The cardiac microenvironment uses non-canonical WNT signaling to activate monocytes after myocardial infarction.
A disturbed inflammatory response following myocardial infarction (MI) is associated with poor prognosis and increased tissue damage. Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microenvironment-dependent changes in inflammatory monocytes after MI RNA sequencing analysis of murine Ly6Chigh monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade. Analysis of WNT modulators revealed a strong upregulation of WNT Inhibitory Factor 1 (WIF1) in cardiomyocytes-but not fibroblasts or endothelial cells-upon hypoxia. Compared to wild-type (WT) littermates, WIF1 knockout mice showed severe adverse remodeling marked by increased scar size and reduced ejection fraction 4 weeks after MI While FACS analysis on day 1 after MI revealed no differences in neutrophil numbers, the hearts of WIF1 knockouts contained significantly more inflammatory monocytes than hearts from WT animals. Next, we induced AAV-mediated cardiomyocyte-specific WIF1 overexpression, which attenuated the monocyte response and improved cardiac function after MI, as compared to control-AAV-treated animals. Finally, WIF1 overexpression in isolated cardiomyocytes limited the activation of non-canonical WNT signaling and led to reduced IL-1β and IL-6 expression in monocytes/macrophages. Taken together, we investigated the cardiac microenvironment's interaction with recruited monocytes after MI and identified a novel mechanism of monocyte activation. The local initiation of non-canonical WNT signaling shifts the accumulating myeloid cells toward a pro-inflammatory state and impacts healing after myocardial infarction.


Odorant-responsive biological receptors and electronic noses for volatile organic compounds with aldehyde for human health and diseases: A perspective review.
Volatile organic compounds (VOCs) are gaseous chemicals found in ambient air and exhaled breath. In particular, highly reactive aldehydes are frequently found in polluted air and have been linked to various diseases. Thus, extensive studies have been carried out to elucidate disease-specific aldehydes released from the body to develop potential biomarkers for diagnostic purposes. Mammals possess innate sensory systems, such as receptors and ion channels, to detect these VOCs and maintain physiological homeostasis. Recently, electronic biosensors such as the electronic nose have been developed for disease diagnosis. This review aims to present an overview of natural sensory receptors that can detect reactive aldehydes, as well as electronic noses that have the potential to diagnose certain diseases. In this regard, this review focuses on eight aldehydes that are well-defined as biomarkers in human health and disease. It offers insights into the biological aspects and technological advances in detecting aldehyde-containing VOCs. Therefore, this review will aid in understanding the role of aldehyde-containing VOCs in human health and disease and the technological advances for improved diagnosis.


Kinetics of the oxidation of lactose by copper(II) complexed with bipyridyl in alkaline medium using chloro-complex of rhodium(III) in its nano-concentration range as homogeneous catalyst: a spectrophotometric study.
Kinetics of the oxidation of lactose by Cu(II) complexed with bipyridyl have been investigated at 40 °C for the first time spectrophotometrically using Rh(III) chloride as homogeneous catalyst in aqueous alkaline medium in its nano-concentration range. The order of reaction was found to be fractional positive-order, when the concentration of Rh(III) chloride was varied from 0.30×10(-9) M to 6.00×10(-9) M. The reaction shows fractional positive-order kinetics with respect to [lactose] and [OH(-)] and zeroth-order kinetics with respect to [Cu(II)]. The reaction also shows slight increase in the rate by decreasing dielectric constant of the medium and remains unaffected by the change in ionic strength of the medium. The reaction was carried out at four different temperatures and observed values of rate constants were utilized to calculate various activation parameters specially the entropy of activation (ΔS(#)). The species, [RhCl(3)(H(2)O)(2)OH](-), was postulated as the main reactive species of Rh(III) chloride for the oxidation of lactose by Cu(II) in alkaline medium. On the basis of kinetic and equivalence studies together with spectrophotometric information for the formation of a complex, [formula see text] the most appropriate mechanism for the aforesaid reaction has been proposed. Support to the proposed mechanism was also given by the observed activation parameters and multiple regression analysis. Sodium salts of formic acid, arabinonic acid and lyxonic acid were identified as the main oxidation products of the reaction under investigation.


The ubiquitin-proteasome system links NADPH metabolism to ferroptosis.
Ferroptosis is the type of cell death arising from uncontrolled and excessive lipid peroxidation. NADPH is essential for ferroptosis regulation because it supplies reducing equivalents for antioxidant defense systems and contributes to the generation of reactive oxygen species. Moreover, NADPH level serves as a biomarker for predicting the sensitivity of cells to ferroptosis. The ubiquitin-proteasome system governs the stability of many ferroptosis effectors. Recent research has revealed MARCHF6, the endoplasmic reticulum ubiquitin ligase, as an unprecedented NADPH sensor in the ubiquitin system and a critical regulator of ferroptosis involved in tumorigenesis and fetal development. This review summarizes the current understanding of NADPH metabolism and the ubiquitin-proteasome system in regulating ferroptosis and highlights the emerging importance of MARCHF6 as a vital connector between NADPH metabolism and ferroptosis.


Efficacy of guselkumab in difficult-to-treat psoriasis regions: Data from VOYAGE 1 and VOYAGE 2 Asian subpopulations.
Patients with psoriasis were randomized to guselkumab, placebo or adalimumab in the VOYAGE 1 and VOYAGE 2 studies. In this post hoc analysis, difficult-to-treat psoriasis regions in the Asian subpopulation for both the guselkumab and adalimumab groups were compared with placebo at week 16 and the active treatment groups were compared at week 24. Endpoints included patients achieving scores of 0 or 1 (clear or near clear) or 0 (clear) on the scalp-specific Investigator's Global Assessment (ss-IGA), Physician's Global Assessment of the hands and/or feet (hf-PGA), and fingernail PGA (f-PGA), and percentage improvement in target Nail Psoriasis Severity Index (NAPSI) score through week 24. Efficacy was also assessed by prior biologic experience at baseline. A total of 199 eligible Asian patients were included. The proportion of patients achieving "clear" or "near clear" with guselkumab was superior to adalimumab at week 24 for scalp psoriasis ss-IGA (Asian patients, 72 [85.7%] vs 35 [67.3%], P = 0.004), hands and/or feet psoriasis hf-PGA (29 [82.9%] vs 16 [61.5%], P = 0.054), and similar for fingernail psoriasis f-PGA (28 [63.6%] vs 17 [54.8%], P = 0.412). Guselkumab mean improvements in NAPSI were comparable to adalimumab (39.9% vs 35.9%, P = 0.618). Overall, the complete clearance response of scalp, and hands and/or feet at week 24 occurred in a greater proportion of patients in the guselkumab group, irrespective of baseline biologic status (treatment-naïve or treatment-experienced). Guselkumab was superior to adalimumab for the treatment of scalp, and hands and/or feet psoriasis, and proportionally higher for fingernail psoriasis. Findings were comparable to the global study population.


Replenishing B lymphocytes in health and disease.
The path from hematopoietic stem cells (HSCs) to functional B lymphocytes has long been appreciated as a basic model of differentiation, but much clinically relevant information has also been obtained. It is now possible to conduct single cell studies with increasingly high resolution, revealing that individual stem and progenitor cells differ from each other with respect to differentiation potential and fates. B lymphopoiesis is now seen as a gradual and unsynchronized process where progenitors eventually become B lineage restricted. Major milestones have been identified, but a precise sequence need not be followed and oscillation between states is possible. It is not yet clear if this versatility has survival value, but information is accumulating about infections and age-related changes.


Systemic eight-cycle anti-CD20 monoclonal antibody (rituximab) therapy in primary cutaneous B-cell lymphomas--an applicational observation.
Primary cutaneous B-cell lymphomas (PCBCLs) are characterized by restriction to the skin and a variable but mostly favourable prognosis. Since 1997 the recombinant, chimeric anti-CD20 antibody rituximab has been used in patients suffering from non-Hodgkin's B-cell lymphomas. Different studies have shown that the effectiveness and safety in the treatment of patients with low-grade follicular lymphoma is comparable to or even higher than the standard CHOP chemotherapy. So far it has been unclear whether an extended duration of therapy leads to a benefit for the patients with PCBCL. To evaluate the objective response rate, time to progression, remission quality and histological changes and to compare our data with the literature. Ten patients with PCBCL [eight with follicle centre cell lymphoma (FCCL), one with marginal zone lymphoma (MZL) and one with diffuse large B-cell lymphoma of the leg (DLBCL)] were treated by intravenous application of a chimeric antibody against the CD20 transmembrane antigen (rituximab) with a dosage of eight cycles, 375 mg m(-2) body surface, weekly. The treatment regimen resulted in clinical overall response in 9 of 10 patients, in particular there were seven complete responses (70%) plus two partial responses (20%). The median duration of remission (durable remission, DR) is 23 months (4-30 months) to date. Histological assessment of responses in four patients showed no tumour-specific infiltration. In two patients histology revealed a residual infiltration and in one patient an increasing infiltration. In two patients no histology was taken after treatment; one patient developed a new lesion. No severe side-effects occurred. Observed side-effects were two bacterial infections, two patients with shivering during infusion, one patient with sweating for months and one patient with persisting itching. As expected the B-cell count in peripheral blood was depressed in all patients after infusion. Intravenous therapy with eight cycles of the anti-CD20 antibody rituximab is a non-toxic and effective treatment for a subset of patients with PCBCL (relapsed, aggressive entity, old patients, multiple lesions) with a long DR.


The role of termites in the decomposition of wood and leaf litter in the Southern Guinea savanna of Nigeria.
This is part of a study on the litter dynamics of Southern Guinea savanna, with special reference to the role of termites (Isoptera) as decomposers of wood and leaves.The biomass of accumulated wood litter on the 6 ha study area varied from 2.299 to 3.488 t ha-1, with a mean of 2.821 t ha-1 Leaf litter biomass varied from 0.290 to 1.643 t ha-1, with a mean of 0.903 t ha-1. The measured decomposition constant for wood of 51% a-1 agreed well with a calculated value of 49% a-1. Leaf decomposition was calculated as 264% a-1. Termites removed an estimated 835.5 kg ha-1a-1 of wood litter (60% of annual wood-fall), and 68.4 kg ha-1a-1 of leaf litter (3% of annual leaf-fall), i.e. 24% of total annual litter production. Conversely, the annual bush-fire removed 1.173 t ha-1a-1 (49%) of annual leaf-fall but only 3 kg ha-1a-1 (0.2%) of annual wood-fall, i.e. 31% of total annual litter production. Baiting studies showed that the fungus-growing Macrotermitinae took 95% of the litter removed by termites (23% of annual litter production).The ability of the Macrotermitinae to utilise fresh litter is a diagnostic feature of decomposition processes in Southern Guinea and other savanna ecosystems. Their fungus combs produce a processed diet which allows the Macrotermitinae to feed in a seasonally arid environment where the curtailment of free fungal and microbial activity inhibits feeding by other decomposer invertebrates.


