D(2)) receptors are coexpressed in the basal ganglia, an area of the brain involved in such processes as cognition, motor function, and emotional control. Several lines of evidence suggest that CB(1) and D(2) receptors may oligomerize, providing a unique pharmacology in vitro and in vivo. However, limited information exists on the regulation of CB(1) and D(2) receptor dimers. We used a novel technique, multicolor bimolecular fluorescence complementation (MBiFC) to examine the subcellular localization of CB(1)-D(2L) heterodimers as well as D(2L)-D(2L) homodimers in a neuronal cell model, Cath. a differentiated cells. MBiFC was then used to explore the effects of persistent ligand treatment on receptor dimerization at the plasma membrane and intracellularly. Persistent (20-h) agonist treatment resulted in increased formation of CB(1)-D(2L) heterodimers relative to the D(2L)-D(2L) homodimers. The effects of the D(2) agonist quinpirole were restricted to the intracellular compartment and may reflect increased D(2L) receptor expression. In contrast, treatment with the CB(1) receptor agonist (2)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP55, 940) produced increases in both membrane and intracellular CB(1)-D(2L) heterodimers independently of alterations in CB(1) receptor expression. The effects of CB(1) receptor activation were attenuated by the CB(1) antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM281) and were both time- and dose-dependent. The effects of CB(1) activation were examined further by combining MBiFC with a constitutively active CB(1) receptor mutant, CB(1)T210I. These studies demonstrated that the expression of CB(1)T210I increased intracellular CB(1)-D(2L) heterodimer formation. In summary, agonist-induced modulation of CB(1)-D(2L) oligomerization may have physiological implications in diseases such as Parkinson's disease and drug abuse.


Effects of Lowering Dialysate Calcium Concentration on Carotid Intima-Media Thickness and Aortic Stiffness in Patients Undergoing Maintenance Hemodialysis: A Prospective Study.
The study aimed to prospectively evaluate the effects of lowering the dialysate calcium concentration (DCa) to 1.25 mmol/l on Chinese patients undergoing maintenance hemodialysis (MHD), which are largely unknown to date. A singer-center, prospective, randomized trial was conducted for 2 years. The DCa in one group was decreased from 1.5 to 1.25 mmol/l but there was no change in the other group. The clinical outcomes, biochemical parameters, medicine treatments and markers of vascular change were compared among the 2 groups at different time intervals. At baseline, the groups were similar with respect to serum levels of calcium, phosphorus, intact parathyroid hormone and fibroblast growth factor-23 as well as carotid intima-media thickness (cIMT) and carotid-femoral pulse wave velocity (cf-PWV). It was found that the serum phosphorus concentration in the lower DCa group had decreased markedly at 2-year follow-up (0-month: 7.13 ± 1.56 mg/dl; 24-month: 5.92 ± 1.73 mg/dl; p = 0.005). Serum calcium (p = 0.018), cIMT (p = 0.029) and cf-PWV (p = 0.024) in DCa 1.25 group were significantly lower than those in 1.5 group at the 24-month visit. Kaplan-Meier curve revealed that patients in DCa 1.25 group had a better rate of survival. In the multivariate Cox regression analysis, cIMT (HR 1.010; 95% CI 1.002-1.217; p = 0.015) and cf-PWV (HR 1.265; 95% CI 1.022-1.567; p = 0.031) were potential risk factors for mortality in those patients. Importantly, we showed that the average change in these 2 risk variables were both associated with the average change in levels of serum calcium and phosphorus. Our results indicate that lowering DCa to 1.25 mmol/l may be suitable for the MHD patients in our unit.


Matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of nonfermenting gram-negative bacilli isolated from cystic fibrosis patients.
The identification of nonfermenting gram-negative bacilli isolated from cystic fibrosis (CF) patients is usually achieved by using phenotype-based techniques and eventually molecular tools. These techniques remain time-consuming, expensive, and technically demanding. We used a method based on matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) for the identification of these bacteria. A set of reference strains belonging to 58 species of clinically relevant nonfermenting gram-negative bacilli was used. To identify peaks discriminating between these various species, the profile of 10 isolated colonies obtained from 10 different passages was analyzed for each referenced strain. Conserved peaks with a relative intensity greater than 0.1 were retained. The spectra of 559 clinical isolates were then compared to that of each of the 58 reference strains as follows: 400 Pseudomonas aeruginosa, 54 Achromobacter xylosoxidans, 32 Stenotrophomonas maltophilia, 52 Burkholderia cepacia complex (BCC), 1 Burkholderia gladioli, 14 Ralstonia mannitolilytica, 2 Ralstonia pickettii, 1 Bordetella hinzii, 1 Inquilinus limosus, 1 Cupriavidus respiraculi, and 1 Burkholderia thailandensis. Using this database, 549 strains were correctly identified. Nine BCC strains and one R. mannnitolilytica strain were identified as belonging to the appropriate genus but not the correct species. We subsequently engineered BCC- and Ralstonia-specific databases using additional reference strains. Using these databases, correct identification for these species increased from 83 to 98% and from 94 to 100% of cases, respectively. Altogether, these data demonstrate that, in CF patients, MALDI-TOF-MS is a powerful tool for rapid identification of nonfermenting gram-negative bacilli.


Outcomes of side-to-end versus end-to-end colorectal anastomosis in nonemergent sigmoid and rectal cancers: a randomized controlled clinical trial.
The outcomes of open colorectal anastomosis of side-to-end versus end-to-end in nonemergent sigmoid and rectal cancer surgery in adults were compared. A randomized controlled trial on individuals with sigmoid and rectal cancers was conducted between September 2016 and September 2018. The mean age was 62.58±12.3 years in the side-to-end anastomotic (SEA) group and 61.03±13.98 years in the end-to-end anastomotic (EEA) group. Except for the operative time, intraoperative data revealed no significant differences between the studied groups, and the SEA group revealed that the mean anastomotic time was significantly shorter. Perioperative blood loss, length of stay, reoperation, inpatient death, infection, and bleeding were significantly associated with leakage. There is a statistically significant change regarding the range of bowel frequency in the EEA group only (P=0.04). There is a statistically significant difference regarding incontinence for flatus in the SEA group only (P≤0.001). A statistically significant change in both groups regards incontinence for liquid stools (P≤0.001) and clustering of stools (P≤0.001 and P=0.043). The quality of life in the SEA group significantly dropped at 6 months and then returned to baseline as regards to physical well-being (PWB), functional well-being (FWB), and colorectal cancer symptoms (CCS) with no difference as regards SWB and EWB, while in the EEA group, the exact change happened only as regard PWB and FWB, but SWB and CCS percentage did not return to baseline. The SEA group offers a safe alternative approach to the EEA group.


[Skin transplantation].
Transplantation of skin was adopted as a clinical method for wound closure soon after Reverdin's introduction of skin grafts in 1869. Split-skin grafts are grafts which consist of epidermis and a portion of dermis, and full thickness skin grafts are grafts consisting of epidermis and the entire dermis including adenexal structures. Composite grafts with skin consist of cartilage and skin coverings. Skin grafts can also be grouped according to source in autograft, isograft, allograft and xenograft. Split-thickness grafts are used to close wounds that cannot be managed by suturing, full thickness-grafts or local flaps. In burn wound surgery and surgery related to necrotizing fasciitis, split-thickness skin grafting is a lifesaving treatment. In vaginal agenesis split-thickness skin graft is used to reconstruct the vagina. In the oral cavity split-thickness skin graft can be used to close wounds and cover cancelleous bone. Split-thickness skin graft can also be used to cover open abdominal wounds. Full-thickness skin grafts are used to reconstruct facial defects after removal of skin cancer. It is also used in hand surgery and for reconstruction of hypospadia. Composite graft can be used for nasal reconstruction. In this article, the indications for skin grafting, the surgical procedures and the follow-up are presented. Skin banking are presented to demonstrate the possibilities for storing skin allograft. Artificial skin or bio-engineered skin substitutes are presently undergoing clinical studies.


Suicide and suicide attempt after a cancer diagnosis among young individuals.
Data are scarce on the potential change in suicidal behavior among adolescents and young adults after receiving a cancer diagnosis. We conducted a population-based cohort study including 7 860 629 Swedes at the age of ≥15 during 1987-2009. Among the cohort participants, 12 669 received a first diagnosis of primary cancer between the age of 15 and 30. We measured the relative risks (RRs) of suicidal behavior (defined as completed suicides or suicide attempts) after cancer diagnosis. We also carried out a case-crossover study nested within the cohort to adjust for unmeasured confounders. Twenty-two completed suicides (versus 14 expected) and 136 suicide attempts (versus 80 expected) were identified among the cancer patients. The RR of suicidal behavior was 1.6 [95% confidence interval (CI), 1.4-1.9] after a cancer diagnosis, compared with cancer-free individuals. Risk increase was greatest immediately after diagnosis; the RR was 2.5 (95% CI 1.7-3.5) during the first year after diagnosis and was 1.5 (95% CI 1.2-1.8) thereafter. This pattern was similar for completed suicide and suicide attempts. The elevated risks were evident for majority of the main cancer types, except for cancer in thyroid, testis and melanoma. The case-crossover analysis of suicidal behavior during the first year after cancer diagnosis revealed similar results. Adolescents and young adults receiving a cancer diagnosis are at substantially increased risk of suicidal behavior, particularly during the first year after diagnosis. Although the absolute excess risk is modest, these findings emphasize the need to support and carefully monitor this vulnerable population.


