The time course of the bilateral release of cytokines and mediators after unilateral nasal allergen challenge.
Late phase reactions after allergen challenge can be understood as a correlate of the inflammatory reaction in allergic rhinitis. To investigate which cytokines are involved in it and to dissect direct and indirect effects of nasal allergen challenge, we performed unilateral nasal allergen provocation with the disc method in 12 seasonal allergic volunteers. Symptom scores, nasal secretions and nasal airflow were quantified. In the secretions that were collected in the early phase and for 8 h after provocation, we measured histamine, and the cytokines interleukin (IL)-1beta, IL-8, IL-4, and the natural antagonist of IL-1beta, IL-1 receptor type 1 (IL-1Ra) using enzyme-linked immunosorbent (ELISA)-assays. Control challenges with diluent instead of allergen were performed in all subjects. We demonstrated a bilateral increase in nasal secretion weights in the early and late phase. Histamine was significantly increased in the early and late phase in nasal secretions from both nostrils. IL-1beta increased in the late phase only, where it was also found on the unchallenged, contralateral side. Its antagonist IL-1Ra was found in very high quantities (1000-fold higher than IL-1beta) but demonstrated only marginal changes after provocation. IL-8 was increased in both nostrils early and late after challenge, whereas IL-4 was significantly elevated in the late phase. We described the time course of mediator and cytokine release into nasal secretions after allergen challenge. We hypothesize that the observed indirect effects on the unchallenged, contralateral side can be at least partially attributed to neuronal reflexes.


The effect of time intervals on neonatal outcome in elective cesarean delivery at term under regional anesthesia.
To measure 3 intervals of time-induction of regional anesthesia to delivery (I-D), initial skin incision to delivery (S-D), and uterine incision to delivery (U-D)-in elective cesareans and to evaluate the impact of the duration of these 3 components on short-term neonatal outcome. We reviewed retrospective data on the duration of the components from the computerized database of the obstetrics operation room at the Sheba Medical Center, Tel Aviv, Israel, and from the medical records of term neonates. Sufficient data were available in 933 cases. The parameters associated with longer time to delivery at any stage were epidural rather than spinal anesthesia, maternal diabetes, previous cesarean delivery, antihypertensive treatment, higher birth weight (3456 g and 3285 g for U-D interval longer than 2 minutes and U-D interval up to 2 minutes, respectively; P=0.02), and male fetus. The duration of the I-D, S-D, and U-D intervals had no significant impact on any of the measured neonatal parameters. With regard to neonatal wellbeing, obstetricians have a relatively large safety margin in the time taken for inducing regional anesthesia and making the first and uterine incisions.


Memokath for treating ureteric stricture post cryoablation of renal mass: A case report of rare complication and proposed alternative management.
The use of cryoablation in the management of small renal masses is widely acceptable. Although rare but ureteral injury during the procedure with subsequent stricture formation can result in devastating effects on renal function. On the other hand, the management of such strictures requires reconstructive surgery as gold standard. Unfortunately, in some cases the reconstructive surgery might not be feasible, and the treatment usually is ureteral stent insertion that need to be changed regularly. Here we present a case of a 53-year-old gentleman who developed an upper ureteric iatrogenic stricture post cryoablation in which the reconstructive surgery was not feasible due to high procedural risk. We used metallic ureteral stent (Memokath) instead of regular ureteral double J stent. We found that if the reconstructive surgery is not possible the usage of Memokath in treating iatrogenic ureteral strictures is associated with better quality of life, lower costs and a similar functional outcome when compared to ureteral double J stent that needs regular frequent changes.


Commensal Cryptosporidium colonization elicits a cDC1-dependent Th1 response that promotes intestinal homeostasis and limits other infections.
Cryptosporidium can cause severe diarrhea and morbidity, but many infections are asymptomatic. Here, we studied the immune response to a commensal strain of Cryptosporidium tyzzeri (Ct-STL) serendipitously discovered when conventional type 1 dendritic cell (cDC1)-deficient mice developed cryptosporidiosis. Ct-STL was vertically transmitted without negative health effects in wild-type mice. Yet, Ct-STL provoked profound changes in the intestinal immune system, including induction of an IFN-γ-producing Th1 response. TCR sequencing coupled with in vitro and in vivo analysis of common Th1 TCRs revealed that Ct-STL elicited a dominant antigen-specific Th1 response. In contrast, deficiency in cDC1s skewed the Ct-STL CD4 T cell response toward Th17 and regulatory T cells. Although Ct-STL predominantly colonized the small intestine, colon Th1 responses were enhanced and associated with protection against Citrobacter rodentium infection and exacerbation of dextran sodium sulfate and anti-IL10R-triggered colitis. Thus, Ct-STL represents a commensal pathobiont that elicits Th1-mediated intestinal homeostasis that may reflect asymptomatic human Cryptosporidium infection.


High-throughput genotyping of single-nucleotide polymorphisms in ace-1 gene of mosquitoes using MALDI-TOF mass spectrometry.
Acetylcholinesterase (AChE) plays a vital role in the nervous system of insects and other animal species and serves as the target for many chemical agents such as organophosphate and carbamate insecticides. The mosquito, Culex pipiens complex, a vector of human disease, has evolved to be resistant to insecticides by a limited number of amino acid substitutions in AChE1, which is encoded by the ace-1 gene. The aims of this study are to identify single nucleotide polymorphism (SNP) sites in the ace-1 gene of the C. pipiens complex and explore an economical high-throughput method to differentiate the genotypes of these sites in mosquitoes collected in the field. We identified 22 SNP sites in exon regions of the ace-1 gene. Four of them led to non-synonymous mutations, that is, Y163C, G247S, C677S and T682A. We used matrix-assisted laser desorption ionization - time-of-flight mass spectrometry for genotyping at these four sites and another site F416V, which was relevant to insecticide resistance, in 150 mosquitoes collected from 15 field populations. We were able to synchronize analysis of the five SNP sites in each well of a 384-well plate for each individual mosquito, thus decreasing the cost to one-fifth of the routine analysis. Heterozygous genotypes at Y163C and G247S sites were observed in one mosquito. The possible influence of the five SNP sites on the activity or function of the enzyme is discussed based on the predicted tertiary structure of the enzyme.


Genomic profile and immune microenvironment in patients with relapsed stage IA lung adenocarcinoma.
Patients with early-stage non-small cell lung cancer (NSCLC), even stage IA, are at substantial risk of relapse and death. We explored the distinct features of molecular alterations and immune-related gene expression in Formalin-fixed paraffin-embedded (FFPE) samples from 25 relapsed patients compared with 25 non-relapsed patients through using whole-exome sequencing and an immune oncology panel RNA sequencing platform. Results showed that the chemokine, cytolytic activity and tumour-associated antigen gene signatures exhibited significantly higher expression in non-relapsed tumours from stage IA lung adenocarcinoma (LUAD) than that in relapsed tumours. Besides, Kaplan-Meier survival analysis revealed that the gene signatures of chemokines and tumour-associated antigens were significantly associated with the patients' disease-free survival (DFS), indicating their prognostic value in early-stage LUAD. Cytolytic activity displayed a similar trend but failed to reach statistical significance. These findings revealed a weakened immune phenotype in relapsed tumours and provide valuable information for improving the treatment management of these high-risk patients. Due to the overall small patient number in this study, these differences should be further validated in a larger cohort.


[Cholesterol content in human and rabbit erythrocytes in atherosclerosis and experimental hypercholesteremia].
Direct correlation was observed between the content of cholesterol in erythrocytes and the level of alimentary hypercholesterolemia as well as the severity of heart ischemic disease in patients. Data on alterations in cholesterol content in erythrocytes may be used as a prognostic test for development of ischemic impairments of heart.


Berberine is a dopamine D1- and D2-like receptor antagonist and ameliorates experimentally induced colitis by suppressing innate and adaptive immune responses.
Berberine is an herbal alkaloid with various biological activities, including anti-inflammatory and antidepressant effects. Here, we examined the effects of berberine on dopamine receptors and the ensuing anti-inflammatory responses. Berberine was found to be an antagonist at both dopamine D1- and D2-like receptors and ameliorates the development of experimentally induced colitis in mice. In lipopolysaccharide-stimulated immune cells, berberine treatment modified cytokine levels, consistent with the effects of the dopamine receptor specific antagonists SCH23390 and L750667. Our findings indicate that dopamine receptor antagonists suppress innate and adaptive immune responses, providing a foundation for their use in combatting inflammatory diseases.


Molnupiravir treatment of 18 cats with feline infectious peritonitis: A case series.
Feline infectious peritonitis (FIP) is a viral disease in cats, caused by certain strains of coronavirus and has a high case fatality rate. This case series reports the outcomes of treatment of cats with FIP using molnupiravir. Eighteen cats diagnosed with FIP at the You-Me Animal Clinic, Sakura-shi, Japan between January and August 2022, and whose owners gave informed consent to this experimental treatment. For this prospective observational study, molnupiravir tablets were compounded in-house at the You-Me Animal Clinic. Owners administered 10-20 mg/kg PO twice daily. Standard treatment duration was 84 days. Among 18 cats, 13 cats had effusive FIP and 5 had noneffusive FIP. Three cats had neurological or ocular signs of FIP before treatment. Four cats, all with effusive FIP, died or were euthanized within 7 days of starting treatment. The remaining 14 cats completed treatment and remained in remission at the time of writing (139-206 days after starting treatment). Elevated serum alanine transaminase (ALT) activity was found in 3 cats, all at Days 7-9, and all recovered without management. Two cats with jaundice were hospitalized, 1 during treatment (Day 37) and 1 with severe anemia at the start of treatment. This case series suggests that molnupiravir might be an effective and safe treatment for domestic cats with FIP at a dose of 10-20 mg/kg twice daily.