Propagation of major depressive disorder: relationship between first episode symptoms and recurrence.
Major depressive disorder is a highly recurrent disorder, with long-term estimates of recurrence ranging as high as 80%. The impact of first episode depressive symptoms on later recurrence has not been previously examined. The present study sought to identify risk factors for recurrent major depressive episodes by investigating first episode symptoms. It was predicted that the presence of depressed mood and sleep disturbance in the first episode would increase the likelihood of recurrence. Four hundred eighty-seven randomly selected community participants who met DSM-III-R criteria for at least one major depressive episode were assessed twice during adolescence and once in young adulthood. We examined the association between first major depressive episode symptoms and the presence of a recurrent episode. Recurrence was significant predicted by the presence of depressed mood and increased appetite at episode 1. A nonsignificant trend suggested that female gender may also be associated with recurrence. First episode depressed mood, increased appetite, and female gender may serve as specific risk factors for recurrence. The centrality of depressed mood to major depressive disorder is highlighted.


Pseudoaneurysm Development after Drug-Eluting Balloon (DEB) Angioplasty of a Venous Femoropopliteal Bypass Graft.
Endovascular recanalization of occluded venous femoropopliteal bypass grafts is widely used because of easy access. This case report describes pseudoaneurysm developing 4 weeks after endovascular recanalization of an occluded in situ venous femoropopliteal graft. The patient was treated for a popliteal aneurysm with a venous femoropopliteal bypass graft, which subsequently occluded. Four weeks after DEB PTA, the occluded graft developed 3 pseudoaneurysms. Impaired vessel wall healing after intraluminal paclitaxel administration could have contributed to this. This case adds a perspective to the choice of treatment of occluded venous femoropopliteal bypass grafts.


Sjögren's Syndrome Complicated With Sarcoidosis With a Repetitive, Prolonged, Non-productive Cough.
Sjögren's syndrome and sarcoidosis are systemic immune-mediated diseases of unresolved pathogenesis, with dry cough being a symptom of both diseases. Due to the low pre-test probability of the diseases, they are not considered in the first differential diagnosis of prolonged non-productive cough. We report the case of a 33-year-old woman presenting with an intermittent, non-productive cough, diagnosed with Sjögren's syndrome coexisting with sarcoidosis.


Efficient pyridine biodegradation by Stenotrophomonas maltophilia J2: Degradation performance, mechanism, and immobilized application for wastewater.
Stenotrophomonas maltophilia J2, a highly efficient pyridine-degrading bacterium, was isolated from the aerobic tank of a pesticide-contaminated wastewater treatment plant. The strain J2 demonstrated an impressive pyridine degradation rate of 98.34% ± 0.49% within 72 h, at a pyridine concentration of 1100 mg·L-1, a temperature of 30 °C, a pH of 8.0, and a NaCl concentration of 0.5%. Notably, two new pyridine metabolic intermediates, 1,3-dihydroxyacetone and butyric acid, were discovered, indicating that J2 may degrade pyridine through two distinct metabolic pathways. Furthermore, the immobilized strain J2 was obtained by immobilizing J2 with biochar derived from the stem of Solidago canadensis L. In the pyridine-contaminated wastewater bioremediation experiment, the immobilized strain J2 was able to remove 2000 mg·L-1 pyridine with a 98.66% ± 0.47% degradation rate in 24 h, which was significantly higher than that of the control group (3.17% ± 1.24%), and remained above 90% in subsequent cycles until the 27th cycle. High-throughput sequencing analysis indicated that the J2 +B group had an elevated relative abundance of bacteria and functional genes that could be associated with the degradation of pyridine. The results offer a foundation for the effective use of immobilized strain in the treatment of recalcitrant pyridine-contaminated wastewater.


Control of the specificity of T cell-mediated anti-idiotype immunity by natural regulatory T cells.
The idiotypes of B cell lymphomas represent tumor-specific antigens. T cell responses induced by idiotype vaccination in vivo are directed predominantly against CDR peptides, whereas in vitro T cells also recognize framework-derived epitopes. To investigate the mechanisms regulating the specificity of idiotype-specific T cells, BALB/c or B10.D2 mice were immunized with mature dendritic cells loaded with H-2K(d)-restricted peptides from influenza hemagglutinin, or from shared (J region) or unique (CDR3) structures of the A20 lymphoma idiotype. Antigen-specific T cells were induced in vivo by the CDR3 and influenza epitopes, but not by the J peptide. Gene expression profiling of splenic regulatory T cells revealed vaccination-induced Treg activation and proliferation. Treg activity involved J epitope-dependent IL-10 secretion and functional suppression of peptide-specific effector T cells. Vaccination-induced in vivo proliferation of transgenic hemagglutinin-specific T cells was suppressed by co-immunization with the J peptide and was restored in CD25-depleted animals. In conclusion, Treg induced by a shared idiotype epitope can systemically suppress T cell responses against idiotype-derived and immunodominant foreign epitopes in vivo. The results imply that tumor vaccines should avoid epitopes expressed by normal cells in the draining lymph node to achieve optimal anti-tumor efficacy.


cDNA, deduced polypeptide structure and chromosomal assignment of human pulmonary surfactant proteolipid, SPL(pVal).
In hyaline membrane disease of premature infants, lack of surfactant leads to pulmonary atelectasis and respiratory distress. Hydrophobic surfactant proteins of Mr = 5,000-14,000 have been isolated from mammalian surfactants which enhance the rate of spreading and the surface tension lowering properties of phospholipids during dynamic compression. We have characterized the amino-terminal amino acid sequence of pulmonary proteolipids from ether/ethanol extracts of bovine, canine, and human surfactant. Two distinct peptides were identified and termed SPL(pVal) and SPL(Phe). An oligonucleotide probe based on the valine-rich amino-terminal amino acid sequence of SPL(pVal) was utilized to isolate cDNA and genomic DNA encoding the human protein, termed surfactant proteolipid SPL(pVal) on the basis of its unique polyvaline domain. The primary structure of a precursor protein of 20,870 daltons, containing the SPL(pVal) peptide, was deduced from the nucleotide sequence of the cDNAs. Hybrid-arrested translation and immunoprecipitation of labeled translation products of human mRNA demonstrated an Mr = 22,000 precursor protein, the active hydrophobic peptide being produced by proteolytic processing to Mr = 5,000-6,000. Two classes of cDNAs encoding SPL(pVal) were identified. mRNA of approximately 900 bases was identified on Northern analysis of fetal and adult RNA. Human SPL(pVal) mRNA was more abundant in the adult than in fetal lung. The SPL(pVal) gene locus was assigned to chromosome 8.


Versatile temperature controlled tissue bath for studies of isolated cells using an inverted microscope.
The design of a small, inexpensive temperature controlled bath (0.25 ml volume) for electrophysiological studies of isolated cells is described. The design creates a uniform temperature (+/- 1 degree C) from ambient temperature to approximately 37 degrees C over a bath chamber area of 0.6 X 1 cm for flow rates from zero to 2 ml/min. Access for microelectrodes and unobstructed preparation viewing with an inverted microscope is afforded by a finely stranded heater sandwiched between two glass cover slips and located beneath the bath chamber. Battery operation of the feedback temperature controller and solution pre-heater minimizes electrical interference.


Survival patterns of childhood neuroblastoma: an analysis of clinical data from Southern-Eastern European countries.
The prognosis of children with neuroblastoma (NBL) can be dismal with significant variations depending on the stage and biology of the tumor. We assessed the event-free (EFS) and overall (OS) survival using harmonized data from three Southern-Eastern European (SEE) countries. Data for 520 incident NBL cases (2009-2018) were collected from Greece, Slovenia and Russia. Kaplan-Meier curves were fitted, and EFS/OS were derived from Cox proportional models by study variables including the protocol-based risk-group (low/observation, intermediate, high). Over one-third of cases were coded in the high-risk group, of which 23 children (4.4%) received treatment with anti-ganglioside 2 (GD2) mAb. Survival rates were inferior in older (OS 5-year; 1.5-4.9 years: 61%; EFS 5-year; 1.5-4.9 years: 48%) compared to children younger than 1.5 years (OS 5-year; <1.5 years: 91%; EFS 5-year; <1.5 years: 78%). Predictors of poor OS included stage 4 (hazard ratio, HR OS : 18.12, 95% confidence intervals, CI: 3.47-94.54), N-myc amplification (HR OS : 2.16, 95% CI: 1.40-3.34), no surgical excision (HR OS : 3.27, 95% CI: 1.91-5.61) and relapse/progression (HR OS : 5.46, 95% CI: 3.23-9.24). Similar unfavorable EFS was found for the same subsets of patients. By contrast, treatment with anti-GD2 antibody in high-risk patients was associated with decreased risk of death or unfavorable events (HR OS : 0.11, 95% CI: 0.02-0.79; HR EFS : 0.19, 95% CI: 0.07-0.52). Our results confirm the outstanding prognosis of the early NBL stages, especially in children <1.5 years, and the improved outcomes of the anti-GD2 treatment in high-risk patients. Ongoing high-quality clinical cancer registration is needed to ensure comparability of survival across Europe and refine our understanding of the NBL biology.


Surgical treatment of retrorectal tumors: a retrospective study of a ten-year experience in three institutions.
The relative rarity and anatomical position of retrorectal tumors may lead to difficulty in diagnosis and surgical management. This was a retrospective review of 93 patients who had resection of retrorectal tumors between 2002 and 2011. All patients in this study were treated with excision of the retrorectal tumors. Surgical approach included transsacral approach (78 cases), transabdominal approach (12 cases) and combined approach (3 cases). Seventy-two benign lesions (77.4%) and 21 malignant (22.6%) were confirmed by histological examination. The 72 benign cases included dermoid cysts (26 cases), simple cysts (12 cases), teratomas (12 cases), neurofibromas (12 cases), fibrolipomas (6 cases), neurilemmomas (3 cases) and synovioma (1 case). The twenty-one malignant cases included lymphomas (6 cases), malignant teratomas (5 cases), fibrosarcomas (3 cases), interstitialomas (6 cases) and malignant mesothelioma (1 case). Complications occurred in 16.1% of patients including intra-operative bleedings (6 cases), rectal injury (6 cases) and presacral infection (3 cases). Primary retrorectal tumors are very rare. Successful treatment of these tumors requires extensive knowledge of pelvic anatomy and expertise in pelvic surgery.