Comparative bio-effects of SiO2/Gd2O3 nanoparticles depending on their core-shell structures.
Engineered nanoparticles (NPs) can produce negative impacts on human health even in low doses. In this study, Gd2O3 nanoparticles were synthesized via the polyol route and coated with silicon to form particles with different sizes. Although all the SiO2/Gd2O3 NPs did not induce obvious cell death at 10 microg/mL on a macrophage-like cell line (RAW 264.7), their DNA damaging effects, which is measured by single cell gel electrophoresis (SCGE), is prominent in cells treated with the sample with an overall size of 120 nm. Besides, the NPs with core size of 20 nm induced greater damaging effect than NPs with similar total size but core size of 50 nm. Further test applying the modified SCGE with endonuclease III indicated that the DNA damaging effect was greatly associated with oxide pyridine after the treatment. Using immunoblotting, we found that p53 protein is activated and accumulated after the damage occurred. These results provide a new insight into the adverse effect of nanoparticles with core-shell structures, that not only the overall size but the core size of the particles determines their effect in cells.


A descriptive epidemiological study of cardiovascular diseases among seafarers.
Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality among seafarers. This study aimed to evaluate CVDs distribution and differences, considering seafarers' rank and worksite groups. A descriptive epidemiological study was employed, and the analysis was based on the telemedical assistance data of the International Radio Medical Centre (C.I.R.M.) from 2010 to 2018. The age, gender, rank, and worksite variables were considered for the analysis. Chi-square or Fisher test was used to assess differences in CVD distribution between rank and worksite groups. Cardiovascular diseases were the sixth leading cause of medical advice requests to C.I.R.M. Distribution of CVD significantly differed between officers and non-officers [x2 (5) = 17.308, p = 0.004]. Officers were often diagnosed with hypertensive CVD (46%), whereas non-officers were frequently diagnosed with ischaemic heart diseases (41%). There were no significant differences in the distribution of CVD diagnoses between worksite groups [x2 (10) = 12.863, p = 0.231]. The frequency of CVD is higher among non-officers and older seafarers who have been more often diagnosed with CVD. Specific interventions such as early diagnosis, regular monitoring, and physical training to reduce cardiovascular risk should be considered on board ships. Future studies should take into account the incidence rate of CVD between rank and worksite groups.


Investigation of a combination therapy approach for the treatment of melioidosis.
The efficacy of finafloxacin as a component of a layered defense treatment regimen was determined in vitro and in vivo against an infection with Burkholderia pseudomallei. Doxycycline was down-selected from a panel of antibiotics evaluated in vitro and used in combination with finafloxacin in a Balb/c mouse model of inhalational melioidosis. When treatment was initiated at 24 h post-infection with B. pseudomallei, there were no differences in the level of protection offered by finafloxacin or doxycycline (as monotherapies) when compared to the combination therapy. There was evidence for improved bacterial control in the groups treated with finafloxacin (as monotherapies or in combination with doxycycline) when compared to mice treated with doxycycline. Survival comparisons of finafloxacin and doxycycline (as monotherapies) or in combination initiated at 36 h post-infection indicated that finafloxacin was superior to doxycycline. Doxycycline was also unable to control the levels of bacteria within tissues to the extent that doxycycline and finafloxacin used in combination or finafloxacin (as a sole therapy) could. In summary, finafloxacin is a promising therapy for use in the event of exposure to B. pseudomallei.


Cannabinoid-induced conditioned place preference in the spontaneously hypertensive rat-an animal model of attention deficit hyperactivity disorder.
Cannabis preparations are the most widely consumed illicit drugs, and their use typically begins in adolescence. The prevalence of cannabis abuse is higher in patients with attention deficit/hyperactivity disorder (ADHD) than in the general population, yet, knowledge about the motivational properties of cannabinoids in animal models of ADHD are lacking. To compare the motivational effects of the synthetic cannabinoid agonist WIN55,212-2 (WIN) in adolescent and adult spontaneously hypertensive rats (SHR), a validated animal model of ADHD, and Wistar rats, representing a "normal" genetically heterogeneous population. We also asked whether the effects of WIN depended (1) on the activation of the cerebral subtype of cannabinoid receptors, namely, the CB(1) cannabinoid receptor and (2) on putative changes by WIN in blood pressure. WIN was tested under an unbiased conditioned place preference (CPP) paradigm. Blood pressure after WIN administration was also monitored in additional groups of rats. In the Wistar rats, WIN produced place aversion only in the adult but not adolescent rats. In contrast, WIN produced CPP in both adolescent and adult SHR rats. The behavioral effects of WIN were CB(1)-mediated and not related to blood pressure. The contrasting effects of WIN in Wistar and SHR, and the higher resistance of adolescent rats to the aversive and rewarding effects of WIN in these two strains suggests that both adolescence and the ADHD-like profile exhibited by the SHR strain constitute factors that influence the motivational properties of cannabinoids.


Postoperative de novo epilepsy after craniotomy: a nationwide register-based cohort study.
The risks of postoperative risk of epilepsy after a craniotomy is widely believed to be raised. A study is warranted to quantify the risks for any neurosurgical indication. In this unselected register-based nationwide cohort study with virtually complete follow-up, the short-term and long-term cumulative risks of postoperative de novo epilepsy for all major neurosurgical indications were estimated. The study was based on 8948 first-time craniotomy patients in Denmark 1 January 2005 to 31 December 2015 with follow-up until 31 December 2016. The patients were classified according to their underlying neurosurgical pathology. Patients with preoperative epilepsy were excluded. The postcraniotomy risks of de novo epilepsy were estimated using the Aalen-Johansen estimator in a multistate model. The overall cumulative 1-year risk of postcraniotomy de novo epilepsy was 13.9% (95% CI 13.2 to 14.6). For patients with intracranial tumour the cumulative 1-year risk was 15.4% (95% CI 14.4 to 16.5), for spontaneous intracranial haemorrhage 11.3% (95% CI 10.1 to 12.6), for traumatic intracranial haemorrhage 11.1% (95% CI 9.6 to 12.9), for cerebral abscess 27.6% (95% CI 22.8 to 33.5) and for congenital malformations 3.8% (95% CI 1.3 to 11.7). The 6-month, 1-year and 5-year risks for all major indications by specific subtypes are provided. The cumulative risk of de novo epilepsy following craniotomy is high for patients with any indication for craniotomy, as compared with the background population. The results provide comprehensive data to support future recommendations regarding prophylactic antiepileptic treatment and driving restrictions.


Estimation of phylogenetic inconsistencies in the three domains of life.
Discrepancies in phylogenetic trees of bacteria and archaea are often explained as lateral gene transfer events. However, such discrepancies may also be due to phylogenetic artifacts or orthology assignment problems. A first step that may help to resolve this dilemma is to estimate the extent of phylogenetic inconsistencies in trees of prokaryotes in comparison with those of higher eukaryotes, where no lateral gene transfer is expected. To test this, we used 21 proteomes each of eukaryotes (mainly opisthokonts), proteobacteria, and archaea that spanned equivalent levels of genetic divergence. In each domain of life, we defined a set of putative orthologous sequences using a phylogenetic-based orthology protocol and, as a reference topology, we used a tree constructed with concatenated genes of each domain. Our results show, for most of the tests performed, that the magnitude of topological inconsistencies with respect to the reference tree was very similar in the trees of proteobacteria and eukaryotes. When clade support was taken into account, prokaryotes showed some more inconsistencies, but then all values were very low. Discrepancies were only consistently higher in archaea but, as shown by simulation analysis, this is likely due to the particular tree of the archaeal species used here being more difficult to reconstruct, whereas the trees of proteobacteria and eukaryotes were of similar difficulty. Although these results are based on a relatively small number of genes, it seems that phylogenetic reconstruction problems, including orthology assignment problems, have a similar overall effect over prokaryotic and eukaryotic trees based on single genes. Consequently, lateral gene transfer between distant prokaryotic species may have been more rare than previously thought, which opens the way to obtain the tree of life of bacterial and archaeal species using genomic data and the concatenation of adequate genes, in the same way as it is usually done in eukaryotes.


Coupling of the lattice and superlattice deformations and hysteresis in thermal expansion for the quasi-one-dimensional conductor TaS3.
An original interferometer-based setup for measurements of length of needlelike samples is developed, and thermal expansion of o-TaS(3) crystals is studied. Below the Peierls transition the temperature hysteresis of length L is observed, the width of the hysteresis loop deltaL/L being up to 5 x 10(-5). The behavior of the loop is anomalous: the length changes so that it is in front of its equilibrium value. The hysteresis loop couples with that of conductivity. With lowering the temperature down to 100 K the charge-density waves' elastic modulus grows achieving a value comparable with the lattice Young modulus. Our results could be helpful in consideration of different systems with intrinsic superstructures.


Effects of sulfonylurea compounds on Pneumocystis carinii.
Two sulfonylurea compounds, carbutamide and tolbutamide, were studied for efficacy against Pneumocystis carinii pneumonitis in the corticosteroid-treated rat model and compared with trimethoprim-sulfamethoxazole (TMP-SMZ). The chemical structures of these sulfonylureas are identical except that an amino group in carbutamide is replaced with a methyl group in tolbutamide. Carbutamide was totally effective in the prevention and treatment of P. carinii pneumonitis in dosages of 100 and 200 mg/kg per day. The carbutamide dosage of 50 mg/kg per day prevented the infection in 90% of animals, whereas tolbutamide in the same dosage permitted infection in 100% of animals. This study shows that carbutamide is at least as effective as TMP-SMZ in the treatment and prevention of murine P. carinii pneumonitis. The presence of an amino group in the para position on the benezene ring is a determinant for this activity.