Lessons learned from employing Medicaid-funded peer recovery support specialists in residential substance use treatment settings: An exploratory analysis.
This article explores the experiences of peer recovery support specialists (PRSS) and their colleagues working in residential adult services (RAS) facilities in a rural state to better understand how the role has been implemented in this setting. In West Virginia, PRSS and RAS services have been covered by Medicaid since 2018 for the treatment of substance use disorder (SUD). Thus, the aim of this study is to uncover what has and has not worked well in the early years of service implementation from the perspectives of both PRSS and their colleagues working in the SUD field. The study interviewed forty-eight clinical and administrative staff at RAS facilities, including nine PRSS, across fourteen focus groups between 2020 and 2021. The study asked participants about general knowledge of West Virginia's 1115 Medicaid Waiver supporting the funding of PRSS, communication among providers, transitioning patients to other providers, scope of practice, barriers and facilitators to providing services, ethical challenges, and COVID-19. Data analysis utilized a phenomenological approach to describe individuals' unique experiences. Three core themes emerged from the analysis: (i) Lived Experience as Added Value, (ii) Inadequate Funding for PRSS Position, and (iii) Role Difficulties. Participants described the lived experience of PRSS as both beneficial to the recovery journey of patients with SUD and unique in that only PRSS can provide the specific skillset that benefits these patients; these characteristics also helped facilities to connect patients to supportive resources. Two funding limitations emerged as barriers to PRSS employment: funding available through Medicaid billing was insufficient to hire staff and the corresponding hourly compensation rate was not competitive against those offered via grants. Finally, participants identified an underdeveloped hiring system and an unclear scope of practice that led to staff feeling unsupported. PRSS's experiential expertise complements clinical expertise by producing effective health care and support for patients. Despite their high value and expertise in SUD treatment, PRSS face major challenges in the workplace, including inadequate pay, underdeveloped support structures, and narrow job eligibility requirements. Future research should further quantify PRSS's levels of expertise and identify "value-added" benefits of this position.


Development of prediction model for alanine transaminase elevations during the first 6 months of conventional synthetic DMARD treatment.
Frequent laboratory monitoring is recommended for early identification of toxicity when initiating conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). We aimed at developing a risk prediction model to individualize laboratory testing at csDMARD initiation. We identified inflammatory joint disease patients (N = 1196) initiating a csDMARD in Turku University Hospital 2013-2019. Baseline and follow-up safety monitoring results were drawn from electronic health records. For rheumatoid arthritis patients, diagnoses and csDMARD initiation/cessation dates were manually confirmed. Primary endpoint was alanine transaminase (ALT) elevation of more than twice the upper limit of normal (ULN) within 6 months after treatment initiation. Computational models for predicting incident ALT elevations were developed using Lasso Cox proportional hazards regression with stable iterative variable selection (SIVS) and were internally validated against a randomly selected test cohort (1/3 of the data) that was not used for training the models. Primary endpoint was reached in 82 patients (6.9%). Among baseline variables, Lasso model with SIVS predicted subsequent ALT elevations of > 2 × ULN using higher ALT, csDMARD other than methotrexate or sulfasalazine and psoriatic arthritis diagnosis as important predictors, with a concordance index of 0.71 in the test cohort. Respectively, at first follow-up, in addition to baseline ALT and psoriatic arthritis diagnosis, also ALT change from baseline was identified as an important predictor resulting in a test concordance index of 0.72. Our computational model predicts ALT elevations after the first follow-up test with good accuracy and can help in optimizing individual testing frequency.


An artificial nucleoside that simultaneously detects and combats drug resistance to doxorubicin.
Doxorubicin is a DNA-damaging agent used to treat hematological cancers. Unfortunately, drug resistance can occur by defective DNA repair activity coupled with the ability of DNA polymerases to misreplicate unrepaired DNA lesions. This study demonstrates that the efficacy of doxorubicin can be improved by using an artificial nucleoside to efficiently and selectively inhibit this activity. In vitro studies using acute lymphoblastic leukemia cell lines define the mechanism of cell death caused by combining an artificial nucleoside with doxorubicin. Flow cytometry experiments demonstrate that combining an artificial nucleoside with doxorubicin potentiates the cell killing effects of the drug by increasing apoptosis. The potentiation effect correlates with expression of TdT, a specialized DNA polymerase overexpressed in acute lymphoblastic leukemia. Cell cycle experiments demonstrate that this combination blocks cells at S-phase prior to inducing apoptosis. Finally, the unique chemical composition of the nucleoside analog was used to visualize the replication of damaged DNA in TdT-positive cells. This represents a potential diagnostic tool to easily identify doxorubicin-resistant cancer cells. Studies demonstrate that a novel artificial nucleoside improves the therapeutic efficacy of doxorubicin, thereby reducing the risk of potential side effects caused by the DNA-damaging agent.


Giant congenital meningioma in a newborn.
The authors report the case of a giant meningioma in a 5-day-old newborn. Congenital meningiomas are extremely rare. Five newborns with meningiomas have been reported in the literature to date. This is the first case of a newborn with a giant meningioma with supra- and infratentorial and intraorbital components.


Incorporating second-tier genetic screening for multiple acyl-CoA dehydrogenase deficiency.
Newborn screening (NBS) for multiple acyl-CoA dehydrogenase deficiency (MADD) has poor sensitivity. This study aimed to evaluate the feasibility of incorporating second-tier genetic screening for MADD. A total of 453,390 newborns were screened for inherited metabolic disorders using tandem mass spectrometry from January 2017 to May 2022. A matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) assay was developed to identify 23 common ETFDH variants and used for second-tier screening of MADD. Overall, 185 newborns with suspected MADD received second-tier genetic screening. Thirty-three (17.8 %) newborns with positive results, of which 7 were homozygotes, 5 were compound heterozygotes, 21 were heterozygotes. Further genetic analysis revealed that 6 of the 21 newborns had a second ETFDH variant. Therefore, 18 patients were finally diagnosed with MADD, with a positive predictive value of 9.73 %. The detection rate and diagnostic rate of MALDI-TOF MS assay were 83.33 % and 66.67 %, respectively. Thus the incidence of MADD in our population was estimated at 1:25,188. Nine different ETFDH variants were identified in MADD patients. The most common ETFDH variant being c.250G > A with an allelic frequency of 47.22 %, followed by c.524G > A (13.89 %) and c.998A > G (13.89 %). All patients had elevation of multiple acylcarnitines at NBS. However, seven patients had normal acylcarnitine levels and two patients showed mild elevation of only two acylcarnitines during the recall review. We have established a high throughput MALDI-TOF MS assay for MADD screening. Half of the MADD patients would not be detected under conventional screening protocols. Incorporating second-tier genetic screening into the current NBS could improve the performance of MADD NBS.


SYSTEMI - systemic organ communication in STEMI: design and rationale of a cohort study of patients with ST-segment elevation myocardial infarction.
ST-segment elevation myocardial infarction (STEMI) still causes significant mortality and morbidity despite best-practice revascularization and adjunct medical strategies. Within the STEMI population, there is a spectrum of higher and lower risk patients with respect to major adverse cardiovascular and cerebral events (MACCE) or re-hospitalization due to heart failure. Myocardial and systemic metabolic disorders modulate patient risk in STEMI. Systematic cardiocirculatory and metabolic phenotyping to assess the bidirectional interaction of cardiac and systemic metabolism in myocardial ischemia is lacking. Systemic organ communication in STEMI (SYSTEMI) is an all-comer open-end prospective study in STEMI patients > 18 years of age to assess the interaction of cardiac and systemic metabolism in STEMI by systematically collecting data on a regional and systemic level. Primary endpoint will be myocardial function, left ventricular remodelling, myocardial texture and coronary patency at 6 month after STEMI. Secondary endpoint will be all-cause death, MACCE, and re-hospitalisation due to heart failure or revascularisation assessed 12 month after STEMI. The objective of SYSTEMI is to identify metabolic systemic and myocardial master switches that determine primary and secondary endpoints. In SYSTEMI 150-200 patients are expected to be recruited per year. Patient data will be collected at the index event, within 24 h, 5 days as well as 6 and 12 months after STEMI. Data acquisition will be performed in multilayer approaches. Myocardial function will be assessed by using serial cardiac imaging with cineventriculography, echocardiography and cardiovascular magnetic resonance. Myocardial metabolism will be analysed by multi-nuclei magnetic resonance spectroscopy. Systemic metabolism will be approached by serial liquid biopsies and analysed with respect to glucose and lipid metabolism as well as oxygen transport. In summary, SYSTEMI enables a comprehensive data analysis on the levels of organ structure and function alongside hemodynamic, genomic and transcriptomic information to assess cardiac and systemic metabolism. SYSTEMI aims to identify novel metabolic patterns and master-switches in the interaction of cardiac and systemic metabolism to improve diagnostic and therapeutic algorithms in myocardial ischemia for patient-risk assessment and tailored therapy. Trial Registration Number: NCT03539133.


Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia.
Insomnia impacts the course of major depressive disorder (MDD), hinders response to treatment, and increases risk for depressive relapse. This study is an initial evaluation of adding cognitive behavioral therapy for insomnia (CBTI) to the antidepressant medication escitalopram (EsCIT) in individuals with both disorders. A randomized, controlled, pilot study in a single academic medical center. 30 individuals (61% female, mean age 35 +/- 18) with MDD and insomnia. EsCIT and 7 individual therapy sessions of CBTI or CTRL (quasi-desensitization). Depression was assessed with the HRSD17 and the depression portion of the SCID, administered by raters masked to treatment assignment, at baseline and after 2, 4, 6, 8, and 12 weeks of treatment. The primary outcome was remission of MDD at study exit, which required both an HRSD17 score < or =7 and absence of the 2 core symptoms of MDD. Sleep was assessed with the insomnia severity index (ISI), daily sleep diaries, and actigraphy. EsCIT + CBTI resulted in a higher rate of remission of depression (61.5%) than EsCIT + CTRL (33.3%). EsCIT + CBTI was also associated with a greater remission from insomnia (50.0%) than EsCIT + CTRL (7.7%) and larger improvement in all diary and actigraphy measures of sleep, except for total sleep time. This pilot study provides evidence that augmenting an antidepressant medication with a brief, symptom focused, cognitive-behavioral therapy for insomnia is promising for individuals with MDD and comorbid insomnia in terms of alleviating both depression and insomnia.


Perspectives on Patient Access to Radiation Oncology Facilities and Services in Mainland China.
The Chinese health care system and specifically, radiation oncology, has clearly improved during the past 30 years in equipment and its use, although the shortage of facilities and workforce remain to be improved. These constitute the targets for a nationwide effort to improve the access to service by patients with cancer, especially in the more remote and rural portions of the country. In this report, we would highlight the positive changes that have occurred during the time and outline what is still needed for the future of this important cancer specialty in China.