Efficacy and effectiveness of Herpes zoster vaccination in adults with diabetes mellitus: a systematic review and meta-analysis of clinical trials and observational studies.
The risk for Herpes zoster (HZ) and its complications is higher in people with diabetes mellitus (DM). Our aim is to assess efficacy and effectiveness of the currently available live-attenuated zoster vaccine (LZV) and recombinant zoster vaccine (RZV) in adults with DM. A Systematic Review and Meta-analysis of clinical trials and observational studies comparing incidence of HZ and its complications in vaccinated and unvaccinated people with DM was performed, on PubMed, Cochrane, Clinical Trials.gov and Embase databases, up to January 15th, 2023. Risk of bias was assessed through the Cochrane Collaboration tool and the Newcastle-Ottawa Scale. The protocol was registered on the PROSPERO website (CRD42022370705). Only three observational studies reported LZV efficacy and effectiveness in people with DM. A lower risk for HZ infection (MH-OH Ratio 95% CI = 0.52 [0.49, 0.56] was observed, for unadjusted analysis, and 0.51 [0.46, 0.56] for adjusted analysis, both with P < 0.00001 and no heterogeneity). No data on LZV safety were reported. A pooled analysis of two trials comparing RZV and placebo, showed a reduced risk for HZ incidence: (95% CI Odds Ratio: 0.09 [0.04-0.19]), with no difference in severe adverse events and mortality. In our meta-analysis of three observational studies LZV showed a 48% effectiveness in reducing HZ incidence in adults with diabetes whereas in a pooled analysis of two RCTs, RZV showed a 91% efficacy. No data are available on the effects of vaccination on the incidence and severity of HZ-related complications among subjects with diabetes.


Fhl1 as a downstream target of Wnt signaling to promote myogenesis of C2C12 cells.
Previous studies have shown that Wnt signaling is involved in postnatal mammalian myogenesis; however, the downstream mechanism of Wnt signaling is not fully understood. This study reports that the murine four-and-a-half LIM domain 1 (Fhl1) could be stimulated by β-catenin or LiCl treatment to induce myogenesis. In contrast, knockdown of the Fhl1 gene expression in C2C12 cells led to reduced myotube formation. We also adopted reporter assays to demonstrate that either β-catenin or LiCl significantly activated the Fhl1 promoter, which contains four putative consensus TCF/LEF binding sites. Mutations of two of these sites caused a significant decrease in promoter activity by luciferase reporter assay. Thus, we suggest that Wnt signaling induces muscle cell differentiation, at least partly, through Fhl1 activation.


Overcoming Age-Based Stereotypes to Optimize Cognitive Performance in Older Adults: A Systematic Review of Methodology and Existing Evidence.
Age-based stereotype threat (ABST) poses serious risks for the cognitive screening of older adults. This review aimed to identify and critically appraise the methodology and existing evidence of studies investigating the use of threat-removal (TR) strategies to overcome the effects of ABST on the cognitive performance of older adults. The types of strategies, their effectiveness in optimizing cognitive performance, and factors influencing their effectiveness were examined. A systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PsycINFO, PubMed, Embase, Web of Science, and Scopus were searched from January 1, 1995 to November 6, 2019. Two authors independently assessed article eligibility and appraised methodological quality of eligible articles using an adaptation of the Strengthening the Reporting of Observational studies in Epidemiology guidelines. Narrative synthesis was used to summarize results. Thirty articles, reporting on 36 studies, were eligible and included. Overall, evidence for the effectiveness of TR was mixed and varied according to the explicitness of strategies and comparison conditions used. Studies examining blatant TR strategies, and those using a combination of blatant and subtle TR strategies, provided limited support for their effectiveness in overcoming ABST. However, studies evaluating subtle TR strategies provided preliminary support for their effectiveness in overcoming ABST. Existing studies provide limited evidence regarding the effectiveness of TR strategies in overcoming ABST due to methodological limitations. Recommendations are made for the design of future studies to differentiate the benefits of TR strategies from the detrimental effects of ABST, thus potentially informing their use in clinical practice.


Participant perceptions of changes in psychosocial domains following participation in an adaptive deep brain stimulation trial.
There has been substantial controversy in the neuroethics literature regarding the extent to which deep brain stimulation (DBS) impacts dimensions of personality, mood, and behavior. Despite extensive debate in the theoretical literature, there remains a paucity of empirical data available to support or refute claims related to the psychosocial changes following DBS. A mixed-methods approach was used to examine the perspectives of patients who underwent DBS regarding changes to their personality, authenticity, autonomy, risk-taking, and overall quality of life. Patients (n = 21) who were enrolled in adaptive DBS trials for Parkinson's disease, essential tremor, obsessive-compulsive disorder, Tourette's syndrome, or dystonia participated. Qualitative data revealed that participants, in general, reported positive experiences with alterations in what was described as 'personality, mood, and behavior changes.' The majority of participants reported increases in quality of life. No participants reported 'regretting the decision to undergo DBS.' The findings from this patient sample do not support the narrative that DBS results in substantial adverse changes to dimensions of personality, mood, and behavior. Changes reported as "negative" or "undesired" were few in number, and transient in nature.


The immunomodulatory proteins B7-DC, B7-H2, and B7-H3 are differentially expressed across gestation in the human placenta.
Placental trophoblast cells form a cellular barrier between the potentially immunogenic fetus and maternal leukocytes. Trophoblasts subvert maternal immunity by producing surface-bound and soluble factors that interact with maternal leukocytes. Here, we describe the distribution of three members of the expanding family of B7 immunomodulatory molecules: B7-DC, B7-H2, and B7-H3. B7-DC and B7-H3 inhibit antigen-stimulated lymphocyte activation while B7-H2 serves in a regulatory capacity, often promoting a Th2 immunophenotype. First trimester and term placentas, purified trophoblast cells, choriocarcinoma cell lines, and human umbilical vein endothelial cells were analyzed for B7 family RNA and protein expression. Transcripts and proteins for all three B7s were present throughout gestation but were differentially expressed within the trophoblast and the stroma. Whereas B7-DC was prominent on the syncytiotrophoblast of early placenta, it was absent from the trophoblast at term. In contrast, B7-H2 and B7-H3 were prominent on the extravillous trophoblast throughout gestation. Lastly, stromal cells, including macrophages and endothelial cells, differentially expressed B7-DC, B7-H2, and B7-H3, depending on gestational age. Thus, all three of these newly discovered B7 proteins are differentially positioned at the maternal-fetal interface such that they could steer maternal leukocytes away from a harmful immune response and toward a favorable one.


Some thoughts on the response to antigens that are effector T-helper independent ('thymus independence')
The Self-Non-Self discrimination is germline-selected for defence mechanisms ('innate immune systems') whereas it is somatically learned for immune systems ('adaptive immune systems'). It is proposed that immune system evolved from defence mechanisms by adding large recognitive repertoires that, by aggregating with antigens, were able to trigger the already existent effector functions of defence mechanisms. Thus today there are two pathways to triggering each class of effector function (macrophage opsonization, complement lysis or natural killer/-natural cytotoxic cell activity). The antigen-antibody complex and the T-cell antigen-receptor interaction trigger the immune pathway: the receptors of the defence mechanism trigger the 'alternate' or 'innate' pathway. The evolutionary selection pressure on defence mechanisms was to increase the size of the recognitive repertoire, which in turn, necessitated the emergence of a somatically learned Self-Non-Self discrimination. By contrast with defence mechanisms that are triggered effector T-helper (eTh) independently by polymers (Signal[3]), immune systems can be activated by monomers, a pathway that requires associative recognition of monomer and the reading of two Signals, Signal[1] resulting from the binding of an epitope to the antigen-receptor complex, Signal[2] delivered by an eTh cell. The evolving immune system hijacked part of this eTh-independent pathway (Signal[3]) into which Signal ([1] + [2]) merged. A model of these relationships is proposed.


Altered balance of inhibitory and active Fc gamma receptors in murine autoimmune glomerulonephritis.
Mag is an MRL-derived glomerulonephritis susceptibility locus that includes the Fcgr2b and Fcgr3 genes encoding the inhibitory Fc gamma receptor IIB (FcgammaRIIB) and active FcgammaRIII, respectively. We measured changes in gene balance in three B6.MRLc1 congenic mouse strains containing the 82-86, 92-100 and 100 cM regions of the MRL chromosome 1. We found that only the strain that has 92-100 (which includes Fcgr loci) developed glomerulonephritis. These congenic mice had splenomegaly, elevated blood urea nitrogen, anti-dsDNA antibodies and higher urinary albumin excretion compared to the parental strain C57BL/6(B6). Prior to the development of glomerulonephritis, large CD3- (T cell) and B220- (B cell) positive areas were identified in the spleens of B6.MRLc1(92-100) mice. Both Fc receptors were found in mesangial and dendritic cells; important sites of immune-complex clearance and antigen presentation. The FcgammaRIII-positive areas were more prominent in the congenic strain. Fcgr2b mRNA was lower in the B6.MRLc1(92-100) kidney and spleen than in those organs of the B6 mice while Fcgr3 expression and the Fcgr3 to Fcgr2b mRNA ratio was higher in the congenic strain kidneys, spleen and thymus than in those of the B6 prior to and at an early stage of glomerulonephritis. We conclude that the imbalance of inhibitory and active Fc gamma receptors influences the pathogenesis of glomerulonephritis.


Use of reporter transposons for tagging and detection of Mycobacterium sp. strain 1B in PAH-contaminated soil.
An environmental Mycobacterium able to degrade phenanthrene, pyrene and fluoranthene was transformed with an IS1096-based transposon marker system. Electroporation and subsequent delivery of the transposon enabled formation of constitutive lacZ transformants, with similar growth rates on pyrene and R2A media to the parental strain. A semi-selective medium was developed to recover and detect colonies of the transformed strain after inoculation into polycyclic aromatic hydrocarbon-contaminated soil. Microcosm experiments involving inoculation of the tagged Mycobacterium strain into a historically PAH-contaminated soil indicated survival when an appropriate carbon source was available. The results reported show that transposon systems developed for clinical mycobacterial isolates are also applicable for use in environmental isolates. The results also show that inoculated Mycobacterium strains could survive for at least 100 days at 10(6)-10(7) cfu g-1 in the PAH-contaminated soil tested here.