PD-1 Signaling Promotes Tumor-Infiltrating Myeloid-Derived Suppressor Cells and Gastric Tumorigenesis in Mice.
Immune checkpoint inhibitors have limited efficacy in many tumors. We investigated mechanisms of tumor resistance to inhibitors of programmed cell death-1 (PDCD1, also called PD-1) in mice with gastric cancer, and the role of its ligand, PD-L1. Gastrin-deficient mice were given N-methyl-N-nitrosourea (MNU) in drinking water along with Helicobacter felis to induce gastric tumor formation; we also performed studies with H/K-ATPase-hIL1B mice, which develop spontaneous gastric tumors at the antral-corpus junction and have parietal cells that constitutively secrete interleukin 1B. Mice were given injections of an antibody against PD-1 or an isotype control before tumors developed, or anti-PD-1 and 5-fluorouracil and oxaliplatin, or an antibody against lymphocyte antigen 6 complex locus G (also called Gr-1), which depletes myeloid-derived suppressor cells [MDSCs]), after tumors developed. We generated knock-in mice that express PD-L1 specifically in the gastric epithelium or myeloid lineage. When given to gastrin-deficient mice before tumors grew, anti-PD-1 significantly reduced tumor size and increased tumor infiltration by T cells. However, anti-PD-1 alone did not have significant effects on established tumors in these mice. Neither early nor late anti-PD-1 administration reduced tumor growth in the presence of MDSCs in H/K-ATPase-hIL-1β mice. The combination of 5-fluorouracil and oxaliplatin reduced MDSCs, increased numbers of intra-tumor CD8+ T cells, and increased the response of tumors to anti-PD-1; however, this resulted in increased tumor expression of PD-L1. Expression of PD-L1 by tumor or immune cells increased gastric tumorigenesis in mice given MNU. Mice with gastric epithelial cells that expressed PD-L1 did not develop spontaneous tumors, but they developed more and larger tumors after administration of MNU and H felis, with accumulation of MDSCs. In mouse models of gastric cancer, 5-fluorouracil and oxaliplatin reduce numbers of MDSCs to increase the effects of anti-PD-1, which promotes tumor infiltration by CD8+ T cells. However, these chemotherapeutic agents also induce expression of PD-L1 by tumor cells. Expression of PD-L1 by gastric epithelial cells increases tumorigenesis in response to MNU and H felis, and accumulation of MDSCs, which promote tumor progression. The timing and site of PD-L1 expression is therefore important in gastric tumorigenesis and should be considered in design of therapeutic regimens.


Testing lncRNAs signature as clinical stage-related prognostic markers in gastric cancer progression using TCGA database.
LncRNA expression can be conducive to gastric cancer (GC) prognosis. The objective of this study is to ascertain five specific lncRNAs involved in tumor progression of GC and their role as prognostic markers to diagnose clinical stage-wise GC. High-throughput RNA sequencing data were obtained from The Cancer Genome Atlas (TCGA) database and performed genome-wide lncRNA expression analysis using edgeR package, Bioconductor.org, and R-statistical computing to analyze differentially expressed lncRNA analysis. Cutoff parameters were FDR < 0.05 and |Log2FC| > 2. Total 351 tumor samples with differentially expressed lncRNAs were divided into group-1 lncRNAs such as AC019117.2 and LINC00941, and group-2 lncRNAs such as LINC02410, AC012317.2, and AC141273.1 by 2:1. The Spearman correlation coefficients (p < 0.05) and correlation test function (cor.test ()) were performed for lncRNAs as per clinical stage. Cytoscape software was used to construct lncRNA-mRNA interaction networks. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway (p < 0.05) analysis were conducted using the clusterProfiler package. Kaplan-Meier survival analysis was performed to determine the overall survival of patients based on the expression of five lncRNAs in different clinical stages of GC. AC019117.2 and LINC00941 of group 1 inferred a positive correlation with clinical stages of stage I to stage IV, and their expressions were higher in tumor tissues than normal tissues. On the contrary, LINC02410, AC012317.2, and AC141273.1 of group 2 exhibited a negative correlation with clinical stage, and they exhibited more expression in normal tissues compared to tumor tissues. GO and KEGG pathway analysis reported that AC019117.2 may interact with LINC00941 via ITGA3 and trophoblast glycoprotein (TPBG) to foster tumor progression. Tumor-specific group-1 lncRNAs were conducive to the poor overall survival and exhibited a positive correlation with the clinical stages of stage I to stage IV in GC as per the lncRNA-mRNA networking analysis. These five lncRNAs could be considered as clinically useful lncRNA-based prognostic markers to predict clinical stage-wise GC progression.


Mothering influences the distribution of activity in young domestic chicks.
The aim of this study was to determine whether the presence of a maternal hen influences the quality, quantity, and distribution of activity in young chicks. Brooded and nonbrooded chicks were observed during the entire light phase when they were 4 d of age. Our results revealed that although both brooded and nonbrooded chicks expressed the same behavioral items and in quite the same quantity, activity bouts were much longer in brooded chicks. However, only brooded chicks presented a high level of ultradian rhythmicity. Moreover, the brooded chicks made greater use of the space. The presence and the behavior of maternal hens appeared to provide structuring factors for the expression of the chicks behavior.


[Some considerations about nurses' use of non traditional therapies in psychiatric nursing care].
In this work, a revision of the literature was carried out to identify articles that described non traditional therapeutic modalities psychiatric nurses can use in their daily practice. The described modalities were Music, Motor Activity, Therapeutic Accompaniment and Yoga. Music is able to reconstruct identities, integrate people, reduce anxiety and provide the construction of positive self-esteem. Motor Activity increases self-esteem, reduces inactivity and increases the participation of the psychiatric patient in other activities. In Therapeutic Accompaniment, nurses follow patients in daily routine with a view to their reintegration in the different situations they have to face. Yoga allows for improved memory, reduces emotional tension, depression, anxiety and irritability, and promotes relaxation and a greater feeling of self-control. All activities should be integrated in a global therapeutic plan for each user and be part of daily service programming.


Cervical lymphadenopathy due to Kikuchi disease: US and CT appearance.
A patient with Kikuchi disease (histiocytic necrotizing lymphadenitis), who came to clinical attention because of cervical lymphadenopathy, is presented. CT and ultrasonographic findings of this disease are described. The importance of this entity lies in the fact that it can be easily confused clinically, pathologically, and radiologically with malignant lymphadenopathy, especially lymphoma.


The evaluation of cocaine-induced chest pain with acute myocardial perfusion imaging.
To use myocardial perfusion imaging to determine the etiology of cocaine-induced chest pain in patients without ECG evidence of acute cardiac ischemia. The authors conducted a prospective study of consecutive consenting patients aged 18-70 years with cocaine-induced chest pain who reported cocaine use within three days and presented with a chief complaint of chest pain occurring within three hours and lasting longer than 15 minutes with a normal or nondiagnostic ECG. Patients were excluded if they had a clear-cut noncardiac cause of chest pain, ECG evidence of acute cardiac ischemia, history of myocardial infarction, pregnancy, or lactation, required immediate hospitalization, or were unable to consent. Patients were injected with Tc-99m tetrofosmin and imaged. Perfusion scans were independently read by two nuclear radiologists. Clinicians blinded to scan results determined patient disposition. Patients with abnormal scans were asked to return for follow-up resting scans. Fourteen patients were enrolled. Twelve of the 14 patients had chest pain at the time of Tc-99m tetrofosmin injection. Ten of the 14 [(71%) 95% CI = 48% to 95%] scans were normal or within normal limits. Four of the 14 [(29%) 95% CI = 5% to 52%] were abnormal. Of the four patients with abnormal scans, two had follow-up scans that demonstrated an irreversible perfusion abnormality, and two who did not return for follow-up reported no subsequent hospitalizations for acute cardiac ischemia. Perfusion imaging did not demonstrate reversible ischemia in most patients (12/14, 86%) with cocaine-induced chest pain without ECG evidence of ischemia. These results suggest that cocaine-induced chest pain in most patients without ECG evidence of ischemia is not due to acute ischemia.


The discovery of potent antagonists of NPBWR1 (GPR7).
The synthesis and evaluation of small molecule antagonists of the G protein-coupled receptor NPBWR1 (GPR7) are reported for the first time. [4-(5-Chloropyridin-2-yl)piperazin-1-yl][(1S,2S,4R)-4-{[(1R)-1-(4-methoxyphenyl)ethyl]amino}-2-(thiophen-3-yl)cyclohexyl]methanone (1) emerged as a hit from a high-throughput screen. Examination of substituents that focused on replacing the 5-chloropyridine and 4-methoxybenzylamino groups of 1 led to the identification of compounds that exhibited subnanomolar potencies as low as 660pM (9k) in the functional assay and 200pM in the binding assay (9i).


Peritoneal lavage fluid protease levels after in vivo administration of tolmetin in hyaluronic acid.
Tolmetin sodium in a hyaluronic acid carrier (tolmetin-HA) was previously shown to reduce adhesion formation and alter the rate and extent to which wound repair cells enter the peritoneal cavity after surgery. In this study, the effect of tolmetin-HA on the levels of protease activities present in lavage fluid from the peritoneal cavity was determined at various postsurgical times. Collagenase activity in peritoneal lavage fluid was suppressed at 6, 12, and 24 hr after administration of tolmetin-HA in comparison to control. Elastase activity levels were biphasic with peak levels at 6 and 72 hr in lavage fluid from controls compared to peak levels at 6 and 48 hr in lavage fluid from treated rabbits. Plasminogen activator activity present in lavage fluid was significantly decreased at 48 hr after surgery in the tolmetin-HA-treated rabbits compared to controls. However, no alteration in the level of plasminogen activator inhibitor activity was observed in either the tolmetin-HA-treated or control rabbits. These data suggest that tolmetin-HA treatment altered the levels of neutral protease activity present in the peritoneal cavity and may therefore effect the proteolytic potential in the peritoneal cavity after surgery.