Mechanisms for endothelial monocyte-activating polypeptide-II-induced opening of the blood-tumor barrier.
Endothelial monocyte-activating polypeptide-II (EMAP-II) increases blood-tumor barrier (BTB) permeability by inducing alterations in the tight junction (TJ) complex between brain endothelial cells. In the present study, an in vitro BTB model was used to search for the interacting and functional cell surface molecule of EMAP-II as well as the signaling pathway involved in the EMAP-II-induced BTB hyperpermeability. Our results revealed that EMAP-II-induced increase in BTB permeability and down-regulation of TJ-related proteins occludin and ZO-1 were associated with its binding to ATP synthase α subunit (α-ATP synthase) on the surface of rat brain microvascular endothelial cells (BMECs). In addition, we observed that EMAP-II administration activated protein kinase C (PKC) and induced the translocation of PKC from the cytosolic to the membrane fraction of BMECs. The effects of EMAP-II on BTB permeability as well as expression levels of occludin and ZO-1 in BMECs were significantly diminished by H7, the inhibitor of PKC. In summary, these data suggest that EMAP-II increases BTB permeability through α-ATP synthase on the surface of BMECs, and PKC signaling pathway might be involved in this process.


Cardiac valve replacement in children: a twenty-year series.
Ninety-four children ranging from 3 months to 19 years of age underwent cardiac valve replacement at Columbia Presbyterian Medical Center from 1965 to 1985. The overall operative mortality was 12%, but mortality was higher among patients less than 2 years of age, patients who had had previous cardiac operations, and patients requiring double-valve replacement. Seven of 11 patients who received mechanical valves and no anticoagulation experienced major thromboembolic events. An episode of gastrointestinal hemorrhage that was easily controlled represents the only bleeding complication in the entire series. Valve replacement in children continues to be a high-risk procedure, and efforts to preserve native valve function should be attempted when technically feasible. Our data also suggest that anticoagulation can be safely accomplished in the pediatric age group and should be employed in patients requiring placement of a mechanical prosthesis, especially in the mitral position.


Indoxyl sulfate induces apoptosis in mononuclear blood cells via mitochondrial pathway.
The consequence of chronic kidney disease is the accumulation of metabolic products called uremic toxins in the body. Indoxyl sulfate (IS) is a toxin with a high affinity for proteins. This study focuses on the deleterious effect of IS, especially apoptosis induction, in mononuclear blood cells (MNCs). Thus, in MNCs treated with IS at three different concentrations for 24 h, the survival, mitochondrial potential, caspases activity and expression, Bcl-2 and Bax protein expression, DNA damage, and PARP degradation were estimated. The study showed a decrease in survival and mitochondrial potential of MNCs treated with IS compared to the control. IS increased the activity of caspase 2-, 3-, 9-, and the expression of caspase 3-, and 9- in MNCs but does not affect the activity of caspase 6- and 8. The treatment of MNCs with IS also increased DNA damage and degradation of PARP. Indoxyl sulfate significantly influences the expression of Bcl-2 and Bax proteins. Indoxyl sulfate induces the programmed death of MNCs through the intrinsic mitochondrial apoptotic pathway. The observed cellular changes are mostly dose-dependent.


Predictors of nonadherence to breast cancer screening guidelines in a United States urban comprehensive cancer center.
This study aimed to identify predictors of nonadherence to breast cancer screening guidelines in an urban screening clinic among high- and average-risk women in the United States. We reviewed records of 6090 women who received ≥2 screening mammograms over 2 years at the Karmanos Cancer Institute to examine how breast cancer risk and breast density were associated with guideline-concordant screening. Incongruent screening was defined as receiving supplemental imaging between screening mammograms for average-risk women, and as not receiving recommended supplemental imaging for high-risk women. We used t-tests and chi-square tests to examine bivariate associations with guideline-congruent screening, and probit regression to regress guideline-congruence unto breast cancer risk, breast density, and their interaction, controlling for age and race. Incongruent screening was more likely among high- versus average-risk women (97.7% vs. 0.9%, p < 0.01). Among average-risk women, incongruent screening was more likely among those with dense versus nondense breasts (2.0% vs. 0.1%, p < 0.01). Among high-risk women, incongruent screening was more likely among those with nondense versus dense breasts (99.5% vs. 95.2%, p < 0.01). The significant main effects of density and high-risk on increased incongruent screening were qualified by a density by high-risk interaction, showing a weaker association between risk and incongruent screening among women with dense breasts (simple slope = 3.71, p < 0.01) versus nondense breasts (simple slope = 5.79, p < 0.01). Age and race were not associated with incongruent screening. Lack of adherence to evidence-based screening guidelines has led to underutilization of supplementary imaging for high-risk women and potential overutilization for women with dense breasts without other risk factors.


Air distribution and size changes in the remediated zone after air sparging for soil particle movement.
In an unconsolidated porous medium, soil particles can be mobilized by physical perturbation. In model systems of fluids flowing over spherical particles attached to flat surfaces, the hydrodynamic shear force depends on the fluid viscosity, particle radius, and flow velocity. Soil particles can be reasonably expected to be transported by flowing water during air sparging when the particle-size distribution does not fit the densest possible particle arrangement. If soil particles are transported during air sparging, then the distribution of the porosity and reservoir permeability will change. The remediated zone changes because of the changes in soil characteristics. This study applied some mathematical models to elucidate the mobilization process of soil particles during in situ air sparging. The changes in the characteristics of the soil and the swept volume of injected air during air sparging were also investigated. The results demonstrated that particle movement reduced the radius of influence (ROI) and the swept volume of injected air. In this case study, the maximum reducing rates in ROI and the swept volume were 24% and 26% for the zone where the gas saturation exceeded 10%.


The potential use of adult stem cells for the treatment of multiple sclerosis and other neurodegenerative disorders.
No specific treatment exists for patients with multiple sclerosis (MS) who fail to respond to conventional immunosuppressive and immunomodulating modalities. Furthermore, no method is available for regeneration of existing defect in the central nervous system (CNS). The ultimate goals of MS treatment, similarly to other autoimmune diseases, are twofold: first, to eliminate self-reactive lymphocytes and to prevent de novo development of self-reactivity by induction of self-tolerance. Second, attempting regeneration and repair of existing damage. In the case of MS, there is a need to stop the ongoing process of inflammation against the CNS by self-reactive lymphocytes thus facilitating spontaneous re-myelinization while in parallel attempt to recover existing neurological deficits caused by the autoimmune process resulting in demyelinization. Cell therapy stands out as the most rationale approach for neurological regeneration. In the absence of clinically applicable approaches involving the use of embryonic stem cells, we are investigating the feasibility and efficacy of enriched autologous mesenchymal stromal cells (MSC) injected intrathecally and intravenously to induce in situ immunomodulation and neuroprotection and possibly facilitate repair of the CNS in patients with MS and other neurodegenerative disorders. Our preclinical results suggest that bone marrow cells may provide a source of stem cells with a potential for migration into inflamed CNS and differentiate into cells expressing neuronal and glial cell markers. Based on the preclinical data, we are currently evaluating the safety of a similar therapeutic approach in a small group of patients with MS and other neurodegenerative diseases.


Ileal Pouch Complications.
Complications after ileal pouch surgery can result in poor pouch function and can have a significant negative impact on a patient's quality of life. Timely diagnosis and appropriate management of complications allows for the best chance of pouch salvage. Many complications require a multimodal approach. As with any reoperative surgery, the success of surgical revision or redo of an ileal pouch is highly dependent on the skill, judgment, and experience of the surgeon and requires an extremely motivated patient.


Osteopathic treatment of patients with shoulder pain. A pragmatic randomized controlled trial.
Shoulder complaints are common in the general population. Typically, the diagnosis of a specific pathology is lacking. The objective of this trial was to evaluate the effectiveness of an osteopathic treatment in patients suffering from shoulder pain. A pragmatic randomized controlled trial was conducted in patients with a history of shoulder pain of 6 weeks to 12 months, and a pain intensity level of at least 40% on the visual analogue scale (VAS). Participants were identified from the general population in Germany and allocated by means of external randomization to an intervention group or a control group. Patients in the intervention group received five osteopathic treatments at intervals of two weeks. Treatment was custom tailored and based on osteopathic principles. Controls received their osteopathic treatment after an 8-week untreated waiting period. Primary outcome parameters were pain intensity and frequency, measured by VAS and Likert Scales. Secondary outcome parameters were shoulder specific pain and disability (Shoulder Pain and Disability Index, SPADI), and quality of life (SF-36). A total of 70 patients aged 25-70 years (average age 45.6 ± 13.4 years) were included, 36 in the intervention group and 34 in the control group. The inter-group comparison of changes revealed clinically relevant improvements in favor of the intervention group for the main outcome parameters maximal pain intensity (VAS: between group difference of means 41.5; 95% CI: 34.6 to 48.3; p < 0.005) and average pain intensity (VAS: between group difference of means 40.4; 95% CI: 33.2 to 47.5; p < 0.005). The proportion of participants with a low frequency of pain increased in the osteopathic group only (from 7 to 34 vs. 9 to 6 in the control group, p = 0.006), and the number of patients with a high frequency decreased in the osteopathic group only (from 29 to 2 vs. 25 to 28, p < 0.0005). Shoulder specific pain and disability also improved. The follow-up assessment in the intervention group showed further improvements. Five osteopathic treatments over a period of eight weeks led to statistically significant and clinically relevant positive changes of pain and disability in patients suffering from shoulder pain.


Impact of Pregnancy on Intra-Host Genetic Diversity of Influenza A Viruses in Hospitalised Women: A Retrospective Cohort Study.
Characterising dynamics of Influenza A Viruses (IAV) within-host evolution is an active field of research which may lead to a better understanding of viral pathogenesis. Using a pregnant mouse model, a study has recently suggested that immune modulation during pregnancy could promote the emergence of IAV quasispecies with increased virulence. Herein, we assess the clinical relevance of these findings in humans. We studied IAV intra-host diversity (ihD) in pregnant (n = 36) and non-pregnant (n = 23) women hospitalized in Lyon for IAV infection (01/2015-05/2018). Whole IAV genomes present in nasopharyngeal samples were sequenced in duplicate to analyze reproducible intra-host single nucleotide variants (ihSNV). Counts, relative frequencies and locations of ihSNV were used as indicators of ihD. The median ihSNV/kb counts per segment were between 0 and 1.3. There was >81% ihSNV at relative frequencies between 1-5% for H1N1 and >51% for H3N2 IAV. No significant difference was noted between pregnant and non-pregnant women when considering all or only non-synonymous ihSNV. Seven convergent non-synonymous ihSNV were found; none were significantly associated with pregnancy. These results suggest that modulation of the immune system during pregnancy in humans does not impact IAV ihD, in contrast to mice.


