Activity of chemotherapy with carboplatin plus paclitaxel in a recurrent mesonephric adenocarcinoma of the uterine corpus.
Malignant lesions derived from mesonephric (Wolffian) remnants are uncommon. The course of these tumors is usually indolent, and the recurrence has only been documented in nine cases. Because of the small number of cases, no current recommendations exist regarding treatment, and little is known about the response to chemotherapeutic agents. A 33-year-old woman was diagnosed with a mesonephric adenocarcinoma arising in the uterine corpus. Ten months after initial surgery and radiotherapy she presented with local and pulmonary relapse. Salvage chemotherapy with carboplatin plus paclitaxel was administered with a good response. Mesonephric adenocarcinomas are uncommon neoplasms. Their treatment remains elusive. We report a case of a recurrent uterine mesonephric adenocarcinoma that presented a good response to therapy with carboplatin plus paclitaxel. A review of the previous literature is also presented.


Tumor cell adhesion to frozen lymph node sections--a correlate of lymphatic metastasis in breast carcinoma models of human and rat origin.
The role of tumor cell adhesion in lymphatic metastasis of breast cancer was investigated in vitro using a rat mammary carcinoma model of four cell lines with different metastatic phenotypes, two human breast cancer cell lines, and cryostast sections of normal rat or human lymph nodes, respectively. A positive correlation was found between the adhesion levels obtained with three metastatic rat mammary cell lines (TMT-081 greater than MT-100M & TMT-50) and a non-metastatic line MT-W9B, the latter being 3-4 fold less adhesive to the lymph node sections than the metastatic tumors. This selective adhesion was specific, as it was not found with cryostat sections of rat liver and brain. Enzyme assays indicated that cell surface glycoproteins bearing terminal beta-galactoside residues were involved in the adhesion of the rat tumors. Adhesion of the human breast carcinoma cells Hs578T to sections of human lymph nodes was significantly higher than that of the normal breast epithelial cell line Hs578Bst, and comparable to adhesion of a second breast carcinoma line, MCF-7. Moreover, Hs578T cells isolated from regional lymph nodes of tumor-bearing nude mice were significantly more adhesive to human lymph node sections than the parental line. Adhesion of both human and rat tumors could be partially blocked by the addition of the synthetic peptide GRGDSPK and by antibodies directed to the beta 1 chain of integrin, suggesting that an integrin receptor may played a role in the adhesion. The results suggest that tumor cell adhesion to cryostat sections of lymph nodes is a correlate of the malignant phenotype in mammary tumors of diverse origins, and could be used to delineate the adhesion factors mediating lymphatic metastasis.


In vitro and in vivo chemotherapy screening of the divalent cation chelator 1,10-orthophenanthroline.
1,10-Orthophenanthroline (OP) is a divalent cation chelating agent with known cytotoxicity to human normal and malignant T-lymphocytes. To determine whether OP might be a useful anticancer agent with specific T cell toxicity, OP's effect on cell growth was determined on colony-forming cells. The assay used supported growth of both malignant lymphoid and normal myeloid colony-forming cells (CFU-C) and thus a direct comparison of OP's antilymphoid and antimyeloid toxicity was obtained. The malignant lymphoid cells tested were established from patients at relapse and were resistant to conventional chemotherapeutic agents in vitro. While OP was found to be toxic to all cells tested, some selective kill of malignant cells over CFU-C occurred. OP's cytotoxicity was time-dependent and a three-log enhanced kill occurred when the drug exposure time was increased from 1 to 24 h. When test cells were continously exposed to OP, the ID50 was less than 1 micrograms/ml for malignant lymphoid cells and the sensitivity index (SI = x ID50 CFU-C divided by x ID50 cell line) ranged from 1.5 to 3.0. The National Cancer Institute currently screens new compounds for antitumor activity by determining whether the test drug is toxic to a mouse lymphocytic leukemia cell line (P388). While the mouse P388 cells were sensitive to OP in vitro, no effect was seen when OP was administered in vivo, even when schedules designed to take advantage of OP's time-dependent toxicity were used. Since malignant cells were sensitive to OP (ID50 less than 1 micrograms/ml), and some selectivity over CFU-C occurred (SI greater than 1), OP may be a useful agent for control of leukemic cell growth in vitro. However, since OP did not control the growth of P388 cells in vivo, additional studies designed to enhance the therapeutic index of OP in vivo are needed.