Comparison of Efficacy of Anti-interleukin-17 in the Treatment of Psoriasis Between Caucasians and Asians: A Systematic Review and Meta-Analysis.
Interleukin-17 (IL-17) monoclonal antibody drugs have been increasingly significant in the treatment of psoriasis, but it is not clear whether the efficacy is equivalent across ethnicities. To explore the differences of short-term efficacy of IL-17 inhibitors between Caucasians and Asians. The pooled log risk ratio (logRR) between the groups was estimated. The meta-regression analysis on the logRR was performed, with the proportion of Caucasian patients as the covariate. The subgroup analysis was performed by specific IL-17 inhibitors. Of the 1,569 potentially relevant studies, sixteen randomized controlled trials (RCTs) were included. For the Psoriasis Area and Severity Index 75 (PASI 75) response at week 12, the pooled logRR of the Asian group and the Caucasian group was 2.81 (95% CI: 2.27-3.35, p < 0.001) and 2.93 (95% CI: 2.71-3.16, p < 0.001), respectively, indicating no significant difference of efficacy between Asians and Caucasians. The meta-regression analysis did not show an association of the proportion of Caucasians with the effect size (β = 0.3203, p = 0.334). In the subgroup analysis, the comparison results of secukinumab were consistent with the main analysis. Only the short-term efficacy was explored. The data from Asian countries were limited. The short-term efficacy of IL-17 inhibitors in the treatment of psoriasis has no significant difference between Caucasians and Asians. PROSPERO, identifier CRD42020201994, https://www.crd.york.ac.uk/prospero/.


Prioritizing industries for occupational injury and illness prevention and research, Washington State Workers' compensation claims, 1999-2003.
The objective of this study was to identify high-risk industry groups for effective allocation of occupational safety and health prevention and research resources. We used all compensable Washington state workers' compensation claims to rank North American Industry Classification System (NAICS) industry groups by a "prevention index" (PI). The PI is the average of the rank orders of each industry group's claim count and claim incidence rate. Of the 274 industry groups ranked by PI for all compensable workers' compensation claims, the following industry groups ranked the highest: NAICS 2381 Foundation, Structure, and Building Exterior Contractors, NAICS 4841 General Freight Trucking, and NAICS 2361 Residential Building Construction. Industry group PI rankings are reported for the seven most common costly occupational injury types. Use of a PI can focus prevention and research resources where they can be of most benefit.


Bioactive Collagen Hydrolysate-Chitosan/Essential Oil Electrospun Nanofibers Designed for Medical Wound Dressings.
In this study, lemon balm (Melissa officinalis L.) and dill (Anethum graveolens L.) essential oils (EOs) were encapsulated into collagen hydrolysates extracted from bovine tendons and rabbit skins, both mixed with chitosan (CS) by using the coaxial electrospinning technique for potential wound dressing applications. The morphology and chemical composition of the electrospun nanofibers were investigated using scanning electron microscopy (SEM) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). The antimicrobial activity of the dill EO and lemon EO, as well as the electrospun samples loaded with essential oils was determined by disk diffusion assay against Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, and Salmonella typhimurium ATCC 14028 bacterial strains; Candida albicans ATCC 10231 and Candida glabrata ATCC 90028 yeast strains; and Aspergillus brasiliensis ATCC 9642 fungal strain. In vivo biocompatibility testing of the collagen hydrolysate-chitosan/essential oil electrospun nanofibers was based on the determination of the hematological, biochemical, and immunological profile and the evaluation of the influence produced on the oxidative stress in white Swiss mice. The synergetic effect of dill and lemon balm EOs can improve the antimicrobial activity of collagen hydrolysate-chitosan nanofibers against the most important bacterial strains. The in vivo test results suggested a good biocompatibility of electrospun samples based on collagen hydrolysate extracted from bovine tendons or rabbit skin mixed with chitosan and containing dill and/or lemon balm essential oils as encapsulated bioactive compounds.


Inhibition of 5alpha-reductase blocks prostate effects of testosterone without blocking anabolic effects.
We studied the effect of the 5alpha-reductase inhibitor MK-434 on responses to testosterone (T) in orchiectomized (ORX) male Brown Norway (BN) rats aged 13 mo. At 4 wk after ORX or sham surgery, a second surgery was performed to implant pellets delivering 1 mg T/day or placebo pellets. During the second 4 wk of the study, rats received injections of MK-434 (0.75 mg/day) or vehicle injections. Treatment with T elevated serum T to 75% above that for sham animals (P = 0.002) and did not affect serum dihydrotestosterone (DHT) or serum estradiol. T treatment also caused an elevation of prostate T and a marked elevation of prostate DHT. During the second half of the study, ORX rats lost an average of 18.86 +/- 4.62 g body wt. T completely prevented weight loss, and the effect was not inhibited by MK-434 (P < 0.001). ORX produced a nonsignificant trend toward a small (5%) decrease in the mass of the gastrocnemius muscle (P = 0.0819). This trend was also reversed by T, and the effect of T was not blocked by MK-434. T caused a significant 16% decrease in subcutaneous fat that was not blocked by MK-434 (P < 0.05). Finally, T caused a 65% decrease in urine excretion of deoxypyridinoline, a marker of bone resorption, and again the effect was not blocked by MK-434 (P < 0.0001). In contrast, T caused a greater than fivefold increase in prostate mass, and the effect was almost completely blocked by MK-434 (P < 0.0001). This study demonstrates that 5alpha-reductase inhibitors may block the undesirable effects of T on the prostate, without blocking the desirable anabolic effects of T on muscle, bone, and fat.


Strategies to address drug interaction potential for antibody-drug conjugates in clinical development.
Antibody-drug conjugates (ADCs) are a unique class of therapeutic proteins with both small and large molecular components. In vivo, ADCs are processed to multiple clinically relevant analytes, each with distinct PK properties. This increases the complexity for ADC drug interaction (DI) assessment. Furthermore, given the usually narrow therapeutic range for ADCs, a thorough risk assessment is essential to establish benefit/risk for patients. Therefore, an early understanding of the ADC catabolism and elimination pathways and cytochrome P450 reaction phenotyping, cytochrome P450 inhibition and induction potential, transporter interaction and inhibition potential for the cytotoxic drug catabolites assessed by in vitro and preclinical studies is essential. This information would be integrated with the clinical PK and PD properties of the ADC-related analytes for a theoretical risk assessment of ADC DI in combination therapy. ADC DI assessment in clinical studies will further support the theoretical risk assessment and the conclusions for the labeling statement.


A facile route towards the synthesis of polystyrene/zinc oxide nanocomposites.
ZnO nanoparticles were covalently wrapped by polystyrene (PS) through surface thiol-lactam initiated radical polymerization using the grafting from approach. The surface of ZnO nanoparticles was initially modified by 3-mercapto propyltrimethoxysilane to afford thiol functionalized ZnO nanoparticles (ZnO-SH). The controlled radical polymerization of styrene (St) was subsequently accomplished by using an initiating system of ZnO-SH and butyrolactam. FT-IR, XPS, XRD, TGA, DSC, TEM and DLS were employed to investigate the chemical structure, morphology, thermal properties, the size and size distribution of nanocomposites. The dispersibility of ZnO nanoparticles was observed to be significantly improved upon functionalization by PS brushes. The controlled nature of the surface initiated thiol-lactam aided polymerization of St from the ZnO nanoparticles surface was confirmed by GPC analysis.


Influence of Clinically Significant Genes on Antiplatelet Effect of Clopidogrel and Clinical Outcomes in Patients with Acute Coronary Syndrome and Atrial Fibrillation.
The interindividual variability of the antiplatelet effect of clopidogrel is determined by multiple clinical and genetic factors. A lot of genotype-oriented studies have concentrated on the impact of CYP2C19 gene polymorphisms on platelet aggregation in patients receiving clopidogrel. However, the influence of this polymorphism may be only 12-20%, so other genetic markers should also be investigated. The aim of this work was to study the impact of carriage of CES1, PON1, ABCG2, CYP4F2, CYP3A4, IGTB3, P2Y12, PEAR1, and B4GALT2 polymorphisms on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome (ACS) and atrial fibrillation (AF). 103 patients who underwent ACS with or without percutaneous coronary intervention and concomitant nonvalvular AF were included in an open multicenter prospective study to assess efficacy and safety of combined antithrombotic therapy. The study assessed the frequency of different primary clinical outcomes (incidence of major bleeding, hospital mortality, cardiovascular mortality, stroke and transient ischemic attacks (TIAs), renal mortality) and secondary outcomes (resistance to therapy - high residual platelet reactivity, excessive platelet suppression). Residual platelet reactivity was examined using the VerifyNow system (Accumetrics, Latham, NY, USA). None of the studied genetic markers had no statistically significant effect on the antiaggregant response to clopidogrel in patients with ACS and AF. However, CYP4F2 C(Val433Met) T, PEAR1 rs41273215 C>T were statistically significantly associated with an increased frequency of bleeding on antithrombotic therapy. B4GALT2 rs1061781 was statistically significantly associated with increased frequency of strokes and TIA. In our study, we determined that carriers of CYP4F2 gene polymorphisms C(Val433Met)T, PEAR1 rs41273215 C>T (CT+TT) were associated with lower safety of antithrombotic therapy in patients with ACS and AF. And, the B4GALT2 rs1061781 gene polymorphism was associated with a greater risk of insufficient efficacy of the therapy. The data obtained in our study may improve the understanding of the effect of less studied genetic markers on the efficacy and safety of antithrombotic therapy in patients with ACS and AF.


Myasthenia gravis: stimulation of antireceptor autoantibodies by autoreactive T cell lines.
We studied autoreactive acetylcholine receptor (AChR)-specific T cell lines from two patients with myasthenia gravis. Anti-AChR autoantibody production by peripheral blood mononuclear cells (PBM) from the donors of the T cell lines was measured with an enzyme-linked immunoadsorbent assay, using purified human AChR as antigen. Freshly isolated PBM produced barely detectable amounts of anti-AChR autoantibodies. If, however, autologous AChR-specific T cells were added to the cultures, the production of anti-AChR autoantibodies, and of total IgM and IgG, was markedly stimulated, depending on the number of T line cells and on the amount of AChR present in the cultures. AChR-specific functional helper T-lymphocytes may have a role in the immunoregulation of myasthenia gravis.