Sodium-glucose co-transporter-2 inhibitors and epicardial adiposity.
Epicardial adipose tissue is a layer of adipocytes that physiologically surround the myocardium and play some physiologic roles in normal heart function. However, in pathologic conditions, the epicardial adipose tissue can present a potent cardiac risk factor that is capable of impairing heart function through several pathways, increasing the risk of dysrhythmia and creating an inflammatory milieu around the heart tissues. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a relatively newly introduced class of antidiabetes drugs which effectively normalize blood glucose via overt glycosuria. Some recent reports suggest that these drugs are able to modulate epicardial adiposity and decrease the risk of cardiac complications in diabetic patients who are at higher risk of epicardial adiposity-dependent cardiac disorders. If proven to be true, these antidiabetic drugs can provide dual benefits as both hypoglycemic agents and as epicardial adiposity normalizing agents, thus providing cardiac benefits. In this study, we discuss the physiological and pathophysiological importance of epicardial adiposity and the potential positive effects of SGLT2is in the diabetic milieu.


Survival of motoneurons following axotomy is enhanced by lactation or by progesterone treatment.
It was shown previously that neuron loss induced by nerve transection in the hypoglossal and facial motor nuclei of female rats could be reduced by long-term testosterone treatment following axotomy. In the present study, it is reported that such neuron loss could also be attenuated by lactation-related hormones and by progesterone treatment following axotomy.


Postpartum Telogen Effluvium Unmasking Traction Alopecia.
Telogen effluvium (TE) is a type of diffuse hair shedding that occurs 2-3 months after an exposure or trigger. The excessive hair loss may "unmask" underlying hair loss disorders such as female pattern hair loss. This is a case series of 3 patients with postpartum TE in which an underlying traction alopecia (TA) was revealed. TE can unmask underlying TA. Awareness of this phenomenon is critical to appropriate diagnosis and treatment.


Simple ultrasonic integration of shapeable, rebuildable, and multifunctional MIL-53(Fe)@cellulose composite for remediation of aqueous contaminants.
Metal-organic frames (MOFs) have been recognized as one of the best candidates in the remediation of aqueous contaminants, while the fragile powder shape restricts the practical implementation. In this work, a shapeable, rebuildable, and multifunctional MOF composite (MIL-53@CF) was prepared from MIL-53 (Fe) and cellulose fiber (CF) using a simple ultrasonic method for adsorption and photocatalytic degradation of organic pollutants in wastewater. The results showed MIL-53(Fe) crystals were uniformly growth on CF surfaces and bonded with surface nanofibrils of CF through physical crosslinking and hydrogen bonding. Because of the high bonding strength, the MIL-53@CF composite exhibited an excellent compressive strength (3.53 MPa). More importantly, the MIL-53@CF composite was rebuildable through mechanical destruction followed by re-ultrasonication, suggesting the excellent reusability of MIL-53@CF for water remediation. The MIL-53@CF composite also had high adsorption capacities for methyl orange (884.6 mg·g-1), methylene blue (198.3 mg·g-1), and tetracycline (106.4 mg·g-1). MIL-53@CF composite could degrade TC through photocatalysis. The photocatalytic degradation mechanism was attributed to the Fe(II)/Fe(III) transform cycle reaction of MIL-53 crystal located on MIL-53@CF. Furthermore, the mechanical property and remoldability of MIL-53@CF composite increased its practicability. Comprehensively, MIL-53@CF composite provided a possible strategy to practically apply MOF in the remediation of aqueous contaminants.


Latrotoxin-induced fusion of liposomes with bilayer phospholipid membranes.
Liposomes containing amphotericin B as ionophoric marker were used to investigate the fusion of bilayer phospholipid membranes with liposomes. It was found that latrotoxin isolated from black widow spider venom induced the fusion of liposomes with planar bilayer when liposomes and latrotoxin were administered at opposite sides of the membrane.


Calcium Carbonate.
Calcium carbonate is a chemical compound with the formula CaCO3 formed by three main elements: carbon, oxygen, and calcium. It is a common substance found in rocks in all parts of the world (most notably as limestone), and is the main component of shells of marine organisms, snails, coal balls, pearls, and eggshells. CaCO3 exists in different polymorphs, each with specific stability that depends on a diversity of variables.


Single-crystal structure analysis of non-deuterated triglycine sulfate by neutron diffraction at 20 and 298 K: a new disorder model for the 298 K structure.
Precise single-crystal structure analyses of the title compound, bis-(glycinium) sulfate-glycine (1/1), 2C2H6NO2 +·SO4 2-·C2H5NO2 (or C6H17N3O10S), non-deuterated triglycine sulfate (HTGS) at 20 K and 298 K were undertaken using time-of-flight neutron diffraction data. At 20 K for the O-H⋯O hydrogen bond between the glycinium cation and the zwitterionic, unprotonated glycine mol-ecule that is associated with the ferroelectric behaviour of HTGS, O-H = 1.070 (3), H⋯O = 1.408 (3) [δ = 0.338 (4)], O⋯O = 2.4777 (15) Å and O-H⋯O = 179.0 (4)°, which is in good agreement with previous studies. Two reasonable structures for the same three atoms were refined for the 298 K dataset. One is a single-minimum potential-energy model, with O-H = 1.090 (12), H⋯O = 1.361 (12) [δ = 0.271 (17)], O⋯O = 2.450 (7) Å and O-H⋯O = 179.2 (10)°, having the H atom with a large ellipticity along the bond path between the O atoms. The other is a double-minimum potential-energy model having two H atom sites with occupancies of 0.876 (8) and 0.124 (8): for the major occupancy component, O-H = 1.065 (12), H⋯O = 1.387 (12), O⋯O = 2.451 (7) Å and O-H⋯O = 178.2 (11)° and for the minor component, O-H = 1.06 (4), H⋯O = 1.41 (4), O⋯O = 2.451 (7) Å and O-H⋯O = 166 (2)°. These models did not show any significant differences in R factors. In addition, the unit-cell parameters and other structural parameters of HTGS did not show any major differences compared to those of partially deuterated TGS and fully deuterated TGS for both 20 K and 298 K.


A quantitative study of anterograde and retrograde axonal transport of exogenous proteins in olfactory nerve C-fibers.
The pike olfactory nerve which consists of a homogeneous population of C-fibers of 0.25 micron diameter or less was used to study quantitatively both anterograde and retrograde axoplasmic transport of wheat germ agglutinin and horseradish peroxidase. It was found that even in these extremely thin axons anterograde and retrograde transport takes place. Activity distribution profiles (transport profiles) for retrograde transport were established and found to be similar to the typical profiles of anterograde transport as they consisted of a small rapidly moving peak and a saddle region followed by the bulk of the material which moved more slowly. Horseradish peroxidase activity profiles were obtained both after injection into the synaptic region and after injection into the perikaryal region. From these transport profiles a maximal velocity of 25 mm/d (19 degrees C) for the leading peak and of about 7 mm/d for the slower component could be determined. There is no significant difference between the velocities for anterograde and retrograde transport. In the case of wheat germ agglutinin, only injection into the synaptic region resulted in typical transport profiles (retrograde transport) with a peak and saddle region. The maximum velocities of retrograde transport were about the same as for horseradish peroxidase [26 mm/d and 7 mm/d (19 degrees C)]. The electron microscopic analysis of horseradish peroxidase revealed that after injection into the olfactory bulb it was taken up into the neurons where it was found mainly in multivesicular bodies (0.5 micron diameter). In longitudinal sections of the nerve similar but slightly more elongated organelles (diameter 0.25 micron, length 0.4 micron) were found in those segments in which the slowly moving bulk of the peroxidase activity was located. The number of these organelles decreased with distance from the site of injection. The horseradish peroxidase transported within the leading peak could not be assigned to specific structures although several electron microscopic-histochemical methods were applied. It was concluded that anterograde and retrograde transport occur simultaneously in these axons, and that, therefore, even the large organelles, each of which almost fills the axon, must be able to pass each other. This would necessitate that the axons are able to transiently enlarge their diameter considerably.


[Quantification of aortic valve area using three-dimensional echocardiography].
To determine whether the reproducibility of left ventricular outflow tract (LVOT) area measurement is greater with three-dimensional echocardiographic (3D-echo) planimetry than with conventional 2D-echo. To determine the LVOT circularity index by means of 3D-echo. To determine the usefulness of measuring the LVOT area by 3D-echo for quantifying the severity of valvular aortic stenosis. The study included 40 patients, of whom 22 had an aortic stenosis. The LVOT area was measured using both 2D-echo and 3D-echo, and the circularity index, using 3D-echo alone. In addition, the severity of valvular aortic stenosis was categorized using both 2D-echo and 3D-echo. The levels of inter- and intra-observer agreement on LVOT area measurements were better with 3D-echo. The circularity index was 1.50 (0.25), and there was a very poor linear correlation with LVOT area (r=-0.34; P=.47). Patients with valvular aortic stenosis were categorized according to the severity of their stenoses using both 2D-echo and 3D-echo. The level of agreement between the two techniques was poor (kappa=0.36). Measurements of the LVOT area made using 3D-echo were more reproducible than those made using 2D-echo. Consequently, 3D-echo may be a better technique for assessing the LVOT area. In addition, 3D-echo showed that the LVOT is elliptical in form and that its size is not related to its circularity. Moreover, 3D-echo could also be helpful in classifying the severity of valvular aortic stenosis.


Differential effects of the simian virus 40 early genes on mammary epithelial cell growth, morphology, and gene expression.
To study the effect of SV40 T-antigen in mammary epithelial cells, a rat beta-casein promoter-driven SV40 early-region construct was stably introduced into the clonal mouse mammary epithelial cell line HC11. With the expression of the viral T-antigens under the control of a hormone-inducible promoter, it was possible to dissociate the effects of different levels of T-antigen expression on cell growth, morphology, and gene expression. Following hormonal induction, a rapid but transient induction of T-antigen was observed, followed by a delayed induction of H4 histone mRNA. In T-antigen-positive HC11 cells cultured in the absence of EGF, the expression of basal levels of T-antigen (in the absence of hormonal induction) led to a decreased doubling time and an increased cell density. In the presence of EGF, T-antigen expression resulted additionally in an altered cell morphology. Despite the effects of T-antigen on cell growth and gene expression, the cells were unable to form colonies in soft agar and were nontumorigenic when transplanted into cleared mammary fat pads. They were, however, weakly tumorigenic in nude mice. Relatively high levels of p53 protein synthesis were observed in both the transfected HC11 cells and the parental COMMA-D cells, as compared to 3T3E fibroblasts and another mammary epithelial cell line. The HC11 and COMMA-D cells synthesized approximately equal levels of wild-type and mutated p53 proteins as defined by their reactivities with monoclonal antibodies PAb246 and PAb240, respectively. Interactions between excess p53 and T-antigen may, in part, explain the failure of these cells to display a completely transformed phenotype.