An alternative tuning approach to enhance NMR signals.
By using spin-noise type measurement we show that the resonance frequency of the reception circuit of classical NMR spectrometers does not match the Larmor frequency even if, in emission, the electronic circuit is perfectly tuned at the Larmor frequency and matches the amplifier impedance. We also show that this spin-noise method can be used to ensure a match between the Larmor frequency and the reception circuit resonance frequency. In these conditions, (i) the radiation damping field is in perfect quadrature to the magnetization and (ii) the NMR signal level and potentially the signal-to-noise ratio, are enhanced. This choice induces a change of the probe resonance frequency by several hundreds of kHz for 500 or 700 MHz spectrometer. We show that the resulting mismatch condition for emission can be removed by adding other tuning and matching degrees of freedom located on the excitation line (or by symmetry on the reception line) decoupled to the probe resonance circuit by the crossed diodes.


A Longitudinal Study on the Mental Health of College Students in Jinan During the Peak Stage of the COVID-19 Epidemic and the Society Reopening.
COVID-19, a continuously emerging human-to-human infectious disease, has exerted a significant impact on the mental health of college students. However, little is known regarding the variations in the mental health issues experienced by college students during the peak versus reopening stages of the COVID-19 epidemic in China. To assess these issues, an online longitudinal survey was conducted via a WeChat applet. Undergraduates (n = 300) were recruited from 26 universities throughout Jinan in February 2020 (T1 - the epidemic peak stage) and in January 2021 (T2 - the society reopening stage). Their mental status was determined using the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7 item, and the Insomnia Severity Index. Of the original 300 college students recruited for this survey, 294 responses at T1 and 285 at T2 were analyzed. Compared with responses obtained at T1, college students at T2 showed a greater prevalence of depression (65.3 vs. 51.0%; p = 0.001) and anxiety (47.7 vs. 38.1%, p = 0.019), and experienced more severe depression (p < 0.001) and anxiety (p < 0.001). Both males (p = 0.03) and females (p < 0.01) showed higher levels of depression at T2 versus T1, while no differences were obtained with regard to anxiety and insomnia. At T1, Grade 4 students showed greater levels of depression (p = 0.005) and anxiety (p = 0.008) than that of Grade 1 students. While at T2, only greater levels of depression (p = 0.004) were present when compared with that of Grade 1 students. Additionally, Grade 4 college students demonstrated a greater prevalence of depression at T2 versus T1 (p = 0.03), but no statistically differences were present for anxiety and insomnia. No statistically significant differences were obtained among the 4 grades of college students for insomnia at either the T1 or T2. With progression of the COVID-19 epidemic, college students showed increasing levels of depression and anxiety, with Grade 4 college students being most seriously affected. It is imperative that intervention strategies be implemented to mitigate against these mental health issues resulting from the COVID-19 epidemic.


Anti-arthritis effect of a novel quinazoline derivative through inhibiting production of TNF-α mediated by TNF-α converting enzyme in murine collagen-induced arthritis model.
TNF-α is a dominant inflammatory mediator in the pathogenesis of inflammatory diseases including rheumatoid arthritis. In our research, we discovered 2-chloro-N-(4-(2-morpholinoethoxy)phenyl)quinazolin-4-amine (9c) exhibited an outstanding anti-inflammatory activity on inhibiting TNF-α production with an IC50 of 8.86 μM in RAW264.7 cells. Interestingly, 9c had no effect on mRNA level of TNF-α but up-regulated the precursor of TNF-α (pro-TNF-α). Then, we studied TNF-α converting enzyme (TACE), which is the most important proteases responsible for the release of TNF-α from pro-TNF-α to soluble TNF-α. The results showed 9c reduced TACE both on the levels of mRNA and protein in a dose-dependent manner. In vivo study, collagen-induced arthritis (CIA) mice were treated by 9c orally. 9c exhibited significant anti-arthritis effect by ameliorating arthritic score, reducing inflammatory cell infiltration, protecting joints from destruction and decreasing the production of systemic TNF-α, IL-6, IL-1β. The underlying mechanism of 9c on CIA was coincided with the in vitro, which was mediated by TACE. In conclusion, we discovered a novel quinazoline derivative which ameliorates arthritis through inhibiting production of TNF-α mediated by TACE for the first time.


Alcohol Consumption and Risky Sexual Behavior Among Persons Attending Alcohol Consumption Venues in Gaborone, Botswana.
Alcohol use is a known key risk factor associated with risky sexual behavior that contributes to HIV transmission. This cross-sectional study used time location sampling to investigate alcohol use and risky sexual behaviors that occurred after ingesting alcohol among 609 patrons of alcohol venues in Gaborone, Botswana. Alcohol Use Disorders Identification Test (AUDIT) scores were categorized as low (1-7), medium (8-15), and high (16+) for analysis. Logistic regression models stratified by gender assessed the association between alcohol use and condom use at last sex after drinking alcohol. Among females, the odds of condom use during last sex after drinking alcohol were significantly lower for high compared to low AUDIT scores (AOR = 0.17, 95% CI 0.06-0.54). Among males, factors significantly associated with condom use at last sex after alcohol use were low levels of education (primary level compared to university and above AOR = 0.13; 95% CI 0.03-0.55) and beliefs that alcohol use did not increase risky sexual behaviors (AOR = 0.26; 95% CI 0.11-0.62). HIV prevention interventions should target females and emphasize sexual risks associated with alcohol use.


Improving tuberculosis contact tracing: the role of evaluations in the home and workplace.
In 2004, the tuberculosis (TB) contact screening strategy in Vila Nova de Gaia, Portugal, was changed from targeting only close contacts identified by interviews with the index patient (reflecting national policy) to include visits to the patient?s home and workplace. To find out 1) whether the new strategy increased adherence to TB screening procedures, 2) whether the strategy identified more at-risk contacts and 3) whether the strategy increased prevention of TB. We compared TB contact tracing during the periods 2001-2003 and 2004-2006. The numbers of identified and screened contacts and the results of screening procedures (number of patients with active TB and latent TB infection [LTBI] detected per index case) were analysed. The number of instances of active TB prevented and the numbers of contacts that had to be screened to prevent one such instance were calculated and compared for both screening strategies. Home and workplace visits helped to identify more at-risk contacts (8.4 per index patient) than interview (2.5 per index patient), and improved adherence (87.3% of identified contacts were screened compared to 67.6% previously). More patients with active TB and LTBI were detected (1.4 per index patient compared with 0.75 per index patient previously), and more TB cases were prevented. The newly implemented contact screening programme, featuring home and workplace evaluation of TB patient contacts, improved adherence to screening procedures, identified more at-risk contacts and should prevent more TB cases in the future.


HindII, HindIII, and HpaI restriction fragment maps of bacteriophage lambda DNA.
The site-specific restriction endonucleases isolated from Hemophilus influenzae strains Rc (HincII) and Rd (HindII + III), and Hemophilus parainfluenzae (HpaI) were used to digest bacteriophage lambda DNA into 34, 40, and 15 specific fragments, respectively. The sites cleaved by each of these enzymes were localized on the lambda physical map and the fragments resulting from these cleavages were electrophoretically identified on gels by (1) analysis of the digestion profiles of deletion and transducing derivatives of lambda; and (2) digesting individual fragments produced by one restriction endonuclease with another restriction endonuclease. This paper presents the HindII, HindIII, and HpaI restriction fragment maps for the entire lambda genome, and the data used to derive these maps for the region of the lambda genome between the attachment site (at 57.3% lambda) and the right vegetative end (100% lambda). The data for mapping the left arm of lambda may be found in the accompanying paper (Robinson and Landy, 1977).


Investigating a high ozone episode in a rural mountain site.
A very high ozone episode with observed hourly values above 350 μg m(-3) occurred in July 2005 at the Lamas d'Olo air quality monitoring station, located in a mountainous area in the north of Portugal. Aiming to identify the origin and formation of this ozone-rich episode, a statistical analysis and a modelling approach were applied. A cross-spectrum analysis in the frequency domain and a synoptic analysis of the meteorological and air quality time series were performed. In order to go further in this analysis, a numerical modelling approach was applied. The results indicate that the transport of ozone and its precursors is the main responsible for the high ozone concentrations. Together with the local mountain breeze and subsidence conditions, the sea-breeze circulation transporting pollutants from the coastal urban and industrialized areas that reach the site during late afternoon turn out to be the driving forces for the ozone peaks.


Functional diversity among 5-substituted nicotine analogs; in vitro and in vivo investigations.
Two 5-substituted derivatives of nicotine (nicotinic acetylcholine receptor: K(i)=2.4 nM) were synthesized and evaluated: 5-bromonicotine (K(i)=6.9 nM) and 5-methoxynicotine (K(i)=14.3 nM). Despite their high affinity, neither 5-bromonicotine nor 5-methoxynicotine mimicked nicotine in producing antinociceptive (tail-flick, hotplate), hypolocomotor, or hypothermic effects in mice. Neither agent antagonized the hypolocomotor actions of nicotine, whereas 5-methoxynicotine, but not 5-bromonicotine, antagonized the antinociceptive (tail-flick) activity of nicotine in a dose-related manner. In tests of stimulus generalization using rats trained to discriminate 0.6 mg/kg of (-)-nicotine from vehicle, 5-bromonicotine substituted for nicotine. Further evaluation of 5-bromonicotine indicated that it might be a partial agonist at alpha4beta2 receptors (stimulation of Rb(+) efflux; alpha4beta2 receptors expressed in oocytes) and at alpha3-containing nicotinic acetylcholine receptors (synaptosomal dopamine release). Thus, 5-bromonicotine might be acting as a partial agonist at alpha4beta2 receptors and/or some of its effects might be related to interactions with non-alpha4beta2 receptors. Clearly, the effects of 5-bromonicotine and 5-methoxynicotine are different from those of nicotine, and from one another. These actions demonstrate that substitution at the 5-position of nicotine exerts a profound influence on the pharmacological profile as well as agonist/antagonist properties of nicotine.


Cycles of light and dark co-ordinate reversible colony differentiation in Listeria monocytogenes.
Recently, several light receptors have been identified in non-phototrophic bacteria, but their physiological roles still remain rather elusive. Here we show that colonies of the saprophytic bacterium Listeria monocytogenes undergo synchronized multicellular behaviour on agar plates, in response to oscillating light/dark conditions, giving rise to alternating ring formation (opaque and translucent rings). On agar plates, bacteria from opaque rings survive increased levels of reactive oxygen species (ROS), as well as repeated cycles of light and dark, better than bacteria from translucent rings. The ring formation is strictly dependent on a blue-light receptor, Lmo0799, acting through the stress-sigma factor, σ(B) . A transposon screening identified 48 mutants unable to form rings at alternating light conditions, with several of them showing a decreased σ(B) activity/level. However, some of the tested mutants displayed a varied σ(B) activity depending on which of the two stress conditions tested (light or H(2) O(2) exposure). Intriguingly, the transcriptional regulator PrfA and the virulence factor ActA were shown to be required for ring formation by a mechanism involving activation of σ(B) . All in all, this suggests a distinct pathway for Lmo0799 that converge into a common signalling pathway for σ(B) activation. Our results show that night and day cycles co-ordinate a reversible differentiation of a L. monocytogenes colony at room temperature, by a process synchronized by a blue-light receptor and σ(B) .