Parallel imaging performance as a function of field strength--an experimental investigation using electrodynamic scaling.
In this work, the dependence of parallel MRI performance on main magnetic field strength is experimentally investigated. Using the general framework of electrodynamic scaling, the B0-dependent behavior of the relevant radiofrequency fields at a single physical field strength of 7 T is studied. In the chosen implementation this is accomplished by adjusting the permittivity and conductivity of a homogeneous spherical phantom. With different mixing ratios of decane, ethanol, purified water, N-methylformamide, and sodium chloride, field strengths in the range of 1.5 to 11.5 T are mimicked. Based on sensitivity maps of an eight-coil receiver array, the field-dependent performance of parallel imaging is assessed in terms of the geometry factor g, which reflects noise enhancement in parallel imaging reconstruction. At low field strengths the SNR penalty was nearly independent of B0 and favorably low for 1D reduction factors up to between 3 and 4. At higher field strengths the transition between favorable and prohibitive parallel imaging conditions was found to shift toward higher feasible reduction factors. These findings are in good agreement with previous theoretical predictions. From this agreement it is concluded that parallel MRI at high B0 benefits specifically from onsetting far-field behavior of the involved radiofrequency fields.


The use of a commercial ELISA for assay of thrombin-antithrombin complexes in purified systems.
Inhibition of thrombin by antithrombin III (AT) results in the formation of stable thrombin-AT complexes (TAT). An enzyme-linked immunosorbent assay (ELISA) following the sandwich principle is available for the determination of TAT complexes in human plasma, however, this ELISA method could not be used in purified systems containing thrombin and AT. It has therefore been modified for use in purified systems and an excellent correlation was found between the disappearance of thrombin and AT and the recovery of TAT complexes. Addition of thrombin inhibitor hirudin and heparin inhibitor polybrene into the reacting thrombin-AT mixture did not interfere with the assay of TAT. It was found that the use of siliconised tubes was necessary for the conservation of the TAT complexes.


Paradoxical emboli secondary to hepatic pathology: common or coincidental?
Paradoxical cerebral emboli from cardiac and pulmonary sources are well described in the peer-reviewed literature. We outline a case with a hepatic etiology and describe diagnostic and management options. Though this paper represents the first documentation of such, we believe that transpulmonary shunting with concurrent paradoxical cerebral microemboli is more prevalent than recognized. We introduce this case report to compel practitioners to consider paradoxical emboli in selected cirrhotic patients since it can often be difficult to elicit subtle neurologic changes on clinical examination of patients with end stage liver disease.


Mammalian immunoassays for predicting the toxicity of malathion in a laboratory fish model.
This study describes the use of a panel of immune assays, originally developed by the National Toxicology Program for assessing xenobiotic-induced immunotoxicity in mice, to quantify the effects of sublethal malathion exposure on the immune responses of fish. For this study, Japanese medaka (Oryzias latipes) were exposed subchronically to the organophosphate pesticide malathion in a series of two experiments. In the first set of studies, fish were exposed for 7 or 14 d to untreated well water (i.e., controls) or to waterborne malathion at 0.2 or 0.8 mg/L. Following exposure, fish from each group were sacrificed and their kidneys (primary organ of leukopoiesis in fish and equivalent to mammalian bone marrow) were used to provide cells for assessing any malathion-induced effects upon nonspecific and acquired immune defense mechanisms. Effects upon humoral-mediated immunity were determined by enumerating antibody plaque-forming cell (PFC) numbers from a subset of fish exposed to malathion for 14 d and then injected intraperitoneally (ip) with sheep erythrocytes (sRBC). Results of these studies demonstrated that while malathion exposure had no significant effect upon hematocrit/leukocrit values or upon mitogen-stimulated T-cell lymphoproliferation, PFC numbers in the kidney of exposed fish were significantly reduced (compared to control fish) in a dose-dependent manner. In addition, total recoverable kidney cell numbers and viability, as well as superoxide anion production by kidney phagocytes, were reduced slightly (compared to control values) in fish exposed for 14 d to the highest malathion concentration tested. In the second set of experiments, medaka exposed for up to 21 d to either 0.1 or 0.3 mg malathion/L were challenged ip with an LD50 dose of the bacterial fish pathogen Yersinia ruckeri. Results from these infectivity studies demonstrated that exposure to either malathion concentration, for 14 or 21 d reduced host resistance against Yersinia infection. Taken together, these findings demonstrate the applicability of mammalian immune assays for predicting malathion-induced immunosuppression in a teleost fish, as well as the potential utility of a small laboratory fish to serve as an alternate model for mammals in immunotoxicological studies.


Synthesis of sequence-specific DNA-protein conjugates via a reductive amination strategy.
DNA-protein cross-links (DPCs) are ubiquitous, structurally diverse DNA lesions formed upon exposure to bis-electrophiles, transition metals, UV light, and reactive oxygen species. Because of their superbulky, helix distorting nature, DPCs interfere with DNA replication, transcription, and repair, potentially contributing to mutagenesis and carcinogenesis. However, the biological implications of DPC lesions have not been fully elucidated due to the difficulty in generating site-specific DNA substrates representative of DPC lesions formed in vivo. In the present study, a novel approach involving postsynthetic reductive amination has been developed to prepare a range of hydrolytically stable lesions structurally mimicking the DPCs produced between the N7 position of guanine in DNA and basic lysine or arginine side chains of proteins and peptides.


Thrombin functions during tissue factor-induced blood coagulation.
Tissue factor-induced blood coagulation was studied in 20 individuals, for varying periods of time during 54 months, in contact pathway-inhibited whole blood at 37 degrees C and evaluated in terms of the activation of various substrates. After quenching over time with inhibitors, the soluble phases were analyzed for thrombin-antithrombin III (TAT) complex formation, prothrombin fragments, platelet activation (osteonectin release), factor Va generation, fibrinopeptide (FP) A and FPB release, and factor XIII activation. TAT complex formation, for 35 experiments, showed an initiation phase (up to 4.6 +/- 0.6 minutes) in which thrombin was generated at an average rate of 0.93 +/- 0.3 nM/min catalyzed by about 1.3 pM prothrombinase yielding approximately 26 nM thrombin. During a subsequent propagation phase, thrombin was generated at a rate of 83.9 +/- 3.8 nM/min by about 120 pM prothrombinase, reaching ultimate levels of 851 +/- 53 nM. Clot time, determined subjectively, occurred at 4.7 +/- 0.2 minutes and correlated with the inception of the propagation phase. The thrombin concentrations associated with the transitions to rapid product formation are 510 +/- 180 pM for platelet activation (1.9 +/- 0.2 minutes), 840 +/- 280 pM for factor XIII activation and factor Va generation (2.2 +/- 0.6 minutes), 1.3 +/- 0.4 nM for FPA release (2.5 +/- 0.7 minutes), 1.7 +/- 0.5 nM for FPB release and prethrombin 2 (2.8 +/- 0.8 minutes), 7.0 +/- 2.2 nM for thrombin B chain (3.6 +/- 0.2 minutes), and 26 +/- 6.2 nM for the propagation phase of TAT formation (4.6 +/- 0.6 minutes). These results illustrate that the initial activation of thrombin substrates occurs during the initiation phase at less than 2 nM thrombin (0.2%). Most thrombin (96%) is formed well after clotting occurs.


The efficacy of serum carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3 (CA15-3), alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) levels in determining the malignancy of solitary pulmonary nodules.
We investigated the utility of the tumour markers carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3 (CA15-3), alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG) for the differential diagnosis of benign and malignant solitary pulmonary nodules in 42 hospitalized patients. Routine medical history and physical examination of each patient was performed and each patient also had a chest X-ray and a thoracic computed tomography scan. The following diagnostic procedures were also undertaken: bronchoscopy, transthoracic needle aspiration biopsy, sputum cytology and culture, analysis of sputum acid-fast bacilli and thoracotomy. Measurement of serum levels of tumour antigens by Immulite 2000 radioimmunoassay found that three tumour markers, CEA, CA125 and CA15-3, could be used in the diagnosis of malignant solitary pulmonary nodules. More research is now required involving a larger group of patients.


Predicting Clinically Significant Improvement After Robot-Assisted Upper Limb Rehabilitation in Subacute and Chronic Stroke.
Prior studies examining predictors of favorable clinical outcomes after upper limb robot-assisted therapy (RT) have many shortcomings. Therefore, the aim of this study was to identify meaningful predictors and a prediction model for clinically significant motor improvement in upper limb impairment after RT for each stroke phase. This retrospective, single-center study enrolled patients with stroke who received RT using InMotion2 along with conventional therapy (CT) from January 2015 to September 2019. Demographic characteristics, clinical measures, and robotic kinematic measures were evaluated. The primary outcome measure was the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and we classified patients with improvement more than the minimal clinically important difference as responders for each stroke phase. Univariable and multivariable logistic regression analyses were performed to assess the relationship between potential predictors and RT responders and determine meaningful predictors. Subsequently, meaningful predictors were included in the final prediction model. One hundred forty-four patients were enrolled. The Hand Movement Scale and time since onset were significant predictors of clinically significant improvement in upper limb impairment (P = 0.045 and 0.043, respectively), as represented by the FMA-UE score after RT along with CT, in patients with subacute stroke. These variables were also meaningful predictors with borderline statistical significance in patients with chronic stroke (P = 0.076 and 0.066, respectively). Better hand movement and a shorter time since onset can be used as realistic predictors of clinically significant motor improvement in upper limb impairment after RT with InMotion2 alongside CT in patients with subacute and chronic stroke. This information may help healthcare professionals discern optimal patients for RT and accurately inform patients and caregivers about outcomes of RT.