Application of atomic force microscopy to assess erythrocytes morphology in early stages of diabetes. A pilot study.
The study aim was to assess the application of atomic force microscopy (AFM) to evaluate erythrocyte morphology in early stages of type 2 diabetes mellitus, and the association with biochemical, anthropometric, diet, and physical activity indicators. This was a pilot cross-sectional study with four groups: healthy individuals, people with prediabetes (PDG), metabolic syndrome (MSG), and diabetes mellitus group (DMG). Blood samples were obtained to assess the erythrocyte morphology and biochemical parameters. Anthropometrical measurements were taken. Besides, a diet and a physical activity questionnaire were applied. The evaluation of the erythrocyte morphology through the AFM showed quantitative and qualitative alterations in the cell's form and size. Compared to the healthy group, the PDG had a reduction in height (-0.80 μm, p < 0.05), and an increase in axial ratio (-0.09 μm, p < 0.05); the MSG had lower concave depth (-0.19 μm, p < 0.05); and the DMG had a decreased height (-0.46 μm, p < 0.05) and concave depth (-0.29 μm, p < 0.05), and higher axial ratio (+0.08 μm) and thickness (+0.32 μm, p < 0.05). The PDG vs. DMG had a statistically significant difference in concave depth (+0.23 μm, p < 0.05) and thickness (-0.26 μm, p < 0.05). The MSG was different than the DMG in variables like axial ratio (-0.05 μm) and thickness (-0.25 μm). Besides, higher values of age, HbA1c, triglycerides, body mass index, waist-to-hip ratio, and physical inactivity were associated with altered erythrocyte morphology. AFM is a promising instrument to assess early but subtle changes in erythrocyte morphology (height, axial ratio, concave depth, thickness) before significant pathological conditions, such as type 2 diabetes mellitus. HbA1c might have a major effect in altered morphology, vs. metabolic parameters like high triglycerides, body mass index, waist, and physical inactivity.


Identification and Computational Analysis of Rare Variants of Known Hearing Loss Genes Present in Five Deaf Members of a Pakistani Kindred.
Hearing loss (HL) is the most common neurosensory defect in humans that affects the normal communication. Disease is clinically and genetically heterogeneous, rendering challenges for the molecular diagnosis of affected subjects. This study highlights the phenotypic and genetic complexity of inherited HL in a large consanguineous Pakistan kindred. Audiological evaluation of all affected individuals revealed varying degree of mild to profound sensorineural HL. Whole exome (WES) of four family members followed by Sanger sequencing revealed candidate disease-associated variants in five known deafness genes: GJB2 (c.231G>A; p.(Trp77 *)), SLC26A4 (c.1337A>G; p.(Gln446Arg)), CDH23 (c.2789C>T; p.(Pro930Leu)), KCNQ4 (c.1672G>A; p.(Val558Met)) and MPDZ (c.4124T>C; p.(Val1375Ala)). All identified variants replaced evolutionary conserved residues, were either absent or had low frequencies in the control databases. Our in silico and 3-Dimensional (3D) protein topology analyses support the damaging impact of identified variants on the encoded proteins. However, except for the previously established "pathogenic" and "likely pathogenic" categories for the c.231G>A (p.(Trp77 *)) allele of GJB2 and c.1377A>G (p.(Gln446Arg)) of SLC26A4, respectively, all the remaining identified variants were classified as "uncertain significance" based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant pathogenicity guidelines. Our study highlights the complexity of genetic traits in consanguineous families, and the need of combining the functional studies even with the comprehensive profiling of multiple family members to improve the genetic diagnosis in complex inbred families.


Comparative transcriptome analysis reveals physiological responses in liver tissues of Epinephelus coioides under acute hypoxia stress.
Hypoxia is a common stressor for aquatic animals, including Epinephelus coioides, with a considerable impact on sustainable aquaculture. E. coioides is a widely consumed fish in China owing to its high nutritious value and taste. However, water hypoxia caused by high density culture process has become a great threat to E. coioides culture, and its response to hypoxia stress has not been discussed before. Therefore, the aim of this study was to examine the response of E. coioides to acute hypoxia using transcriptomic techniques. To this end, RNA sequencing was performed on the liver tissues of fish exposed to normoxic and hypoxic conditions for 1 h. The results presented 503 differentially expressed genes (DEGs) in the liver tissue of fish exposed to hypoxic condition compared with those in the normoxic group. Enrichment analysis using the Gene Ontology database showed that the DEGs were mainly enriched for functions related to cell apoptosis signaling pathways, insulin resistance, antioxidant enzymes, and glycolysis/gluconeogenesis signaling pathways. KEGG enrichment analysis showed that HIF-1, PI3K-AKT, IL-17, NF-kappa B, and MAPK signaling pathways were significantly enriched by the DEGs. The DEGs were mainly involved in immune response, inflammatory response, cell apoptosis regulation, energy metabolism, and substance metabolism. Additionally, the hypoxia response in E. coioides was mainly regulated via the PI3K-AKT-HIF-1 signaling axis. Overall, the findings of this study contribute to the understanding of hypoxia stress response in E. coioides, and provides target genes for breeding hypoxia-tolerant Epinephelus spp.


Endothelium adjustments to acute resistance exercise are intensity-dependent in healthy animals.
We evaluated the acute effects of different intensities of resistance exercise over endothelium-dependent vasodilatation, eNOSser1177 phosphorylation level and endothelial production of NO in superior mesenteric artery of healthy rats. Groups: control (Ct), resistance exercise in the intensities of 30% (Ex30%), 50% (Ex50%) and 70% (Ex70%) of the maximal load established by the maximal repetition test (1RM). Exercise protocol: 15 sets of 10 repetitions. The rings of mesenteric artery were mounted in an isometric system or were prepared for further implementation of Western blot and DAF-FM techniques. The maximal response of the relaxation induced by insulin was not altered in the animals of the Ex30% group when compared to the Ct group. However, the animals of the Ex50% and Ex70% groups presented an increase in this response when compared to the Ct group. The eNOSser1177 phosphorylation levels showed an increase in Ex50% and Ex70% groups when compared to the Ct (1.6-fold and 3.3-fold, respectively). In the endothelial production of NO, it was observed that the Ex30% group did not show alteration in the NO production when compared to the Ct group. On the other hand, the animals exercised in the Ex50% and Ex70% groups showed increase in the NO synthesis when compared to the animals in the Ct group. Our results suggest that the magnitude of these vascular endothelium adjustments is strongly related to the increase of the resistance exercise intensity from the intensity of 50% of 1 RM.


Solid-phase synthesis of oligomers carrying several chromophore units linked by phosphodiester backbones.
A method for the preparation of oligomers by linking chromophore units is described. Specifically, the synthesis of chromophore units having a protected-hydroxyl group and a phosphoramidite function is described, along with a method to link several units using solid-phase phosphite-triester protocols.


Bacterial division. Mechanical crack propagation drives millisecond daughter cell separation in Staphylococcus aureus.
When Staphylococcus aureus undergoes cytokinesis, it builds a septum, generating two hemispherical daughters whose cell walls are only connected via a narrow peripheral ring. We found that resolution of this ring occurred within milliseconds ("popping"), without detectable changes in cell volume. The likelihood of popping depended on cell-wall stress, and the separating cells split open asymmetrically, leaving the daughters connected by a hinge. An elastostatic model of the wall indicated high circumferential stress in the peripheral ring before popping. Last, we observed small perforations in the peripheral ring that are likely initial points of mechanical failure. Thus, the ultrafast daughter cell separation in S. aureus appears to be driven by accumulation of stress in the peripheral ring and exhibits hallmarks of mechanical crack propagation.


Formation of 1:2 host-guest complexes based on triptycene-derived macrotricycle and paraquat derivatives: anion-π interactions between PF6(-) and bipyridinium rings in the solid state.
A triptycene-derived macrotricyclic host containing two dibenzo-[30]-crown-10 moieties forms stable 1:2 host-guest complexes with paraquat derivatives in both solution and the solid state, in which anion-π interactions between PF(6)(-) and the bipyridinium rings play an important role. Moreover, it was found that binding and release of the guest molecules in the complexes could be easily controlled by the addition and removal of potassium ions.


Artificial intelligence for the detection of vertebral fractures on plain spinal radiography.
Vertebral fractures (VFs) cause serious problems, such as substantial functional loss and a high mortality rate, and a delayed diagnosis may further worsen the prognosis. Plain thoracolumbar radiography (PTLR) is an essential method for the evaluation of VFs. Therefore, minimizing the diagnostic errors of VFs on PTLR is crucial. Image identification based on a deep convolutional neural network (DCNN) has been recognized to be potentially effective as a diagnostic strategy; however, the accuracy for detecting VFs has not been fully investigated. A DCNN was trained with PTLR images of 300 patients (150 patients with and 150 without VFs). The accuracy, sensitivity, and specificity of diagnosis of the model were calculated and compared with those of orthopedic residents, orthopedic surgeons, and spine surgeons. The DCNN achieved accuracy, sensitivity, and specificity rates of 86.0% [95% confidence interval (CI) 82.0-90.0%], 84.7% (95% CI 78.8-90.5%), and 87.3% (95% CI 81.9-92.7%), respectively. Both the accuracy and sensitivity of the model were suggested to be noninferior to those of orthopedic surgeons. The DCNN can assist clinicians in the early identification of VFs and in managing patients, to prevent further invasive interventions and a decreased quality of life.


Development of an antibody-lectin enzyme immunoassay for fucosylated α-fetoprotein.
Fucosylation is one of the most important types of glycosylations related to cancer. Our previous studies of the enzymatic basis and structural studies of α-fetoprotein (AFP) samples from liver cancer patients indicated that core-fucosylation by α1,6-fucosyltransferase (FUT8) resulted in the production of fucosylated AFP, and in fact fucosylated AFP allowed differential diagnosis in some types of liver cancer from liver cirrhosis. This served as a predictive biomarker for the development of liver cancer 3 to 18 months before it could be detected using imaging techniques. Fucosylated AFP is currently measured by means of a liquid-phase binding assay (LBA) or by an electrokinetic analyte transport assay (EATA). However, these methods require special instrumentation that is currently available only in major medical laboratories. To overcome this problem, we attempted to develop an enzyme immunoassay (EIA) based on the sandwich technique with specific antibody and lectin. Dilute solutions of highly fucosylated AFP in human sera were assayed using a microtiter plate coated with a periodate-oxidized anti-AFP antibody, a fucose-specific biotinylated Aleuria aurantia lectin (AAL), a peroxidase-conjugated streptoavidin, and a chemiluminescent detection system. The technique was able to measure highly fucosylated AFP diluted to 5 to 80ng/ml in human sera using the developed antibody-lectin EIA in combination with the enrichment of AFP. A simple method using an antibody-lectin EIA for quantifying fucosylated AFP that does not require special instrumentation was developed. The method can be generally applied to the quantitative measurement of various fucosylated glycoproteins using specific antibodies. This article is part of a Special Issue entitled Glycoproteomics.