Revegetating fly ash landfills with Prosopis juliflora L.: impact of different amendments and Rhizobium inoculation.
A revegetation trial was conducted to evaluate the feasibility of growing a legume species, Prosopis juliflora L., on fly ash ameliorated with combination of various organic amendments, blue-green algal biofertilizer and Rhizobium inoculation. Significant enhancements in plant biomass, photosynthetic pigments, protein content and in vivo nitrate reductase activity were found in the plants grown on ameliorated fly ash in comparison to the plants growing in unamended fly ash or garden soil. Higher growth was obtained in fly ash amended with blue-green algae (BGA) than farmyard manure or press mud (PM), a waste from sugar-processing industry, due to the greater contribution of plant nutrients, supply of fixed nitrogen and increased availability of phosphorus. Nodulation was suppressed in different amendments of fly ash with soil in a concentration-duration-dependent manner, but not with other amendments. Plants accumulated higher amounts of Fe, Mn, Cu, Zn and Cr in various fly ash amendments than in garden soil. Further, inoculation of the plant with a fly ash tolerant Rhizobium strain conferred tolerance for the plant to grow under fly ash stress conditions with more translocation of metals to the above ground parts. The results showed the potential of P. juliflora to grow in plantations on fly ash landfills and to reduce the metal contents of fly ash by bioaccumulation in its tissues.


New foci of trichinellosis in western Romania, 2011.
Romania reported the highest incidence of trichinellosis in the world in 2004, and the figures continue to be high. This report aims to bring new information regarding 2 foci of trichinellosis that occurred in the winter of 2011 in a western Romanian region. Data were collected from the outbreak reports and hospitalization documents of the patients diagnosed with this condition. Of 22 patients admitted to hospitals, the medical records were available in 20 cases. The mean age of the study group was 37.4±13.6 years (range: 3-56) with most of them (n=7; 35%) aged 30-39 years old. The majority of the patients (n=19; 95%) were adults (≥18 years old), males (n=13; 65%) and rural inhabitants (n=13; 65%). Mylagia represented the most common clinical symptom (n=17; 85%). All but one of the patients had benign and moderately severe courses of the disease. The mean eosinophil counts and leukocyte counts were 17±10.7% and 10,162.4±3798.4 cells/mm(3), respectively. Re-emergence of trichinellosis in this region has deep roots in the population's ancestral customs and education. To limit the occurrence of the disease, new and efficient public health strategies should be designed and implemented in the nearest future.


The sympathetic contributions to the cardiac plexus.
Cardiac sympathetic denervation for intractable angina pectoris in patients unsuitable for conventional revascularization is currently gaining popularity since this procedure may be performed via minimally invasive surgery. A thorough understanding of cardiac innervation and its variations is crucial to successfully effect cardiac denervation. This study aimed to demonstrate the cervical and thoracic sympathetic contributions to the cardiac plexus. The cervical and thoracic sympathetic trunks in 21 fetuses and eight adults were micro-dissected bilaterally and documented ( n=58 sides). The superior cervical cardiac ramus originated from the superior cervical ganglion (present in all specimens) in 53% of cases. The middle cervical ganglion (incidence 81%) gave rise to the middle cervical cardiac ramus in 88% of cases. The cervico-thoracic ganglion (incidence 85%) gave the cervico-thoracic cardiac ramus in 84%. In the thoracic region, four cardiac rami arose from the T2-T6 segment of the thoracic sympathetic trunk. All cervical and thoracic cardiac rami were traced consistently to the deep cardiac plexus. Khogali et al.'s (1999) success of limited T2-T4 sympathectomy in relieving pain at rest of patients with intractable angina pectoris appears to indicate that a significant afferent pain pathway from the heart is selectively interrupted. The variability in pattern of the cervical ganglia, cardiac rami and cervical contributions to the cardiac plexus does not appear to affect the outcome of limited sympathectomy. The complexity of cardiac pain pathways is not fully understood. The study is continuing and attempts to contribute to defining these cardiac neuronal pathways.


Paeoniflorin Promotes Angiogenesis in A Vascular Insufficiency Model of Zebrafish in vivo and in Human Umbilical Vein Endothelial Cells in vitro.
To investigate the pro-angiogenic effects of paeoniflorin (PF) in a vascular insufficiency model of zebrafish and in human umbilical vein endothelial cells (HUVECs). In vivo, the pro-angiogenic effects of PF were tested in a vascular insufficiency model in the Tg(fli-1:EGFP)y1 transgenic zebrafish. The 24 h post fertilization (hpf) embryos were pretreated with vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor II (VRI) for 3 h to establish the vascular insufficiency model and then post-treated with PF for 24 h. The formation of intersegmental vessels (ISVs) was observed with a fluorescence microscope. The mRNA expression of fms-like tyrosine kinase-1 (flt-1), kinase insert domain receptor (kdr), kinase insert domain receptor like (kdrl) and von Willebrand factor (vWF) were analyzed by real-time polymerase chain reaction (PCR). In vitro, the pro-angiogenic effects of PF were observed in HUVECs in which cell proliferation, migration and tube formation were assessed. PF (6.25-100 μmol/L) could rescue VRI-induced blood vessel loss in zebrafish and PF (25-100 μmol/L), thereby restoring the mRNA expressions of flt-1, kdr, kdrl and vWF, which were down-regulated by VRI treatment. In addition, PF (0.001-0.03 μmol/L) could promote the proliferation of HUVECs while PF stimulated HUVECs migration at 1.0-10 μmol/L and tube formation at 0.3 μmol/L. PF could promote angiogenesis in a vascular insufficiency model of zebrafish in vivo and in HUVECs in vitro.


Mechanisms of cardiogenesis in cardiovascular progenitor cells.
Self-renewing cells of the vertebrate heart have become a major subject of interest in the past decade. However, many researchers had a hard time to argue against the orthodox textbook view that defines the heart as a postmitotic organ. Once the scientific community agreed on the existence of self-renewing cells in the vertebrate heart, their origin was again put on trial when transdifferentiation, dedifferentiation, and reprogramming could no longer be excluded as potential sources of self-renewal in the adult organ. Additionally, the presence of self-renewing pluripotent cells in the peripheral blood challenges the concept of tissue-specific stem and progenitor cells. Leaving these unsolved problems aside, it seems very desirable to learn about the basic biology of this unique cell type. Thus, we shall here paint a picture of cardiovascular progenitor cells including the current knowledge about their origin, basic nature, and the molecular mechanisms guiding proliferation and differentiation into somatic cells of the heart.


A kinetic assay to determine prothrombin binding to membranes.
Activation of prothrombin by multisquamase, the prothrombin activator from the venom of Echis multisquamatus (Central Asian sand viper), is inhibited by membranes containing negatively charged anionic phospholipids. This inhibition appears to be due to the fact that the venom activator cannot activate membrane-bound prothrombin. Initial steady state rates of prothrombin activation by multisquamase in the presence of phospholipids appeared to depend on the fraction unbound prothrombin only and this phenomenon was used to quantitate binding of prothrombin to membranes of varying phospholipid composition. In this method, the initial rate of prothrombin activation by multisquamase is measured in the absence (total prothrombin) and in the presence of a procoagulant surface (rate depending only on free prothrombin) and from the difference in activation rates the amount of membrane-bound prothrombin is calculated. The validity of the method was established by determination of the binding parameters for prothrombin binding to 100 microM phospholipid vesicles composed of 20 mole% phosphatidylserine and 80 mole% phosphatidylcholine. The binding parameters obtained were Kd=0.84 microM and n=0.021 micromoles prothrombin bound per micromole phospholipid which is in agreement with literature. Due to the nature of the measurement the method is especially suitable to quantitate binding of prothrombin at concentrations as low as 5 nM prothrombin.


Effect of Metformin on Anthropometric Measurements and Hormonal and Biochemical Profile in Patients with Prediabetes.
Metformin is the most widely preferred first-line oral antidiabetic agent that results in clear benefits in blood sugar regulation and diabetes-related complications. This study is aimed at assessing the effect of metformin on anthropometric, hormonal, and biochemical parameters in patients with prediabetes or insulin resistance. A prepoststudy was conducted among 52 patients with prediabetes or insulin resistance who met the inclusion criteria. Weight, body mass index (BMI), and waist circumference were measured before and 12 months after metformin treatment. Serum concentrations of sex steroids, gonadotropins, and lipids were also assessed. Homeostasis model assessment (HOMA) index and quantitative sensitivity check (QUICKI) index scores were calculated before metformin treatment and after 12 months of use. After 12 months of metformin treatment, female patients had significant reduction in weight, BMI, and waist circumference after adjusting for age. Metformin use for 12 months resulted in significant reduction in mean fasting blood glucose and HbA1c in females only. Total cholesterol decreased significantly among men only and serum HDL-C showed a significant rise among females only. Serum LDL-C and triglycerides did not change significantly in females and males. Our study did now significant changes in ACTH and cortisol levels in both females and males after metformin treatment. Metformin use resulted in significant increase in luteinizing hormone (LH) and progesterone levels in males, while it was associated with significant increase in prolactin, follicular stimulating hormone (FSH), and dehydroepiandrostenedione-sulphate (DHEA-S) levels and significant decrease in total testosterone level in females. Metformin treatment in females with prediabetes reduces BMI, waist circumference, fasting blood glucose, and HbA1c. The changes in the studied parameters differed significantly according to sex.


Management and the creation of occupational stressors in an Australian and a UK ambulance service.
Qualitative methods were used to explore the aetiology of occupational stress experienced by on-road ambulance officers. The researcher found that the way in which a service is organised and its officers valued can create and reproduce workplace stressors that are as causative of occupational stress as the often acknowledged occupational specific stressors like night shifts, irregular work hours and witnessing human trauma and tragedy. These stressors thought to be intrinsic to the work of ambulance officers were found to have an organisational dimension.


Role of antigen in the regulation of the immune response to dextran B512.
Dextranase mixed with dextran in vitro or injected into mice before the antigen abolished the immunogenicity of both thymus-dependent and thymus-independent forms of dextran. Dextranase could degrade dextran in vivo even when given 6-15 days after the antigen. Dextranase injected after the antigen suppressed the immune response when given 24 h, but not 48 h, after the antigen, indicating that the antigen must interact with the immune system for 48 h to initiate a response. Thereafter , the B cells are independent of further antigen stimulation. The induction of autoanti -idiotypic anti-dextran antibodies was abolished if dextranase was given 24 h, but not 48 h, after the antigen, indicating that anti-idiotypic antibodies can be induced in the absence of antigen or immune complexes once anti-dextran antibodies have been synthesized.