[Basic methods for extraction and molecular analysis of micromycetic DNA].
The methods for extraction of nucleic acids from the fungi and clinical materials containing various microorganisms have currently modified and make it possible to extract DNA with its highest yield and to minimize its destruction. In particular, this concerns mycelial fungi that have a rigid cell wall. Addition of glass microbeads to the lysed sample, followed by mixture stirring, gives rise to undamaged DNA from fungi and their spores. Extracted DNA is suitable for the identification of micromycetes by qualitative or quantitative polymerase chain reaction (PCR), real-time PCR-based hybridization, and LightCycler PCR and for the polymorphism analysis of the spacer regions of ribosomal genes by the sequencing technique. A combination of quantitative PCR and sequencing permits co-determination of the number of gene target copies in 9 different micromycetes in the clinical material being examined, which is of great importance for the diagnosis and treatment of patients with higher immunosuppression and, of those after transplantation of organs and tissues in particular.


[Clinical significance of flow cytometry in diagnosis of immunorelated pancytopenia].
This study was purposed to explore the diagnostic role of flow cytometry in immunorelated pancytopenia (IRP). After 50 IRP patients were hospitalized, the concentration of serum ferritin, folic acid and vitamin B(12), immunologic test, platelet antibody, test of hepatitis A, B and C, haemolysis test and bone marrow smear examination were carried out, meanwhile the chromosome karyotype analysis and some routine examinations were performed. The 50 patients were divided into group A and group B. Group A consisted of 22 patients who were undefinedly diagnosed and intended to diagnosed as IRP, group B consisted of 28 definedly diagnosed patients with hematologic malignancies, including 7 cases of aplastic anemia, 2 of paroxysmal nocturnal hemoglobinuria, 10 of myelodysplastic syndrome, 9 of megaloblastic anemia. In addition, 30 normal people were used as normal control group (group C). For groups A and B, the binding autoantibodies of bone marrow stem/progenitor cells, erythroblasts and myelocytes were detected by flow cytometry, meantime the ratio of total B-(CD10(+)) and CD5(+) B-lymphocytes in peripheral blood was assayed. For control group, the ratios of CD19(+) and CD5(+) B lymphocytes in peripheral blood were determined alone. The results indicated that the detection of bone marrow autoantibodies in 20 patients of group A showed positive with 90.90%. The IgG type was found mostly in antibody binding types, next the IgM type, the IgA type was fewer. The detection of bone marrow autoantibodies of 2 patients in group B showed positive with 7.14%. The positive rate in group A was obviously higher than that in group B (p < 0.01). The ratios of CD19(+) and CD5(+) B lymphocyte in peripheral blood were significant higher in group A than that in group B and control group (p < 0.01), but there was no significant difference between groups B and control. It is concluded that the application of flow cytometry in detecting the autoantibodies of bone marrow cells and CD19(+) B-and CD5(+) B-lymphocyte in peripheral blood can provide reliable diagnostic evidence and detection measure for diagnosis and differential diagnosis of IRP, as well as may contribute to draw up more effective therapeutic strategy.


Correlations between CCN1 immunoexpression and myocardial histologic lesions in sudden cardiac death.
CCN1 (CYR61) is a member of the CCN family of secreted matricellular proteins; it can regulate the expression of genes involved in angiogenesis and matrix remodeling. The latter mechanisms seem to be of vital importance in the pathophysiology of sudden cardiac death. We performed an immunohistochemical analysis on 62 cardiac tissue specimens derived from individuals of young and middle age who had died of sudden cardiac death. CCN1 immunopositivity was detected in 80.6% of all specimens. Semiquantitative statistical analysis of the staining results revealed that CCN1 immunoreactivity was significantly associated with ischemic morphology and hypertrophy of myocardial fibers, interstitial edema, and atheromatosis of coronary arteries in more than 10% of the myocardial fibers. Taking the previously mentioned correlations into account, ischemia seems to induce myocardial expression of CCN1; therefore, CCN1 immunostaining could be evaluated as a complementary tool in the assessment of ischemic areas when no tissue evidence of necrosis is available.


Dopamine-induced bradycardia in two dogs under isoflurane anaesthesia.
Dopamine is a commonly used positive inotropic agent for the treatment of hypotension in small animals. Two dogs that had undergone surgery, under isoflurane anaesthesia, developed a sudden and profound bradycardia when a dopamine infusion was administered. Bradycardia was attributed to the activation of the Bezold-Jarisch reflex, an inhibitory reflex, characterised by bradycardia and hypotension.


Transiting Out of Full-Time National Service: A Qualitative Study of Barriers and Motivators of Weight Change in Young Adult Men in Singapore.
Higher prevalence of obesity in men compared with women, particularly among those 18 to 40 years of age, has been observed in Singapore. We explored young men's perceptions of weight change after transiting out of National Service (NS) over a 12-month period and sought to understand the underlying drivers. In-depth interviews, guided by the Health Belief Model (HBM), were conducted with young men 12 months after they had completed full-time NS. Six constructs from the HBM, namely, perceived susceptibility, perceived severity, perceived benefits, perceived barriers, cues to action, and perceived self-efficacy, were utilized to guide the analysis. Thematic analysis revealed that participants generally perceived a gain in body weight after the transition and attributed this to decreased exercise-related physical activity (PA) levels and increased consumption of unhealthy food. However, many did not display immediate concerns nor view leading a healthy lifestyle as priority, citing time constraints, inertia to comply, or lack of access to sports facilities and healthy food options as barriers. Healthy lifestyle behaviors, mainly PA, were mostly pursued for physical health and appearance. Motivators toward a healthy lifestyle tended to be internal factors such as self-motivation, personal preference, and habit, whereas external motivators included peer or familial influence and environmental factors. Our findings align with key concepts of the HBM and suggest a need to educate young men transiting out of NS on lifestyle, weight, and health, in particular addressing their misconceptions.


A novel TLR2 agonist from Bordetella pertussis is a potent adjuvant that promotes protective immunity with an acellular pertussis vaccine.
Bordetella pertussis causes whooping cough, a severe and often lethal respiratory infection in infants. A recent resurgence of pertussis has been linked with waning or suboptimal immunity induced with acellular pertussis vaccines (Pa) that were introduced to most developed countries in the 1990s because of safety concerns around the use of whole-cell pertussis vaccines (Pw). Pa are composed of individual B. pertussis antigens absorbed to alum and promote strong antibody, T helper type 2 (Th2) and Th17 responses, but are less effective at inducing cellular immunity mediated by Th1 cells. In contrast, Pw, which include endogenous Toll-like receptor (TLR) agonists, induce Th1 as well as Th17 responses. Here we report the identification and characterization of novel TLR2-activating lipoproteins from B. pertussis. These proteins contain a characteristic N-terminal signal peptide that is unique to Gram-negative bacteria and we demonstrate that one of these lipoproteins, BP1569, activates murine dendritic cells and macrophages and human mononuclear cells via TLR2. Furthermore, we demonstrated that a corresponding synthetic lipopeptide LP1569 has potent immunostimulatory and adjuvant properties, capable of enhancing Th1, Th17, and IgG2a antibody responses induced in mice with an experimental Pa that conferred superior protection against B. pertussis infection than an equivalent vaccine formulated with alum.


Budgetary policies and available actions: a generalisation of decision rules for allocation and research decisions.
The allocation problem in health care can be characterised as a mathematical programming problem but attempts to incorporate uncertainty in costs and effect have suffered from important limitations. A two-stage stochastic mathematical programming formulation is developed and applied to a numerical example to explore and demonstrate the implications of this more general and comprehensive approach. The solution to the allocation problem for different budgets, budgetary policies, and available actions are then demonstrated. This analysis is used to evaluate different budgetary policies and examine the adequacy of standard decision rules in cost-effectiveness analysis. The research decision is then considered alongside the allocation problem. This more general formulation demonstrates that the value of further research depends on: (i) the budgetary policy in place; (ii) the realisations revealed during the budget period; (iii) remedial actions that may be available; and (iv) variability in parameters values.


Valproic acid: long-term effects on children exposed in utero.
(1) Numerous follow-up studies of pregnancies in women with epilepsy show that valproic acid is more teratogenic than other antiepileptics. The risk of malformations increases with doses above 1000 mg/day; (2) Malformations associated with valproic acid include neural tube defects in 1-2% of exposed children, as well as urogenital, craniofacial and digital abnormalities. Cardiac disorders and limb defects have also been reported; (3) Convergent results of several cohort studies show that exposure to valproic acid in utero has detrimental effects on intelligence, language and behavior, which appear in school-age children; (4) In practice, the use of valproic acid should be avoided throughout pregnancy, as well as by women of childbearing age not using effective contraception. If a woman is planning pregnancy, the choice of valproic acid should be reassessed with the patient. If valproic acid therapy is maintained, the minimum effective daily dose should be determined and folic acid supplementation initiated.