Voluntary stopping of eating and drinking in advance directives for adults with late-stage dementia.
The objective of this paper is to explore the ethical and legal validity of advance directives that request the voluntary stopping of eating and drinking against a backdrop of late-stage dementia. Doctrinal research and analysis of primary and secondary materials including Australian legislation, Australian case law and journal articles was undertaken. There is legal uncertainty in Australia around whether an advance directive to voluntarily stop eating and drinking will be followed should the adult become incompetent. Voluntary stopping of eating and drinking should be viewed in law as a form of "treatment" that competent adults can nominate in advance directives, thereby providing dementia patients with the opportunity to choose in advance, if they wish, to end their life legally, with dignity and comfort, and in a manner that does not implicate others in criminal behaviour such as assisted suicide, acceleration of death or euthanasia.


Network analysis and proteomic identification of vimentin as a key regulator associated with invasion and metastasis in human hepatocellular carcinoma cells.
Poor prognoses have long been associated with the high relapse and metastasis of human hepatocellular carcinoma (HCC). To achieve long-term survival, it is necessary to identify new HCC biomarkers and investigate their roles in cell mobility and invasiveness. Of note, overexpression of vimentin (Vim) was significantly correlated with tumor nuclear grade (p=0.01) and the invasive potential, indicating that Vim may be a promising candidate in regulating HCC metastasis. RNA interference-mediated silencing of Vim (siVim) suppressed the invasive and migratory propensity, and matrix metalloproteinase (MMP)-9 activity, and elicited morphological changes in poorly differentiated SK-Hep-1 cells. Moreover, we performed a comprehensive proteomic analysis to survey global protein changes mediated by siVim in SK-Hep-1 cells. Significant changes in cytoskeleton protein but not messenger RNA levels encoding these targeted proteins were observed. All of the data in the current study and a network analysis implied that abolition of Vim may disturb the expression and stability of various cytoskeletal proteins through promoting the ubiquitin system, resulting in impaired cell adhesion and motility. Collectively, an integrated approach represents a modality to explore novel relationships in a proteome complex and highlights the functional roles of Vim in HCC metastasis. This article is part of a Special Issue entitled: Translational Proteomics.


Optochin resistance in Streptococcus pneumoniae strains isolated from blood and middle ear fluid.
Optochin resistant Streptococcus pneumoniae having typical pneumococcal morphology in culture and Gram stain and giving clear agglutination with anti-pneumococcal polysaccharide antisera were isolated from primary cultures of blood and middle ear fluid. The isolated pneumococci were either fully sensitive to penicillin and other antimicrobial agents commonly used or relatively resistant to penicillin and resistant to cloxacillin, tetracycline, erythromycin, sulphatrimethoprim and clindamycin.


A review of adverse events in animals and children after secondary exposure to transdermal hormone-containing medicinal products.
Hormonal replacement therapy is widely used to treat conditions in humans, the most well-known indication being the relief of menopausal symptoms in women. Many of the hormone-containing products (HCP) are applied to the skin. This transdermal delivery poses a risk to animals and humans through secondary exposure, especially when product information is not strictly followed. The aim of this article is to raise awareness among veterinarians and human healthcare providers of this risk; based on evidence from spontaneous reporting of suspected adverse events (AEs) in animals and humans. Interventions are also explored to mitigate the risk of secondary exposure to transdermal HCP (THCP). The Swedish Medical Products Agency has received several, mainly serious, AE reports in animals and children following secondary exposure to THCPs. The AE reports were reviewed together with worldwide data from the EudraVigilance Veterinary database and human EudraVigilance Data Analysis System. The clinical signs reported in animals included persistent signs of oestrus, poor growth rate and birth defects. In humans, reported clinical signs included precocious puberty, unresolved virilisation, accelerated growth rate and female infertility. It is important that THCP are used according to manufacturer's instructions and users are made aware of risks and mitigating measures. This review of AEs in animals and children provides evidence to show that the use of THCP poses a risk for secondary exposure. Efficient communication strategies that stretch across veterinary and human medicinal disciplines are required to raise mutual awareness and minimise the risk of AEs in animals and humans.


Production of glucose 6-phosphate dehydrogenase from genetically modified Saccharomyces cerevisiae grown by batch fermentation process.
In a 5-L fermentor (NBS-MF 105), Saccharomyces cerevisiae W303-181 (1.0 g dry matter/L) was inoculated into 3.0 L of liquid medium containing glucose (10 or 20 g/L), yeast nitrogen base (YNB, 3.7 or 7.4 g/L), l-histidine (0.02 g/L), l-tryptophan (0.02 g/L), uracil (0.02 g/L), and adenine (0.02 g/L). The culture was carried out batchwise for 12 or 24 h at 30 degrees C, pH 4.6 or 5.7, aeration of 0, 0.8, 1.7 or 2.2 vvm, and agitation of 400 rpm. The highest G6PDH productivity (10.5 U/L.h) and specific activity (320 U/mg of protein) occurred at aeration of 2.2 vvm, pH 5.7, 10 g/L of glucose, and 3.7 g/L of YNB. The G6PDH specific activity attained was comparable with those of commercial preparations, which are between 50 and 600 U/mg of protein.


Knowledge of parents/caregivers about the sleep bruxism of their children from all five Brazilian regions: A multicenter study.
Sleep bruxism (SB) is a masticatory muscle activity that affects children. Parents' knowledge is important for its identification and report to dentists. To investigate parents' knowledge about SB among their children. A cross-sectional study included 1325 parents of children from dental clinics of seven institutions from all regions of Brazil. Parents answered questions about child's sleep, knowledge about SB and its occurrence among children and parents. SB definition given by parents was dichotomized as "correct"/"incorrect", based on the American Academy of Sleep Medicine definition. Descriptive, bivariate and multivariate analyses were performed (P < 0.05). Most parents (57.3%) did not know what SB is and 88.9% would like to receive more information. SB prevalence among parents was 15.4% and 24.0% among children. Between parents who correctly defined SB, its prevalence increased to 27.5% among parents and 40.6% among children. Parents whose children had/have SB, who would like to receive more information about SB and were from the North, Central-West, Southeast, and South regions were more likely to define SB correctly (P > 0.05). There is a lack of knowledge of parents about SB. SB among children, parents' interest in receiving more information and their location were factors associated to their knowledge.


Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors.
The combination of vinblastine and mammalian target of rapamycin (mTOR) inhibitor sirolimus inhibits the growth of neuroblastoma xenografts through pro-apoptotic and anti-angiogenic mechanisms. This phase I study aimed to explore the safety and toxicity of this combination in pediatric patients with advanced solid tumors. Patients ≤21 years of age with recurrent/refractory solid tumors (including CNS) were eligible. Sirolimus was administered daily by mouth or nasogastric (NG) tube, with doses adjusted to achieve a target trough concentration of 10-15 ng/ml, with weekly intravenous vinblastine (dose escalated 4-6 mg/m(2)/dose according to 3 + 3 phase I design). Fourteen patients were enrolled (median age 8.7 years; range 2.3-19) of whom 12 were evaluable for toxicity and 11 for response. One patient experienced a dose-limiting toxicity (grade 3 mucositis) at the highest vinblastine dose level. Myelosuppression was the most common toxicity. Dose-adjusted sirolimus trough concentrations were significantly lower in patients receiving drug via NG tube (1.50 ± 0.75 ng/ml/mg vs. 2.25 ± 1.07 ng/ml/mg for oral administration). Correlative biomarker analysis demonstrated a significant reduction in serum concentration of soluble vascular endothelial growth factor receptor (sVEGFR2) at 28 days compared to baseline consistent with inhibition of angiogenesis. One patient had a partial response and three had stable disease for more than 3 months. The combination of mTOR inhibitor and vinblastine given over an extended continuous schedule is safe, associated with a reduction in circulating angiogenic factor (CAF) VEGFR2 and resulted in clinical responses. Future studies using the intravenously administered mTOR inhibitor temsirolimus are planned.


Risk of suicide attempt and suicide associated with benzodiazepine: A nationwide case crossover study.
Previous studies that found an association between benzodiazepines and suicidal behaviours were confounded by indication bias. To limit this bias, a case crossover study (CCO) was conducted to estimate the risk of suicide attempt and suicide associated with benzodiazepines. Patients ≥16 years, with hospitalised suicide attempt or suicide between 2013 and 2016, and at least one benzodiazepine dispensing within the 120 days before their act were selected in the nationwide French reimbursement healthcare system databases (SNDS). For each patient, frequency of benzodiazepine dispensing was compared between a risk period (days -30 to -1 before the event) and two matched reference periods (days -120 to -91, and -90 to -61). A total of 111,550 individuals who attempted suicide and 12,312 suicide victims were included, of who, respectively, 77,474 and 7958 had recent psychiatric history. Benzodiazepine dispensing appeared higher in the 30-day risk period than in reference ones. The comparison yielded adjusted odds ratios of 1.74 for hospitalised suicide attempt (95% confidence interval 1.69-1.78) and 1.45 for suicide (1.34-1.57) in individuals with recent psychiatric history, and of 2.77 (2.69-2.86) and 1.80 (1.65-1.97) for individuals without. This nationwide study supports an association between recent benzodiazepine use and both suicide attempt and suicide. These results strengthen the need for screening for suicidal risk carefully before initiation and during treatment when prescribing benzodiazepines. EUPAS48070 (http://www.ENCEPP.eu).