Clinical efficacy of selenium supplementation in patients with Hashimoto thyroiditis: A systematic review and meta-analysis.
Evidence suggests that selenium supplementation could be useful in the treatment of Hashimoto thyroiditis (HT), but the available trials are heterogeneous. This study investigates clinically relevant effects of selenium supplementation in patients with HT. A systematic search was performed in PubMed, Web of Science, EMBASE, Scopus, and the Cochrane Library. The latest update was performed on December 3, 2022. We investigated the changes in thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TgAb) after selenium supplementation. The effect sizes were expressed as weighted mean difference (WMD) with 95% confidence intervals (CIs). After screening and full-text assessment, 7 controlled trials comprising 342 patients were included in the systematic review. The results showed that there was no significant change in TPOAb levels (WMD = -124.28 [95% CI: -631.08 to 382.52], P = .631, I2 = 94.5%) after 3 months of treatment. But there was a significant decrease in TPOAb levels (WMD = -284.00 [95% CI: -553.41 to -14.60], P < .05, I2 = 93.9%) and TgAb levels (WMD = -159.86 [95% CI: -293.48 to -26.24], P < .05, I2 = 85.3%) after 6 months of treatment. Selenium supplementation reduces serum TPOAb and TgAb levels after 6 months of treatment in patients with HT, but future studies are warranted to evaluate health-related quality or disease progression.


Fetal glucocorticoid exposure is associated with preadolescent brain development.
Glucocorticoids play a critical role in normative regulation of fetal brain development. Exposure to excessive levels may have detrimental consequences and disrupt maturational processes. This may especially be true when synthetic glucocorticoids are administered during the fetal period, as they are to women in preterm labor. This study investigated the consequences for brain development and affective problems of fetal exposure to synthetic glucocorticoids. Brain development and affective problems were evaluated in 54 children (56% female), aged 6 to 10, who were full term at birth. Children were recruited into two groups: those with and without fetal exposure to synthetic glucocorticoids. Structural magnetic resonance imaging scans were acquired and cortical thickness was determined. Child affective problems were assessed using the Child Behavior Checklist. Children in the fetal glucocorticoid exposure group showed significant and bilateral cortical thinning. The largest group differences were in the rostral anterior cingulate cortex (rACC). More than 30% of the rACC was thinner among children with fetal glucocorticoid exposure. Furthermore, children with more affective problems had a thinner left rACC. Fetal exposure to synthetic glucocorticoids has neurologic consequences that persist for at least 6 to 10 years. Children with fetal glucocorticoid exposure had a thinner cortex primarily in the rACC. Our data indicating that the rACC is associated with affective problems in conjunction with evidence that this region is involved in affective disorders raise the possibility that glucocorticoid-associated neurologic changes increase vulnerability to mental health problems.


Vascular patterning: xylem or phloem?
Xylem and phloem are the major conduits for the transport of water and solutes through the plant. Recent work has helped to elucidate the mechanisms that determine the identity and arrangement of these two tissues.


Protonic conductor: better understanding neural resting and action potential.
With the employment of the transmembrane electrostatic proton localization theory with a new membrane potential equation, neural resting and action potential is now much better understood as the voltage contributed by the localized protons/cations at a neural liquid- membrane interface. Accordingly, the neural resting/action potential is essentially a protonic/cationic membrane capacitor behavior. It is now understood with a newly formulated action potential equation: when action potential is <0 (negative number), the localized protons/cations charge density at the liquid-membrane interface along the periplasmic side is >0 (positive number); when the action potential is >0, the concentration of the localized protons and localized nonproton cations is <0, indicating a "depolarization" state. The nonlinear curve of the localized protons/cations charge density in the real-time domain of an action potential spike appears as an inverse mirror image to the action potential. The newly formulated action potential equation provides biophysical insights for neuron electrophysiology, which may represent a complementary development to the classic Goldman-Hodgkin-Katz equation. With the use of the action potential equation, the biological significance of axon myelination is now also elucidated as to provide protonic insulation and prevent any ions both inside and outside of the neuron from interfering with the action potential signal, so that the action potential can quickly propagate along the axon with minimal (e.g., 40 times less) energy requirement.NEW & NOTEWORTHY The newly formulated action potential equation provides biophysical insights for neuron electrophysiology, which may represent a complementary development to the classic Goldman-Hodgkin-Katz equation. The nonlinear curve of the localized protons/cations charge density in the real-time domain of an action potential spike appears as an inverse mirror image to the action potential. The biological significance of axon myelination is now elucidated as to provide protonic insulation and prevent any ions from interfering with action potential signal.


Clinical value of immunochemotherapy with OK-432 or PS-K for stomach cancer patients.
A prospective clinical trial was undertaken in 121 patients with stomach cancer to compare immunochemotherapy with 5-fluorouracil and FT-207 combined with OK-432 or PS-K, immunostimulators, and plain chemotherapy with 5-fluororacil and FT-207. Of the 121 patients who received immunochemotherapy, 67 patients (group A) had undergone curative removal of the tumor. The other 54 patients had undergone noncurative tumor removal or had recurrence after non-curative tumor removal and they were divided into two groups (groups B and C) on the basis of lymphocyte reactivity induced with PHA. Although group A exhibited a significant increase in PHA-induced lymphocyte transformation and a trifling increase in lymphocyte counts, its survival rate within a 36 month period did not differ from that of the peer controls. Group B, composed of 21 patients showing improvement of PHA-induced lymphocyte transformation, significantly prolonged its survival compared to the peer controls. The survival of group C, composed of 33 patients showing a gradual drop in PHA-induced lymphocyte transformation, was not prolonged compared to the peer control patients; and they showed significant decreases in lymphocyte counts. The overall survival of group B and group C was not superior to that of the 48 peer controls.


Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells.
Whereas chromosomal translocations are common pathogenetic events in cancer, mechanisms that promote them are poorly understood. To elucidate translocation mechanisms in mammalian cells, we developed high-throughput, genome-wide translocation sequencing (HTGTS). We employed HTGTS to identify tens of thousands of independent translocation junctions involving fixed I-SceI meganuclease-generated DNA double-strand breaks (DSBs) within the c-myc oncogene or IgH locus of B lymphocytes induced for activation-induced cytidine deaminase (AID)-dependent IgH class switching. DSBs translocated widely across the genome but were preferentially targeted to transcribed chromosomal regions. Additionally, numerous AID-dependent and AID-independent hot spots were targeted, with the latter comprising mainly cryptic I-SceI targets. Comparison of translocation junctions with genome-wide nuclear run-ons revealed a marked association between transcription start sites and translocation targeting. The majority of translocation junctions were formed via end-joining with short microhomologies. Our findings have implications for diverse fields, including gene therapy and cancer genomics.


Contributions to the lymphatic filariasis elimination programme and post-elimination surveillance in China by NIPD-CTDR.
China was once one of the most heavily endemic for lymphatic filariasis (LF), with a heavy disease burden. Due to decades of sustained efforts, LF was eliminated from China in 2007. The historical tales in the control and elimination of LF in China and current post-elimination surveillance are reviewed and concluded. In the course of LF control and elimination, National Technical Steering Group for Filariasis Control and Research, and Collaborating Research Group on the Transmission Threshold of Filariasis, led by the National Institute of Parasitic Diseases, carried out researches, developed control measures, and applied in practical control and surveillance. The main of the results include: in theoretical study, (1) formulating the microfilaria rate below 1% as the transmission threshold of filariasis, (2) developing anti-filarial drugs and establishing animal model for drug screening, (3) studying the vectorial capacity of mosquitoes transmitted filariasis; in clinical diagnostic and therapy, (1) developing antigens for serological diagnostics, (2) studying different administration regimes for alleviating the side-response of diethylcarbamazine (DEC), (3) studying on the recurrence of acute adenolymphangitis and lymphadenitis of malayan filariasis, (4) observing lymphoedema of the lower extremity using lymphangiography; in practical control and surveillance, (1) establishing the control strategy taking elimination of infection source as the major focus, (2) formulating safe, feasible and effective DEC-mass drug administration, (3) revealing the transmission pattern of filariasis at the post-control phase, (4) establishing comprehensive active surveillance system, (5) formulating the criteria of basic elimination and elimination of filariasis. In the post-elimination surveillance phase, special monitoring and investigation in key areas were conducted for clearing way potential residual infection sources. Two schemes on LF surveillance in the post-elimination phase and caring for chronic filariasis patients were issued to maintain the diagnosis and treatment skills of filariasis all levels of disease control and prevention workers in future. Also, the Notifiable Diseases Reporting System, which included LF in 2004, plays an important role in LF post-elimination surveillance to prevent LF resurgence in China. The strategies and measures of LF control, elimination and post-elimination surveillance in China provide valuable practical experience and promote the progress of Global Programme of Elimination of Lymphatic Filariasis in worldwide.


Role of recombinant interferon alpha 2 and cimetidine in patients with advanced malignant melanoma.
Following recent reports suggesting that the addition of cimetidine to interferon may enhance response rates in patients with metastatic malignant melanoma, we have completed a Phase II study of the use of recombinant alpha 2 interferon and cimetidine in patients with advanced malignant melanoma and who had progressive disease following interferon therapy alone. We observed two partial responses, no complete responses, and two patients had stable disease. Toxicity encountered was analogous to that of interferon alone. We conclude that the additional of cimetidine to alpha interferon is not beneficial in the treatment of advanced metastatic malignant melanoma.


Effects of Growth Hormone on Bone.
Describe the effects of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) on the skeleton. The GH and IGF-1 axis has pleiotropic effects on the skeleton throughout the lifespan by influencing bone formation and resorption. GH deficiency leads to decreased bone turnover, delayed statural growth in children, low bone mass, and increased fracture risk in adults. GH replacement improves adult stature in GH deficient children, increases bone mineral density (BMD) in adults, and helps to optimize peak bone acquisition in patients, during the transition from adolescence to adulthood, who have persistent GH deficiency. Observational studies suggest that GH replacement may mitigate the excessive fracture risk associated with GH deficiency. Acromegaly, a state of GH and IGF-1 excess, is associated with increased bone turnover and decreased BMD in the lumbar spine observed in some studies, particularly in patients with hypogonadism. In addition, patients with acromegaly appear to be at an increased risk of morphometric-vertebral fractures, especially in the presence of active disease or concurrent hypogonadism. GH therapy also has beneficial effects on statural growth in several conditions characterized by GH insensitivity, including chronic renal failure, Turner syndrome, Prader-Willi syndrome, postnatal growth delay in patients with intrauterine growth retardation who do not demonstrate catchup growth, idiopathic short stature, short stature homeobox-containing (SHOX) gene mutations, and Noonan syndrome. GH and IGF-1 have important roles in skeletal physiology, and GH has an important therapeutic role in both GH deficiency and insensitivity states.