Thyroarytenoid muscle activity during loaded and nonloaded breathing in adult humans.
Previous fiber-optic studies in humans have demonstrated narrowing of the glottic aperture in expiration during application of expiratory resistive loads. Nine healthy subjects were studied to determine the effect of expiratory resistive loads on the electromyographic activity of the thyroarytenoid (TA) muscle, a vocal cord adductor. Four of the nine subjects also underwent the application of inspiratory resistive loads and voluntary prolongation of either inspiratory (TI) or expiratory (TE) time. TA activity was recorded by intramuscular hooked-wire electrodes. During quiet breathing in all subjects, the TA was phasically active on expiration and often tonically active throughout the respiratory cycle. TA expiratory activity progressively increased with increasing levels of expiratory load. Inspiratory loads resulted in increased TA "inspiratory" activity. Voluntary prolongation of TE to times similar to those reached during loaded breathing induced increases in TA expiratory activity similar to those reached during the loaded state. Voluntary prolongation of TI was associated with an increase in TA inspiratory activity. Similar increases in TI during inspiratory loading or voluntary conditions were associated with comparable increases in TA inspiratory activity in three of the four subjects. In conclusion, increased activation of TA during the application of expiratory resistive loads implies that the reported narrowing of glottic aperture during expiratory loading is an active phenomenon. Changes in activation of the TA with resistive loads appear to be related to changes in respiratory pattern.


Dystroglycan function requires xylosyl- and glucuronyltransferase activities of LARGE.
Posttranslational modification of alpha-dystroglycan (α-DG) by the like-acetylglucosaminyltransferase (LARGE) is required for it to function as an extracellular matrix (ECM) receptor. Mutations in the LARGE gene have been identified in congenital muscular dystrophy patients with brain abnormalities. However, the precise function of LARGE remains unclear. Here we found that LARGE could act as a bifunctional glycosyltransferase, with both xylosyltransferase and glucuronyltransferase activities, which produced repeating units of [-3-xylose-α1,3-glucuronic acid-β1-]. This modification allowed α-DG to bind laminin-G domain-containing ECM ligands.


Human malignant mesothelial cells: variability of ultrastructural features in established and nude mice transplanted cell lines.
The aim of this study was to determine, by transmission electron microscopy, the differentiation features of 21 human malignant mesothelioma cell lines (HMCLs) established from 13 specimens of 12 confirmed human malignant mesotheliomas, and of tumours induced in nude mice injected with 16 HMCLs. Fifty per cent of HMCLs showed typical mesothelial differentiation (long and slender microvilli, desmosomes, perinuclear intermediate filaments); 29 per cent did not show differentiation; and the remainder were poorly differentiated. Three human tumour specimens gave several different HMCLs; the cell lines obtained from a given tumour exhibited variable mesothelial differentiation. Eleven HMCLs were compared with the native tumour. Four were similar to the tumour and seven were less well differentiated, in most cases in relation to their microvilli. With six HMCLs, tumours induced in nude mice were less well differentiated than the corresponding cell lines, whereas with four HMCLs, tumours were equally or better differentiated. However, in most nude mice tumours, typical mesothelial microvilli were present. These results show that cell lines established from malignant mesothelioma may exhibit dedifferentiated features. However, while the variability in ultrastructural differentiation may result from the culture microenvironment, it could also be related to the state of differentiation, of the native tumour sample and to tumour cell heterogeneity.


Mature ovarian teratoma associated with anti-N-Methyl-D-aspartate receptor encephalitis: A case report.
Encephalitis associated with anti-N-Methyl-D-aspartate (NMDA) receptor is a rare form of autoimmune encephalitis. We report the first case of anti-NMDAR encephalitis in an unmarried 16-years old female who was admitted to the Neurology Emergency Unit Faculty of Medicine, Udayana University, Sanglah General Hospital Bali, Indonesia due to decreased consciousness, repetitive talking, headache, involuntary movements in the mouth and feet, and seizures. She was initially diagnosed with viral encephalitis and symptomatic epilepsy. After four weeks of treatment, she was referred to the Gynecology Department. Rectal ultrasound revealed a cystic lesion with a solid component measuring 3.6x2.64x3.18 cm from the left ovary. Laparotomy cystectomy was performed, and the histopathological examination revealed glial cells and mesoderm components in the form of cartilage tissue. Serum and cerebrospinal fluid were positive for anti-NMDA receptor antibodies. She was treated with human intravenous immunoglobulin and rituximab. Her condition was improved gradually. She recovered fully after almost six weeks of hospitalisation.


Acculturation and Campus Carry: Examining the Effect of Mexico Versus United States Cultural Orientations on College Students' Support for Campus Carry.
Several U.S. states have authorized carrying concealed firearms on campuses. These measures are controversial, with support falling along ideological lines. This study examines whether cultural proximity to the U.S., relative to Mexico, influences support for campus carry. Using a random sample of 1,447 college students from two Texas public universities, structural equation modeling results revealed that individuals more oriented toward U.S. culture were more likely to support campus carry than individuals oriented more toward Mexican culture. Besides this direct effect, acculturation also indirectly influenced support for campus carry through public attitudes toward the police. Specifically, individuals more oriented toward the U.S. held more favorable views of the police, which in turn predicted greater support for campus carry. Collectively, these findings suggest that cultural values influence support for public policies such as campus carry.


Growth mechanism of textured MgO thin films via SSCVD.
Magnesium oxide thin films have been deposited with use of single source chemical vapor deposition (SSCVD). The resultant films were examined by using transmission electron microscopy, X-ray texture analysis, and pole figure analysis. Due to the nature of the chemical reactions occurring at the surface during SSCVD growth, which result in a high growth rate/low flux environment, films of (111) orientation have been achieved without an amorphous underlayer, an unusual result for films of this orientation. Moreover the films have a strong degree of biaxial texturing in the x-y plane as found with X-ray texture analysis. These findings have important implications for buffer layers in perovskite thin film devices. The mechanism producing these structures has been revealed by using TEM and is discussed here.


The association between nuclear receptors and ocular diseases.
Nuclear hormone receptors (NRs) are one of the most abundant transcription factors in the human cells. They regulate expression of genes via interactions with corresponding ligands, co-activators, and co-repressors. These molecular pathways play important roles in the development, cell differentiation, and physiologic and metabolic processes. Increasingly, targeting nuclear receptors is becoming a promising strategy for new drug development. The aim of this review is to discuss the association between nuclear receptors and eye development, and expand their role in various ocular diseases such as keratitis, cataract, glaucoma, uveitis, retinopathy, and ophthalmic tumors. Recent studies in this area are highlighted as well as future research directions and potential clinical applications. Finally, various strategies will be elucidated to inspire more targeted therapies for ocular diseases through the use of nuclear receptors.


Molecular physiology of the insect K-activated amino acid transporter 1 (KAAT1) and cation-anion activated amino acid transporter/channel 1 (CAATCH1) in the light of the structure of the homologous protein LeuT.
K-activated amino acid transporter 1 (KAAT1) and cation-anion-activated amino acid transporter/channel 1 (CAATCH1) are amino acid cotransporters, belonging to the Na/Cl-dependent neurotransmitter transporter family (also called SLC6/NSS), that have been cloned from Manduca sexta midgut. They have been thoroughly studied by expression in Xenopus laevis oocytes, and structure/function analyses have made it possible to identify the structural determinants of their cation and amino acid selectivity. About 40 mutants of these proteins have been studied by measuring amino acid uptake and current/voltage relationships. The results obtained since the cloning of KAAT1 and CAATCH1 are here discussed in the light of the 3D model of the first crystallized member of the family, the leucine transporter LeuT.


Theoretical Evaluation of the Influence of Molecular Packing Mode on the Intramolecular Reorganization Energy of Oligothiophene Molecules.
Accurate determination of the relationships among packing mode, molecular structure and charge transfer mobility for oligothiophene analogues has been significantly impeded, due to the lack of crystal structure information. In the current study, molecular dynamics (MD) were used to investigate the packing mode of non-, methyl- and ethyl-substituted poly(3-alkylthiophenes) (P3ATs). Obvious conformational changes were observed when comparing the packed and isolated oligothiophene molecules, indicating the important influence of packing mode on the geometric structures of these materials. Considering the crucial role played by reorganization energy (RE) in the charge transfer process, both quantum mechanics (QM) and quantum mechanics/molecular mechanics (QM/MM) were performed to examine the impact of different conformations on energy. Our simulations revealed that the geometric structures have distinct effects on the RE. Our data suggest that MD could give a reliable packing mode of oligothiophene analogues, and that QM/MM is indispensable for precisely estimating RE.


Unravelling the functional biomechanics of dental features and tooth wear.
Most of the morphological features recognized in hominin teeth, particularly the topography of the occlusal surface, are generally interpreted as an evolutionary functional adaptation for mechanical food processing. In this respect, we can also expect that the general architecture of a tooth reflects a response to withstand the high stresses produced during masticatory loadings. Here we use an engineering approach, finite element analysis (FEA), with an advanced loading concept derived from individual occlusal wear information to evaluate whether some dental traits usually found in hominin and extant great ape molars, such as the trigonid crest, the entoconid-hypoconulid crest and the protostylid have important biomechanical implications. For this purpose, FEA was applied to 3D digital models of three Gorillagorilla lower second molars (M2) differing in wear stages. Our results show that in unworn and slightly worn M2s tensile stresses concentrate in the grooves of the occlusal surface. In such condition, the trigonid and the entoconid-hypoconulid crests act to reinforce the crown locally against stresses produced along the mesiodistal groove. Similarly, the protostylid is shaped like a buttress to suffer the high tensile stresses concentrated in the deep buccal groove. These dental traits are less functional in the worn M2, because tensile stresses decrease physiologically in the crown with progressing wear due to the enlargement of antagonistic contact areas and changes in loading direction from oblique to nearly parallel direction to the dental axis. This suggests that the wear process might have a crucial influence in the evolution and structural adaptation of molars enabling to endure bite stresses and reduce tooth failure throughout the lifetime of an individual.