Drugging aquaporins.
Water is essential for all life because it is required for the proper functioning of the cells and tissues of all organisms. It crosses biological membranes down osmotic gradients through the pores of aquaporin membrane channels at rates of up to 3 billion molecules per second. In the twenty years since Peter Agre was awarded the 2003 Nobel Prize in Chemistry for the discovery of the aquaporin family, aquaporin structure and function have become established in the literature. As a consequence, we understand in fine detail the mechanism by which aquaporins facilitate membrane water flow while excluding protons. We also know that some aquaporins facilitate the permeation of other small neutral solutes, ions or even unexpected substrates across biological membranes. The thirteen aquaporins in the human body have been implicated in pathologies including oedema, epilepsy, cancer cell migration, tumour angiogenesis, metabolic disorders and inflammation. Surprisingly, however, there is no aquaporin-targeted drug in the clinic. Some scientists have therefore concluded that aquaporins are intrinsically non-druggable targets. Discovering medicines to treat disorders of water homeostasis is thus an enduring challenge for the aquaporin field. Success in this endeavour will meet the urgent clinical need of millions of patients suffering from a range of life-threatening conditions and for whom no pharmacological interventions are currently available.


Micronutrient Fortification of Commercially Available Biscuits Is Predicted to Have Minimal Impact on Prevalence of Inadequate Micronutrient Intakes: Modeling of National Dietary Data From Cameroon.
Voluntarily fortified snack products are increasingly available but are not necessarily formulated to meet known dietary nutrient gaps, so potential impacts on population micronutrient intake adequacy are uncertain. We modeled the impacts of hypothetical micronutrient-fortified biscuits on inadequate micronutrient intake in children and women of reproductive age (WRA) in Cameroon. In a nationally representative survey stratified by macro-region (North, South, and Yaoundé/Douala), 24-h dietary recall data were collected from 883 children aged 12-59 mo and from 912 WRA. We estimated usual nutrient intake by the National Cancer Institute method for vitamin A, folate, vitamin B-12, zinc, and iron. We simulated the impact of biscuit fortification on prevalence of micronutrient intake below the estimated average requirement, given observed biscuit consumption, in the presence and absence of large-scale food fortification (LSFF) programs. Biscuit consumption in the prior 24-h by children and WRA, respectively, ranged from 4.5% and 1.5% in the South, to 20.7% and 5.9% in Yaoundé/Douala. In the absence of LSFF programs, biscuits fortified with retinol (600 μg/100 g), folic acid (300 μg/100 g), and zinc (8 mg/100 g) were predicted to reduce the prevalence of inadequacy among children by 10.3 ± 4.4, 13.2 ± 4.2, and 12.0 ± 6.1 percentage points, respectively, in Yaoundé/Douala. However, when existing vitamin A-fortified oil, and folic acid-fortified and zinc-fortified wheat flour programs were considered, the additional impacts of fortified biscuits were reduced substantially. Micronutrient-fortified biscuits were predicted to have minimal impact on dietary inadequacy in WRA, with or without LSFF programs. Given observed patterns of biscuit consumption in Cameroon, biscuit fortification is unlikely to reduce dietary inadequacy of studied micronutrients, except possibly for selected nutrients in children in urban areas in the absence of LSFF programs. As voluntary fortification becomes increasingly common, modeling studies could help guide efforts to ensure that fortified products align with public health goals.


The longitudinal psychological, physical activity, and financial impact of a COVID-19 lockdown on older adults in Singapore: The PIONEER-COVID population-based study.
Several countries have implemented 'lockdown' measures to curb the spread of the coronavirus disease 2019 (COVID-19). To examine the psychological, physical activity (PA), and financial impact of a 2-month COVID-19 lockdown on older adults aged ≥60 years in Singapore, and to identify factors associated with adverse lockdown-related outcomes. We interviewed 496 community-dwelling adults (mean age [standard deviation]: 73.8 [7.6] years; 54.8% female) during the lockdown who had previously participated in a population-based epidemiological study. Validated questionnaires were utilised to assess loneliness and depressive symptoms at both timepoints, while inhouse questionnaires were used to assess PA and financial difficulty during lockdown. Multivariable regression models determined the lockdown-related change in loneliness and depression scores, and the factors associated with adverse outcomes. Loneliness increased significantly during the lockdown period (p < 0.001) while depressive symptoms decreased (p = 0.022). Decreased PA, greater financial problems, male gender, Indian ethnicity, living alone, having a greater body mass index and perceived susceptibility to COVID-19 were all associated with worsening loneliness scores. A total of 36.9% and 19.6% participants reported decreased PA and had financial problems during the lockdown, respectively. Unemployment was associated with decreased PA, while self-employed individuals, cleaners, retail workers and smokers had greater odds of experiencing financial difficulty. Despite a decrease in depressive symptoms, our population of older Asians reported a significant increase in loneliness and decreased PA, with one-fifth experiencing financial problems during lockdown. Our data suggest that more targeted public health efforts are needed to reduce repercussions of future lockdowns.


A molecular dissection of the glycoprotein hormone receptors.
In glycoprotein hormone receptors, a subfamily of rhodopsin-like G protein-coupled receptors, the recognition and activation steps are carried out by separate domains of the proteins. Specificity of recognition of the hormones thyrotropin (TSH), lutropin (LH), human chorionic gonadotropin (hCG) and follitropin (FSH) involves leucine-rich repeats (LRRs) present in an N-terminal ectodomain, and can be associated with a limited number of residues at key positions of the LRRs. The mechanism by which binding of the hormones results in activation is proposed to involve switching of the ectodomain from a tethered inverse agonist to a full agonist of the serpentine, rhodopsin-like region of the receptor. Unexpectedly, the picture is complicated by the observation that promiscuous activation of one of the receptors (FSHr) by hCG or TSH can result from activating mutations affecting the serpentine region of the receptors.


Fulminant tropical hepatitis--experimental reproduction.
After a review of the literature on epidemiological, serological and histopathological data concerning so-called "Amazon Black Fever" (Labrea disease), an experimental model of morphological reproduction of the disease is presented. The model is based on the probable causal synergism of Labrea hepatitis, i.e., viral injury plus protein-caloric malnutrition. Mice infected with the Oriboca arbovirus presented classic yellow-fever-like lesions of the liver, with a few malnourished animals showing the characteristic morular changes of the human disease.


Locative inferences in medical texts.
Medical research relies on epidemiological studies conducted on a large set of clinical records that have been collected from physicians recording individual patient observations. These clinical records are recorded for the purpose of individual care of the patient with little consideration for their use by a biostatistician interested in studying a disease over a large population. Natural language processing of clinical records for epidemiological studies must deal with temporal, locative, and conceptual issues. This makes text understanding and data extraction of clinical records an excellent area for applied research. While much has been done in making temporal or conceptual inferences in medical texts, parallel work in locative inferences has not been done. This paper examines the locative inferences as well as the integration of temporal, locative, and conceptual issues in the clinical record understanding domain by presenting an application that utilizes two key concepts in its parsing strategy--a knowledge-based parsing strategy and a minimal lexicon.


An Evidence-Based Staging System for Mucosal Melanoma: A Proposal.
There is no widely employed staging system for mucosal melanoma (MuM) that incorporates all anatomic sites. We hypothesized that MuM patients arising from different anatomical sites could be staged using a common approach. A prospective database contained 1814 MuM patients with a median follow-up of 5.14 years was employed. Overall survival (OS) was calculated from the time of pathological diagnosis to the date of death from any cause. Multivariate analyses of prognostic variables and OS were performed using the Cox proportional hazard model. For localized MuM, the most significant median OS differences were primary tumors invading submucosa (i.e., T1) versus deeper (i.e., T2/T3/T4): 4.3 versus 3.4, 3.1, and 2.9 years, respectively (p < 0.001). For patients only with regional node metastasis at presentation, the most significant were: 1 versus ≥ 2 regional nodes (N1 vs. N2, 2.5 vs. 2.1 years, p < 0.001). For patients with distant metastasis at presentation, the median OS was 1.5, 1.2, 0.8, and 0.6 years respectively for skin/subcutaneous tissue/distant lymph nodes (M1a), lung metastasis (M1b), all other visceral sites except brain (M1c), and brain (M1d) (p < 0.001). Based on these results, the staging system for MuM is proposed: (1) Stage I: T1N0M0 (median OS, 4.3 years); (2) Stage II: T2-4N0M0 (3.1 years); (3) Stage IIIA: T1-4N1M0 (2.5 years), Stage IIIB: T1-4N2M0 (2.1 years); (4) Stage IV: TanyNanyM1 (0.9 years) (p < 0.001). A single, unified, staging system for mucosal melanoma inclusive of all anatomical primary tumor sites can harmonize staging of MuM and the design of clinical trials.


The effect of exposure to elevated temperatures on membrane permeability to adriamycin in Chinese hamster ovary cells in vitro.
The effect of environmental temperature on plasma membrane permeability to Adriamycin was studied in Chinese hamster ovary (CHO) cells in vitro using flow cytometry. Initial rates of uptake increased steadily between 23 degrees C and 47 degrees C and there was a greater than 2-fold increase in permeability between 37 degrees C and 47 degrees C. The increase in permeability with increasing temperature was greater than expected based on the model of passive drug influx. Adriamycin uptake was also measured at 37 degrees C following previous exposure of the cells to elevated temperatures. Twenty-minute preexposures to temperatures above 41 degrees C caused a significant decrease in membrane permeability, which fell to approximately 60% of control levels after exposure to 45 degrees C. Longer periods of pre-exposure to temperatures as low as 40 degrees C were also shown to decrease membrane permeability to Adriamycin subsequently measured at 37 degrees C. The state of decreased permeability to Adriamycin induced by hyperthermia persisted for at least 2 h. The thermally induced decrease in membrane permeability to Adriamycin is of potential importance to the design of optimal schedules for thermochemotherapy.


Hoplostethus roseus, a new roughy fish from the western Pacific based on morphology and DNA barcoding (family Trachichthyidae).
A new species of the roughy fish genus Hoplostethus is described from 11 types and a non-type specimen collected from Taiwanese waters. It can be distinguished from its congeners by a combination of characters: pectoral-fin rays 14-17 (modally 15-16); pyloric caeca 65-84; total gill rakers 19-20; predorsal scales 18-22; oral cavity, branchial chamber, top and underside of tongue, and peritoneum uniformly black; distal margin of membrane between dorsal-fin spines black; caudal fin without a black margin; caudal-fin base brownish. Comparisons of the new species with similar species are provided. DNA barcoding supports the monophyly of the new species, which appears to be closely related to Hoplostethus japonicus [average cytochrome c oxidase subunit I Kimura-2-parameter (COI K2P) distance of 4.1%].