Treatment of Helicobacter pylori gastritis improves dyspeptic symptoms in children.
In adults, the treatment of Helicobacter pylori infection is only recommended for patients with active gastric or duodenal ulcers. It is not known whether similar guidelines can be applied to children because the prevalence of peptic ulcer disease in childhood is estimated to be much lower than in adults. The purpose of this study was to determine whether treatment of H. pylori gastritis would improve symptoms of dyspepsia in children. Sixteen patients (5 boys, 11 girls) aged 14 +/- 1.2 years who had symptoms of dyspepsia were evaluated using upper gastrointestinal endoscopy with biopsies to establish the diagnosis of H. pylori gastritis. They were treated for 2 weeks with clarithromycin, amoxicillin, and a proton pump inhibitor. Dyspepsia symptoms were evaluated by a questionnaire before and after treatment of the infection. The effect of H. pylori treatment on the total symptom score was analyzed with use of the Student t test. Values are presented as mean +/- SEM. All patients had antral nodularity and chronic active gastritis with spiral-shaped organisms but no evidence of peptic ulcer disease. Mean total symptom score decreased significantly at 2 to 4 weeks after treatment (12.6 +/- 0.9 vs. 2.1 +/- 0.5 P < 0.001), and it remained low (2.9 +/- 0.7) at follow-up 9.7 +/- 1.4 months (range, 2-24 months later). These results suggest that the treatment of H. pylori gastritis can improve dyspeptic symptoms in children.


Dietary habits, nutrition and esophageal cancer: A case-control study on Kazakhs in Xinjiang.
To explore associations between dietary habits and esophageal epithelial cell carcinoma (ESCC) and provide a potential direction for exploring how different dietary habits and nutrient intake might affect ESCC development. 198 ESCC cases and 200 controls on Kazakhs were recruited in Xinjiang from 2010 to 2019 for a group-matched case-control study. The case group were recruited from the First Affiliated Hospital of Xinjiang Medical University and Affiliated Cancer Hospital of Xinjiang Medical University. The control population were recruited from two parts: hospital-based control and population-based control. The diagnosis was confirmed by histological examination. The food frequency questionnaire was used to investigate the dietary nutrients intake. Folic acid, vitamin B12, and DNA-methyltransferase 1(DNMT1) levels were measured in serum samples obtained from cases and controls. The cholesterol intake of ESCC group was significantly higher than that of the control group while the intakes of protein, thiamin, riboflavin, folic acid, vitamin A, B6, C and E were significantly lower than the control group. Factors including lacking fresh vegetables and fruits, low educational level, low income, alcohol drinking, eating solid and dry food and smoked meat, dieting irregularly, salty taste preference, low serum folic acid level and high serum DNMT1 level were associated with increased risk of ESCC in Kazakhs. Dietary habits and nutrient intake were associated with increased risk of ESCC in Kazakhs that may provide a potential direction for further studies.


Morphological events occuring in the seminiferous tubules of the Brazilian Nelore zebu associated with puberty.
The morphological events occurring in the Brazilian Nelore zebu testis from 3 to 18 months of age are described. Spermatozoa were seen only at 16--18 months of age indicating a considerable delay in the sexual development of the Nelore zebu when compared with taurine breeds.


RdDM pathway components differentially modulate Tobamovirus symptom development.
The crop yield losses induced by phytoviruses are mainly associated with the symptoms of the disease. DNA modifications as methylation can modulate the information coded by the sequence, process named epigenetics. Viral infection can change the expression patterns of different genes linked to defenses and symptoms. This work represents the initial step to expose the role of epigenetic process, in the production of symptoms associated with plants-virus interactions. Small RNAs (sRNAs) are important molecules for gene regulation in plants and play an essential role in plant-pathogen interactions. Researchers have evaluated the relationship between viral infections as well as the endogenous accumulation of sRNAs and the transcriptional changes associated with the production of symptoms, but little is known about a possible direct role of epigenetics, mediated by 24-nt sRNAs, in the induction of these symptoms. Using different RNA directed DNA methylation (RdDM) pathway mutants and a triple demethylase mutant; here we demonstrate that the disruption of RdDM pathway during viral infection produce alterations in the plant transcriptome and in consequence changes in plant symptoms. This study represents the initial step in exposing that DNA methylation directed by endogenous sRNAs has an important role, uncoupled to defense, in the production of symptoms associated with plant-virus interactions.


Early and repeated screening detects children with persistent attention-deficit/hyperactivity disorder.
Preschool screening of attention-deficit/hyperactivity disorder (ADHD) has been found too inaccurate to be clinically useful. This may be due to the known instability of ADHD symptoms from preschool onwards, and the use of a single screening only. We hypothesized that by identifying a group of children with persistent ADHD from preschool to school age and repeating the screening, the clinical usefulness of screening would increase. This study is part of the prospective longitudinal, population-based Norwegian Mother, Father and Child Cohort Study, with a diagnostic parent interview at 3.5 years and follow-up with parent questionnaires at ages 5 and 8 years (n = 707). We identified a group classified with ADHD at all three time points (persistent ADHD). We then used the Child Behavior Checklist ADHD DSM-oriented scale at ages 3.5 and 5 years to investigate the accuracies of single- and two-stage screening at different thresholds to identify children with persistent ADHD. About 30% of the children were classified with ADHD at least once across time (at ages 3.5, 5, and/or 8 years), but only 4% (n = 30) had persistent ADHD. At all thresholds, the two-stage screening identified children with persistent ADHD more accurately than single screening, mainly due to a substantial reduction in false positives. Only a small group of children were classified with persistent ADHD from preschool to school age, underlining that future screening studies should distinguish this group from those with fluctuating symptoms when estimating screening accuracies. We recommend a two-stage screening process to reduce false positives.


Changes in depressive and anxiety symptoms during COVID-19 in children from the PROGRESS cohort.
We assessed associations between maternal stress, social support, and child resiliency during the COVID-19 pandemic in relation to changes in anxiety and depression symptoms in children in Mexico City. Participants included 464 mother-child pairs from a longitudinal birth cohort in Mexico City. At ages 8-11 (pre-COVID, 2018-2019) and 9-12 (during COVID, May-Nov 2020) years, depressive symptoms were assessed using the child and parent-reported Children's Depressive Inventory. Anxiety symptoms were assessed using the child-reported Revised Manifest Anxiety Scale. Linear regression models were used to estimate associations between maternal stress, social support, and resiliency in relation to changes in depressive and anxiety symptoms. We additionally assessed outcomes using clinically relevant cut-points. Models were adjusted for child age and sex and maternal socioeconomic status and age. Higher continuous maternal stress levels during the COVID-19 pandemic were associated with increases in depressive symptoms (β: 0.72; 95% CI: 0.12, 1.31), and higher odds of clinically relevant depressive and anxiety symptoms in the children. Maternal stress during the pandemic may increase mental health symptoms in pre-adolescent children. Additional studies are needed that examine the long-term pandemic-related impacts on mental health throughout the adolescent years. In this longitudinal cohort study of children in Mexico City, we observed that depressive symptoms were higher from before to during the pandemic. Maternal stress surrounding the pandemic may increase mental health symptoms in pre-adolescent children. Child resiliency may help to protect against pandemic-related stressors.


Tumor necrosis factor enhances expression of tissue factor mRNA in endothelial cells.
We have examined the effect of recombinant tumor necrosis factor on the expression of tissue factor activity and tissue factor mRNA levels in vascular endothelial cells. Following exposure of human umbilical vein endothelial cells to this cytokine, the appearance of tissue factor procoagulant activity was detected following cell disruption, and was maximal at 6 hours. Northern blot analysis of cytokine-treated cells demonstrated a similar increase in the synthesis of tissue factor mRNA, followed by a gradual decline to the basal level by 18 hours. Cycloheximide by itself induced the accumulation of high levels of tissue factor mRNA in these cells. This result suggests that the proteins necessary for transcription of the tissue factor gene are present in the endothelial cell prior to cytokine stimulation, and synthesis of the tissue factor mRNA may be controlled, in part, by a labile repressor protein.


What to do after you have made a mistake.
All nurses dread making an error, but if it does happen, there are things you can do to rebuild your confidence and reduce the risk of future mistakes.


Suppression of the hypothalamus-pituitary somatotrope axis in men with spinal cord injuries.
Thirty-two men with spinal cord injury (SCI) were studied for evaluation of the hypothalamus-pituitary somatotrope axis, using growth hormone-(GH)-releasing hormone (GHRH) and insulin-induced hypoglycemia. Twenty-six age-matched normal male volunteers served as controls. Six SCI subjects (18.7%) had elevated basal follicle-stimulating hormone (FSH) levels, eight (25.0%) had hyperprolactinemia, and 11 (34.4%) had reduced serum insulin-like growth factor-1 (IGF-1) levels. Twenty SCI subjects (62.5%) had reduced and/or delayed GH responses to GHRH, and eight (25.8%) had reduced GH response to insulin-induced hypoglycemia. Seven of eight hyperprolactinemic SCI subjects showed reduced GH response to GHRH and/or insulin-induced hypoglycemia. These findings are consistent with the notion that SCI subjects have a reduced central dopaminergic tone.


Depression and Inflammatory Markers in Veterans With Multiple Sclerosis.
Multiple sclerosis (MS), an inflammatory neurodegenerative disease of the central nervous system (CNS), afflicts over one per thousand people in the United States. The pathology of MS typically involves lesions in several regions, including the brain and spinal cord. The manifestation of MS is variable and carries great potential to negatively impact quality of life (QOL). Evidence that inflammatory markers are related to depression in MS is accumulating. However, there are barriers in precisely identifying the biological mechanisms underlying depression and inflammation. Analysis of cytokines provides one promising approach for understanding the mechanisms that may contribute to MS symptoms. In this pilot study, we measured salivary levels of interleukin (IL)-6, IL-1beta (β), and IL-10 in 24 veterans with MS. Descriptive statistics were reported and Pearson correlation coefficients were obtained between cytokines and depression. The anti-inflammatory cytokine IL-10 was significantly negatively associated with depression in veterans with MS (r = -0.47, p = .024). Cytokines may be useful for elucidating biological mechanisms associated with the depression and a measure for nurses caring for veterans with MS.