The updated landscape of tumor microenvironment and drug repurposing.
Accumulating evidence shows that cellular and acellular components in tumor microenvironment (TME) can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Cancer research and treatment have switched from a cancer-centric model to a TME-centric one, considering the increasing significance of TME in cancer biology. Nonetheless, the clinical efficacy of therapeutic strategies targeting TME, especially the specific cells or pathways of TME, remains unsatisfactory. Classifying the chemopathological characteristics of TME and crosstalk among one another can greatly benefit further studies exploring effective treating methods. Herein, we present an updated image of TME with emphasis on hypoxic niche, immune microenvironment, metabolism microenvironment, acidic niche, innervated niche, and mechanical microenvironment. We then summarize conventional drugs including aspirin, celecoxib, β-adrenergic antagonist, metformin, and statin in new antitumor application. These drugs are considered as viable candidates for combination therapy due to their antitumor activity and extensive use in clinical practice. We also provide our outlook on directions and potential applications of TME theory. This review depicts a comprehensive and vivid landscape of TME from biology to treatment.


Laminar-dependent dendritic spine alterations in the motor cortex of adult rats following callosal transection and forced forelimb use.
Previously, the authors found that partial denervation of the motor cortex in adult animals can enhance this region's neuronal growth response to relevant behavioral change. Rats with partial corpus callosum transections that were forced to rely on one forelimb for 18 days had increased dendritic arborization of layer V pyramidal neurons in the opposite motor cortex compared to controls. This was not found as a result of denervation alone or of forced forelimb use alone. However, it seemed possible that each independent manipulation (i.e., forced forelimb use alone and callosal transections alone) resulted in neural structural alterations that were simply not revealed in measurements of dendritic branch number and/or not inclusive of layer V dendrites. This possibility was assessed in the current study with a reexamination of the Golgi-Cox impregnated tissue generated in the previous study. Tissue was quantified from rats that received either partial transections of the rostral two-thirds of the corpus callosum (CCX) or sham operations (Sham) followed either by 18 days of forced use of one forelimb (Use) or unrestricted use of both forelimbs (Cont). Measurements of apical and basilar dendrites from pyramidal neurons of layer II/III and layer V were performed to detect spine addition resulting from either increased spine density or the addition of dendritic material. As hypothesized, significant spine addition was found following forced forelimb use alone (Sham+Use) and callosal transections alone (CCX+Cont). However, forced use primarily increased spines on layer II/III pyramidal neurons, whereas callosal transections primarily increased dendritic spines on layer V pyramidal neurons in comparison to Sham+Cont. A much more robust increase in layer V dendritic spines was found in animals with the combination of forced forelimb use and denervation (CCX+Use). In contrast to the effects of forced use alone, however, CCX+Use rats failed to show major net increases in spines on layer II/III neurons. These results indicate that while callosal denervation may greatly enhance the neuronal growth and synaptogenic response to behavioral change in layer V, it may also limit spine addition associated with forced forelimb use in layer II/III of the motor cortex.


[Evaluation of Basic Performance of "Point Strip ferritin-3000" for Simple and Rapid Quantification of Serum Ferritin].
Serum ferritin is an excellent marker for total iron content in the body and is essential for the diagnosis of iron deficiency or iron overload. Recently, a simple and rapid method, which utilizes immunochromatography for the quantification of serum ferritin, was developed. However, the range of measurement in previous reagents was limited (10-500 ng/mL). This range is rather narrow and is not fully helpful for the diagnosis of iron overload which sometimes occurs as a result of prolonged transfusions, or for monitoring iron contents during iron chelation therapy against iron overload. In the present study we evaluated the basic performance of the newly developed "Point Strip ferritin-3000", which can measure serum ferritin in the range of 300-3,000 ng/mL. Coefficient of variation (CV) s of within and inter-day assays were in the ranges of 7.3-11.1% and 2.1-5.2%, respectively. Using 87 serum samples obtained from the patients with written informed consents, the correlation coefficient was calculated to be 0.93 compared to the control method. In addition, the quantification of serum ferritin by "Point Strip ferritin-3000" was not influenced by bilirubin, hemoglobin, chyle, rheumatoid factor, or ascorbic acid. From our data, "Point Strip ferritin-3000" is reliable reagent in the range of 300-3,000 ng/mL, and is therefore considered to be useful for the diagnosis of iron overload, as well as for monitoring iron contents during iron chelation therapy. In addition, this quantification method can be easily performed using a small desktop equipment without any special technique, making this system applicable for epidemiological surveys and clinical studies.


An overview of the barbary macaque, Macaca sylvanus, vocal repertoire.
This study provides an overview of the vocalizations of Barbary macaques, Macaca sylvanus. Spectrographic displays of calls are presented along with photographs of the accompanying facial gestures. We give a general description of the contexts in which the different calls are uttered, with special regard to the age and sex of the caller. The vocal repertoire of Barbary macaques mainly consists of screams, shrill barks, geckers, low-frequency pants and grunts, with gradation occurring within and between call types. The spectrograms document that typically, Barbary macaques produce series of several consecutive calls. The influence of habitat, social structure and phylogenetic descent on the morphology of the repertoire and call diversity are discussed in comparison to other species.


Establishment and validation of a nomogram to predict the risk of ovarian metastasis in gastric cancer: Based on a large cohort.
Ovarian metastasis is a special type of distant metastasis unique to female patients with gastric cancer. The pathogenesis of ovarian metastasis is incompletely understood, and the treatment options are controversial. Few studies have predicted the risk of ovarian metastasis. It is not clear which type of gastric cancer is more likely to metastasize to the ovary. A prediction model based on risk factors is needed to improve the rate of detection and diagnosis. To analyze risk factors of ovarian metastasis in female patients with gastric cancer and establish a nomogram to predict the probability of occurrence based on different clinicopathological features. A retrospective cohort of 1696 female patients with gastric cancer between January 2006 and December 2017 were included in a single center, and patients with distant metastasis other than ovary and peritoneum metastasis were excluded. Potential risk factors for ovarian metastasis were analyzed using univariate and multivariable logistic regression. Independent risk factors were chosen to construct a nomogram which received internal validation. Ovarian metastasis occurred in 83 of 1696 female patients. Univariate analysis showed that age, Lauren type, whether the primary lesion contained signet-ring cells, vascular tumor emboli, T stage, N stage, the expression of estrogen receptor, the expression of progesterone receptor, serum carbohydrate antigen 125 and the neutrophil-to-lymphocyte ratio were risk factors for ovarian metastasis of gastric cancer (all P < 0.05). Multivariate analysis showed that age ≤ 50 years, Lauren typing of non-intestinal, gastric cancer lesions containing signet-ring cell components, N stage > N2, positive expression of estrogen receptor, serum carbohydrate antigen 125 > 35 U/mL, and a neutrophil-to-lymphocyte ratio > 2.16 were independent risk factors (all P < 0.05). The independent risk factors were constructed into a nomogram model using R language software. The consistency index after continuous correction was 0.840 [95% confidence interval: (0.774-0.906)]. After the internal self-sampling (Bootstrap) test, the calibration curve of the model was obtained with an average absolute error of 0.007. The receiver operating characteristic curve of the obtained model was drawn. The area under the curve was 0.867, the maximal Youden index was 0.613, the corresponding sensitivity was 0.794, and the specificity was 0.819. The nomogram model performed well in the prediction of ovarian metastasis. Attention should be paid to the possibility of ovarian metastasis in high-risk populations during re-examination, to ensure early detection and treatment.


Effect of Monoammonium Glycyrrhizinate on the Development of Hepatotoxicity After Initial Intrathecal Chemotherapy for Leukemia.
Chemotherapy for acute leukemia includes agents known to cause hepatotoxicity. This study evaluated the role of monoammonium glycyrrhizinate for the prevention of hepatotoxicity after the first methotrexate-containing intrathecal chemotherapy (ITC) in children and adolescents with leukemia. Patients with newly diagnosed acute leukemia (age 0-18 years) who received ITC during the first week of induction therapy at our hospital between April 2016 and March 2021 were enrolled. Intravenous monoammonium glycyrrhizinate (IVMG) was defined as the intravenous administration of monoammonium glycyrrhizinate initiated on the day before or the day of the first ITC. Overall, 39 of 118 patients (33%) developed grade 3-4 hepatotoxicity. The inverse probability of treatment weighting logistic regression model showed that IVMG was not associated with the development of grade 3-4 hepatotoxicity (OR=1.9, 95%CI=0.808-4.468). IVMG did not protect against the development of grade 3-4 hepatotoxicity after the first methotrexate-containing ITC for leukemia.


Methyltransferase-like (METTL)14-mediated N6-methyladenosine modification modulates retinal pigment epithelial (RPE) activity by regulating the methylation of microtubule-associated protein (MAP)2.
The expression of METTL14 is significantly reduced in patients with retinitis pigmentosa (RP). To clarify the significance of the N6-methyladenosine (m6A) RNA modification in RP, we examined phagocytosis, apoptosis, and cell cycle distribution in a human RPE cell line, ARPE-19, following lentivirus-mediated knockdown of METTL14. Differentially expressed genes and changes in m6A level were evaluated by RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq), respectively. The results showed that phagocytosis and proliferation were decreased whereas apoptosis was increased in RPE cells by METTL14 silencing. We found that METTL14 directly regulated m6A level and the expression of MAP2, as determined by RNA-seq, MeRIP-seq, MeRIP quantitative PCR, and the RNA pull-down assay. Additionally, MAP2 could bind to neuronal differentiation (NEUROD)1, a pathogenic gene in RPE-associated diseases. A family member of the YTH domain, (YTHDF)2 was recognized as an m6A reader of MAP2 mRNA. MAP2 overexpression had the same effects as METTL14 knockdown in RPE cells. Thus, METTL14 regulates the expression of MAP2 via the modification of m6A, resulting in the dysregulation of NEUROD1 and pathologic changes in RPE cells. These findings suggest that therapeutic strategies targeting the m6A modification of MAP2 or the METTL14/YTHDF2/MAP2/NEUROD1 signaling axis may be effective in the treatment of RPE-associated ocular diseases.