Effects of storage on brown rice (Oryza sativa L.) metabolites, analyzed using gas chromatography and mass spectrometry.
Metabolomic studies were carried out using gas chromatography and mass spectrometry (GC-MS) on Daohuaxiang variety rice (Oryza sativa L.) from the Wuchang Geographical Indication Rice Protection Area in Heilongjiang Province, to investigate the effects of storage on brown rice metabolism. The data were subjected to principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), and cluster analysis using software such as SIMCA. Analysis of the samples led to the identification of a total of 160 metabolites. No significant differences were found in the amount of metabolites before and after storage. A total of 31 differential metabolites were screened, and the changes in metabolite content showed a "reverse change" overall. Storage significantly changed the content of various metabolites in rice, with fatty acids impacted most significantly. Metabolic pathway analysis revealed that fatty acid biosynthesis is a key metabolic pathway in rice storage. The degradation of brown rice quality caused by storage is closely related to the composition and content of its metabolites, and that change in lipid content significantly affects brown rice quality during storage.


Single-strand conformation polymorphism (SSCP) analysis of the molecular pathology of hemophilia B.
In the present study, we report the application of polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis to the screening of seven functionally important factor IX gene (FIX) regions (total length 2.66 kb) in 9 unrelated haemophilia B patients of Portuguese or African origin. In eight of the patients an altered migration pattern of single-stranded DNA was observed. Direct sequencing of the relevant DNA fragments unveiled the following sequence alterations: two novel mutations, namely FIXBarcelos Thr-380-Pro and FIXLousada 9bp insertion at position 31,309 or 31,318; five mutations previously reported in other ethnic groups (FIXPorto Arg-145-His, FIXLuanda Gly-207-Arg, FIXPenafiel Arg-248-Gln, FIXSesimbra Arg-333-Gln, FIXCascais Arg-333-Stop); and a normal variant, G-->T transvertion at position 6,596 in intron 2. We propose hypothetical models for the generation of the 9 bp duplication (FIXLousada). We have performed molecular modeling studies in order to predict the structure of the variant FIX molecules.


A novel inhibitor of ARfl and ARv7 induces protein degradation to overcome enzalutamide resistance in advanced prostate cancer.
Enzalutamide (ENZ) is a second-generation androgen receptor (AR) antagonist used for the treatment of castration-resistant prostate cancer (CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance (ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR (ARfl) or dominantly active androgen receptor splice variant 7 (ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.


Comparing the performance of various advanced oxidation processes for treatment of acetone contaminated water.
Removal of low levels of organic pollutants can be quite challenging to many water treatment processes. Ketones, such as acetone, are often found in groundwaters and wastewaters at levels too low for supporting a bioreactor, yet since acetone is so soluble, it does not adsorb onto activated carbon very well, nor does it volatilize from water influent using air stripping. This study was undertaken to evaluate three advanced oxidation processes for their comparative ability to remove acetone from aqueous media. Optimization of the oxidation processes was attempted via adjustments of oxidizer inputs. The results indicated that all of the AOPs tested showed promise for removing acetone from water; however, ozonated systems undergoing UV photolysis achieved the highest rate and extent of treatment observed.


Influence of time to treatment on early infarct-related artery patency after different thrombolytic regimens. ALKK-Study Group.
In an in vitro model, recombinant tissue-type plasminogen activator was significantly more effective than streptokinase in dissolving 24-hour-old human blood clots. Therefore there might be a difference in the effect of time to treatment on the efficacy of these fibrinolytics with different fibrin specificity in patients with acute myocardial infarction. The effect of the interval between symptom onset and initiation of therapy on the efficacy of 6 different thrombolytic regimens was studied in a retrospective analysis of 6 angiographic trials with similar design. The patency of the infarct-related artery was assessed by angiography 90 minutes after initiation of thrombolysis in patients who were seen within 6 hours after symptom onset. Patency rates of patients with an interval of </=3 hours and >3 hours between symptom onset and start of therapy were compared. There was no difference for Thrombolysis in Myocardial Infarction (TIMI) grade 3 perfusion after front-loaded alteplase (72.5% vs 76. 3%) and reteplase (63.6% vs 63.2% ) between the 2 groups. In contrast, in patients treated with streptokinase (36.8% vs 27.6%, P =.09), anisoylated plasminogen streptokinase activator complex (59. 5% vs 34.8%, P =.004), and urokinase (62.3% vs 41.7%, P =.03), TIMI 3 patency decreased with the increasing interval between symptom onset and initiation of therapy. We conclude from our data that the thrombolytic efficacy of recombinant tissue-type plasminogen activator and reteplase does not decrease with the increasing interval between symptom onset and initiation of therapy. In contrast, after anisoylated plasminogen streptokinase activator complex, streptokinase, and urokinase treatment, a decrease in patency, especially TIMI-3 patency in patients treated after >3 hours after symptom onset, was observed. These results may influence the choice of the thrombolytic agent in patients who are seen >3 hours after symptom onset.


A new colorimetric method for determination of creatine phosphokinase.
A new colorimetric method has been developed for the determination of creatine phosphokinase (CPK). This method is based on the reaction of creatine, formed enzymatically from creatine phosphate and ADP, with p-nitrophenylglyoxal (PNPG) under alkaline conditions to produce a colored product which absorbs maximally at 480 nm. At 25 degrees C the reaction was complete after 10 min in 0.1 M sodium pyrophosphate, pH 12, containing 0.15 M sodium ascorbate. The colored product was stable for at least 24 h and obeyed Beer's law in the range 0.005-0.05 mM creatine. The color reaction was used to determine the activity of CPK in serum and tissue extracts. The results obtained by this method agreed well with the results obtained by other available methods for CPK determination. However, the PNPG method was more rapid and more sensitive than other colorimetric methods and required a single chromogenic reagent.


Chinese experience on comparison of clinical efficacy and safety of hemodialysis and peritoneal dialysis in the treatment of diabetic kidney failure: a systematic review and meta-analysis.
This meta-analysis aims to compare the efficacy and safety of peritoneal dialysis (PD) and hemodialysis (HD) in the treatment of diabetic kidney failure. Five databases were selected to retrieve research on PD and HD for diabetic kidney failure until 6 August 2022. A fixed-effects or random-effects model was utilized to calculate the standardized mean difference (SMD) or odds ratio (OR) based on the heterogeneity among studies. Sixteen studies were included. The results showed that patients with diabetic kidney failure treated with PD had lower levels of albumin, total protein, and systolic blood pressure (SBP) and higher levels of urine volume, creatinine, and blood urea nitrogen (BUN) and lower risk of cardiovascular and bleeding events, with significant statistical difference when compared with patients treated with HD (albumin: SMD = -1.22, 95%CI: -1.53, -0.91; total protein: SMD = -0.96, 95%CI: -1.16, -0.77; SBP: SMD = -0.35, 95%CI: -0.64, -0.06; urine volume: SMD = 0.68, 95%CI: 0.40, 0.96; creatinine: SMD = 0.49, 95%CI: 0.27, 0.72; BUN: SMD = 0.55, 95%CI: 0.25, 0.85; cardiovascular events: OR = 0.42, 95%CI: 0.28, 0.62; bleeding: OR = 0.41, 95%CI 0.27, 0.62). This meta-analysis summarized the advantages and disadvantages of PD and HD for treating diabetic kidney failure patients. Compared with HD, PD is more effective in preserving residual kidney function, reducing hemodynamic effect, and lowering the risk of bleeding and cardiovascular events in diabetic kidney failure patients, but it also predisposes to protein-energy malnutrition and increases the risk of infection.


Crystallization and preliminary X-ray diffraction studies of a replication initiator protein (RepE54) of the mini-F plasmid complexed with iteron DNA.
A replication initiator protein (RepE54) complexed with iteron DNA at its binding site was crystallized by the hanging drop vapor diffusion method. The crystals belong to monoclinic space group C2 with unit cell dimensions of a = 108.4 A, b = 81.9 A, c = 73.9 A, and beta = 121.5 degrees, where one molecule of the protein-DNA complex exists per asymmetric unit. They diffract X-rays up to 2.6 A resolution with synchrotron radiation.


Using the o,p'-DDT/p,p'-DDT ratio to identify DDT sources in China.
Dichlorodiphenyltrichloroethane (DDT) has been banned in China for decades, and yet high DDT concentrations are still being detected in the Chinese environment. This might be at least partly due to the current use of dicofol formulation, which contains DDT as an impurity. In this study, a method based on the ratios of two DDT isomers, o,p'-DDT and p,p'-DDT, was established and used to estimate the relative contributions of dicofol formulation and those of technical DDT to overall environmental DDT. Based on this method and field data from the literature, we calculated that dicofol formulation contributed >72% of atmospheric DDT in 2004 in the Taihu Lake region, China, and this value was >84% in summer when dicofol was applied for agricultural purposes. Sediment and soil, however, contained mostly residual DDT from the historical use of technical DDT. In most other regions of China, we found that dicofol contributed to a significant fraction of DDT in air samples.


Biomechanical and neuromuscular control characteristics of sit-to-stand transfer in young and older adults: A systematic review with implications for balance regulation mechanisms.
Falls are major health concerns in older adults. Sit-to-stand transfer is an important functional movement that can predict falling risk in older adults. Aging-associated declines in neuromechanical control of movement may negatively impact sit-to-stand performance. This systematic review aims to summarize differences in neuromechanical characteristics of younger vs. older adults that likely affect balance regulation during sit-to-stand. Five databases (Academic search complete, MEDLINE, APA PsycInfo, Pubmed, and SPORTDiscus) were systematically searched from January 1985 through March 2023. Three reviewers assessed the quality of methodology, study design, results, and risk of bias using the Appraisal tool for Cross-Sectional Studies. Studies reported neuromuscular and biomechanical characteristics during sit-to-stand in young versus older adults were included. Seventeen studies (343 older and 225 younger adults) were included. Compared to younger adults, older adults showed slower sit-to-stand time, higher trunk flexion, postural sway, agonist-antagonist muscle co-activation of the ankle and knee muscles, and lower ankle dorsiflexion torque. Lower magnitude and rate of vertical ground reaction force development and lower vertical momentum during rising were observed with aging during fast-speed sit-to-stand. There was heterogeneity among studies on sit-to-stand speed, foot position, use of arms, and seat height adjustability. Higher trunk angular displacement and velocity accompanied by higher anterior momentum, likely to compensate for knee extensor muscle weaknesses, may lead to higher postural sway upon standing and therefore require higher knee and ankle muscle co-activation to maintain balance stability. Thus, additional attention to trunk control strategies is needed during clinical evaluations.