Structure-based design and screening of inhibitors for an essential bacterial GTPase, Der.
Der is an essential and widely conserved GTPase that assists assembly of a large ribosomal subunit in bacteria. Der associates specifically with the 50S subunit in a GTP-dependent manner and the cells depleted of Der accumulate the structurally unstable 50S subunit, which dissociates into an aberrant subunit at a lower Mg(2+) concentration. As Der is an essential and ubiquitous protein in bacteria, it may prove to be an ideal cellular target against which new antibiotics can be developed. In the present study, we describe our attempts to identify novel antibiotics specifically targeting Der GTPase. We performed the structure-based design of Der inhibitors using the X-ray crystal structure of Thermotoga maritima Der (TmDer). Virtual screening of commercially available chemical library retrieved 257 small molecules that potentially inhibit Der GTPase activity. These 257 chemicals were tested for their in vitro effects on TmDer GTPase and in vivo antibacterial activities. We identified three structurally diverse compounds, SBI-34462, -34566 and -34612, that are both biologically active against bacterial cells and putative enzymatic inhibitors of Der GTPase homologs. We also presented the possible interactions of each compound with the Der GTP-binding site to understand the mechanism of inhibition. Therefore, our lead compounds inhibiting Der GTPase provide scaffolds for the development of novel antibiotics against antibiotic-resistant pathogenic bacteria.


First-Line Osimertinib in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: Effectiveness, Resistance Mechanisms, and Prognosis of Different Subsequent Treatments.
Although the clinical application of osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been a new step forward in the first-line treatment of non-small cell lung cancer (NSCLC), an increasing number of patients with progression on osimertinib represents a great challenge clinically. The patterns of resistance mechanisms and subsequent treatment strategies after first-line osimertinib resistance are not well established. Between January 1, 2016 and October 31, 2020, a consecutive of 56 EGFR-mutant lung cancer patients treated with osimertinib as first-line therapy at Daping Hospital (Chongqing, China) were retrospective screened. The samples of pre-osimertinib and osimertinib-resistance were all detected by next-generation sequencing (NGS) panels. Statistical analyses were carried out using SPSS 23.0 software. Survival analyses were performed using the Kaplan-Meier method and compared using a log-rank test between groups. Among 47 patients with osimertinib effectiveness analysis, the median progression free survival (mPFS) was 15.4 months (95% confidence interval [CI]: 12.2-24.9 months), and median overall survival (mOS) was 35.5 months (95% CI: 23.9 months -NA). A total of 21 patients underwent repeated NGS tests upon osimertinib resistance. MET amplification was the most common resistance mechanism (6/21, 28.6%), followed by C797S mutation (5/21, 23.8%). A total of 15 patients received subsequent treatments, with mPFS of 7.3 months (95% CI 5.0 months -NA). Among them, 7 patients with EGFR C797 S or/and MET amplification received subsequent second-line targeted therapy, achieving mPFS of 7.3 months (95% CI 4.5 months -NA). Of note, 3 patients received immunotherapy as second- or third-line treatment after osimertinib resistance, achieving median clinical benefit of 37.3 months. MET amplification and C797S mutation are main resistance mechanisms, which could be targeted by crizotinib and gefitinib, respectively. More than 50% patients could receive subsequent anticancer targetable therapies after first-line osimertinib resistance. Immunotherapy may also be an acceptable choice after osimertinib resistance.


Lack of norovirus replication and histo-blood group antigen expression in 3-dimensional intestinal epithelial cells.
Noroviruses (NoVs) are a leading cause of gastroenteritis worldwide. An in vitro model for NoV replication remains elusive, making study of the virus difficult. A previous study, which used a 3-dimensional (3-D) intestinal model derived from INT-407 cells reported NoV replication and extensive cytopathic effects (CPE). Using the same 3-D model, but with highly purified Norwalk virus (NV), we attempted to replicate this study. Our results showed no evidence of NV replication by real-time PCR of viral RNA or by immunocytochemical detection of viral structural and nonstructural proteins. Immunocytochemical analysis of the 3-D cultures also showed no detectable presence of histo-blood group antigens that participate in NV binding and host tropism. To determine the potential cause of CPE observed in the previous study, we exposed 3-D cultures to lipopolysaccharide concentrations consistent with contaminated stool samples and observed morphologic features similar to CPE. We conclude that the 3-D INT-407 model does not support NV replication.


Potential of Capric Acid in Neurological Disorders: An Overview.
To solve the restrictions of a classical ketogenic diet, a modified medium-chain triglyceride diet was introduced which required only around 60% of dietary energy. Capric acid (CA), a small molecule, is one of the main components because its metabolic profile offers itself as an alternate source of energy to the brain in the form of ketone bodies. This is possible with the combined capability of CA to cross the blood-brain barrier and achieve a concentration of 50% concentration in the brain more than any other fatty acid in plasma. Natural sources of CA include vegetable oils such as palm oil and coconut oil, mammalian milk and some seeds. Several studies have shown that CA has varied action on targets that include AMPA receptors, PPAR-γ, inflammatory/oxidative stress pathways and gut dysbiosis. Based on these lines of evidence, CA has proved to be effective in the amelioration of neurological diseases such as epilepsy, affective disorders and Alzheimer's disease. But these studies still warrant more pre-clinical and clinical studies that would further prove its efficacy. Hence, to understand the potential of CA in brain disease and associated comorbid conditions, an advance and rigorous molecular mechanistic study, apart from the reported in-vitro/in-vivo studies, is urgently required for the development of this compound through clinical setups.


Efficacy of corticosteroids in suppression of intimal hyperplasia.
The effect of steroids and immunosuppression on the development of intimal hyperplasia was studied in 24 New Zealand white rabbits. Staged bilateral arteriotomy and stripping of intima of the common carotid artery was performed by means of a 2F balloon catheter under 700 mm Hg of pressure. At 3 months, after the control side artery was harvested (N = 24), the rabbits were assigned to three groups of eight animals each: (1) dexamethasone 0.1 mg/kg, (2) cyclophosphamide (Cytoxan) 1 mg/kg, or (3) azathioprine 1 mg/kg intramuscularly. The animals were treated on the day before the contralateral intimal stripping and then were treated six times a week for 8 weeks; the vessels were harvested at 3 months. Twelve-week patency rates were 62.5% in the control group, 83.3% in the dexamethasone group, 100% in the Cytoxan group, and only 33.3% in the azathioprine group. The ratio of the luminal area to the area enclosed by the internal elastic lamina was used as an index of intimal hyperplasia, with a higher ratio indicating less intimal thickening. This ratio of the patient vessels was 0.74 +/- 0.14 (N = 15) for the controls, 0.79 +/- 0.11 (N = 6) for the Cytoxan group, and 0.91 +/- 0.06 (N = 5, p less than 0.05) for the dexamethasone group, which is statistically significant by means of analysis of variance. Occluded vessels had evidence of organized thrombus without any intimal hyperplasia. The decrease in intimal hyperplasia seen in the steroid group suggests a potential role for steroids in small vessel revascularization, but further studies are required.


Circadian regulation of feeding in rats: suprachiasmatic versus ventromedial hypothalamic nuclei.
The role of the suprachiasmatic nuclei as a major component of a specific circadian system controlling feeding periodicity is reviewed. Evidence is presented supporting the assumption that the ventromedial hypothalamus and the suprachiasmatic nucleus may act as a constant (tonic) regulator and a circadian modulator respectively of feeding in rats. It is concluded that a specific circadian system differing from the metabolic control mechanism superimposes the circadian periodicity of feeding. A model is put forward for the possible functional relationships between circadian and metabolic (homeostatic) control mechanisms of feeding in rats.


False-positive intercellular cement substance antibodies due to group A/B red cell antibodies: frequency and approach.
Antibodies to the intercellular cement substance of skin (ICSA) are characteristic of pemphigus vulgaris, and are commonly detected by indirect immunofluorescence (IIF). However, false-positive staining may arise when blood group antibodies, directed against A and B red cell antigens, bind to epitopes of similar distribution in the substrate. We sought to determine the frequency of such false-positive ICSA staining and to establish optimal conditions for its elimination. IIF was performed on 100 de-identified routine serum samples of known blood group (A, B or O), along with serum from four pemphigus patients. Blocking was performed on samples which displayed typical ICSA staining using either a mixture of soluble A and B antigens in solution ('soluble A/B antigens'), or red blood cells from a group AB donor ('AB-RBCs'). ICSA staining was detected in 12 of 100 (12%) routine samples at a titre of between 1:10 and 1:160, and was most frequent in (but not restricted to) samples of blood group O (10/54, 19%). Blocking with soluble A/B antigens eliminated staining in 10 of 12 (83%) samples, whilst blocking with AB-RBCs eliminated staining in 11 of 12 (92%); one sample failed to block using either method, suggesting true ICSA reactivity. Blocking had no effect on the positive pemphigus samples, the titres of which were significantly higher (1:160 to 1:640). Staining of the intercellular cement substance arising from group A/B red cell antibodies is common, particularly but not exclusively in patients of blood group O, making blocking mandatory in the routine evaluation of samples with such staining, particularly in a hospital-based population. Blocking using either soluble A/B antigens or AB-RBCs appears to be of comparable efficacy, although the former method is more convenient for a diagnostic laboratory.


Morphometric variability of pyramidalis muscle and its clinical significance.
The goal of the study is to analyze the morphometric diversity of the pyramidalis muscle (PM) and to evaluate how it is affected by gender and side of occurrence. Ninety-six (50 male and 46 female) formalin-embalmed Greek cadavers were dissected. The PM was present in 93.8 %, usually bilaterally (79.2 %) than unilaterally (14.6 %) (p = 0.003) and more frequently in females (91.3 %) than in males (68 %) (p = 0.0001). Side symmetry was detected. The mean length of PM in males and females was 8.37 ± 2.80 and 6.18 ± 1.64 cm on the right and 7.50 ± 2.66 and 6.56 ± 1.68 cm on the left side. Male predominance existed on the right and left-sided PM lengths (p = 0.0001 and p = 0.054). The mean width of the right-sided PMs in males and females was 1.61 ± 0.55 and 1.50 ± 0.44 cm and the left-sided 1.56 ± 0.53 and 1.55 ± 0.38 cm without gender dimorphism. The positive correlation between the PM length and width indicates a symmetrical muscle augmentation on the two dimensions. The study demonstrates that the PM is almost constant in Greeks. Among populations the muscle morphometric variability, its clinical significance and its variable uses will help surgeons when intervening in the lower abdominal wall.