The superiority of ketofol and etomidate against propofol or thiopental anesthesia for ECT.
Most anesthetic drugs used for electroconvulsive therapy (ECT) have dose-dependent anticonvulsive effects, counter-acting seizure induction, lowering seizure quality. However, a consummate drug for ECT anesthesia has not yet been established. Therefore, in this study, we aimed to investigate the effects of etomidate, thiopental, propofol and co-administration of ketamine-propofol (ketofol) on seizure quality and hemodynamic safety. Registries of 121 patients (1077 sessions) were retrospectively evaluated. The effects of anesthetics on ECT-related parameters (stimulation charge, central seizure duration, number of failed stimulation trials, mean arterial pressure, and peak heart rate) were analyzed via linear mixed-effects models. Overall, the seizure duration decreased, and the stimulation charge increased in time with continuing sessions within a course of ECT. The decrease in seizure duration and the increase in required stimulation charge was significantly lower with etomidate and ketofol. Additionally, ketofol was significantly related to a lower number of failed stimulation trials compared to propofol. Ketofol and propofol use was associated with a significantly lower postictal mean arterial pressure. Ketofol and etomidate were equivalently superior in the rate of decrease in seizure duration and the required elevation in stimulus charge, which would interpret into valuable clinical guidance, especially for "seizure resistant" patients, and their use may potentially lower ECT related cognitive side effects.


Observational studies of traditional Chinese medicine may provide evidence nearly consistent with the randomized controlled trials: A meta-epidemiological study.
In traditional Chinese medicine (TCM) field, the benefits of observational studies was more significant. Whether the evidence from observational studies agreed with RCTs in the field of TCM was still unclear. A meta-epidemiological study was conducted. Meta-analyses and systematic reviews including cohort studies and case-control studies of TCM were included. Ratio of odds ratio (ROR) of randomized controlled trials and observational studies were calculated individually and intercomparisons were conducted by pool analysis. A total of 11 studies and 30 outcome pairs were included in the pool analysis. Using results from the observational studies as the reference group, the polled ROR comparing randomized controlled trials with observational studies was 1.23 (95% confidence interval 1.05 to 1.44, and 95% prediction interval 0.90 to 1.68). The ROR by subgroup analysis were 1.15 (95% confidence interval 0.96 to 1.38; 95% prediction interval 0.95 to 1.39) and 1.12 (95% confidence interval 0.86 to 1.46; 95% prediction interval 0.51 to 2.47) for cohort studies and case-control studies, respectively. There is difference in pooled results between randomized controlled studies and observational studies on TCM. However, the prediction interval shows the difference is small, which suggests observational studies of TCM can be included in data analysis to provide evidence for TCM. Future studies are needed to verify the above conclusion.


A multicenter non-inferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stages IB1, IB2, and IIA1): study protocol of the LAUNCH 2 trial.
A retrospective study and a randomized controlled trial published in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early-stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology; therefore, this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stages IB1, IB2, and IIA1) patient survival under stringent operation standards and consistent surgical oncologic principles. This is an investigator-initiated, Prospective, Randomized, Open, Blinded End-point (PROBE)-controlled non-inferiority trial. A total of 780 patients with stage IB1, IB2, and IIA1 cervical cancer will be enrolled over a period of 3 years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed up for at least 5 years. The primary endpoint will be 5-year progression-free survival, and secondary endpoints include 5-year overall survival, recurrence, and quality of life measurements. The debate on laparoscopic versus abdominal RH is still ongoing, and high-quality evidences are needed to guide clinical practice. The study results will provide more convincing evidence-based information for early-stage cervical cancer patients and their gynecologic cancer surgeons in their choice of surgical method. ClinicalTrials.gov NCT04929769 . Registered on 18 June 2021.


FOXO1 regulates Th17 cell-mediated hepatocellular carcinoma recurrence after hepatic ischemia-reperfusion injury.
Hepatic ischemia-reperfusion injury (IRI) is considered as an effecting factor for hepatocellular carcinoma (HCC) recurrence. Th17/Treg cells are a pair of essential components in adaptive immune response in liver IRI, and forkhead box O1 (FOXO1) has the properties of maintaining the function and phenotype of immune cells. Herein, we illuminated the correlation and function between Th17/Treg cell balance and FOXO1 in IRI-induced HCC recurrence. RNA sequencing was performed on naive CD4+ T cells from normal and IRI model mice to identify relevant transcription factors. Western blotting, qRT-PCR, immunohistochemical staining, and flow cytometry were performed in IRI models to indicate the effect of FOXO1 on the polarization of Th17/Treg cells. Then, transwell assay of HCC cell migration and invasion, clone formation, wound healing assay, and Th17 cells adoptively transfer was utilized to assess the function of Th17 cells in IRI-induced HCC recurrence in vitro and in vivo. Owning to the application of RNA sequencing, FOXO1 was screened and assumed to perform a significant function in hepatic IRI. The IRI model demonstrated that up-regulation of FOXO1 alleviated IR stress by attenuating inflammatory stress, maintaining microenvironment homeostasis, and reducing the polarization of Th17 cells. Mechanistically, Th17 cells accelerated IRI-induced HCC recurrence by shaping the hepatic pre-metastasis microenvironment, activating the EMT program, promoting cancer stemness and angiogenesis, while the upregulation of FOXO1 can stabilize the liver microenvironment homeostasis and alleviate the negative effects of Th17 cells. Moreover, the adoptive transfer of Th17 cells in vivo revealed its inducing function in IRI-induced HCC recurrence. These results indicated that FOXO1-Th17/Treg axis exerts a crucial role in IRI-mediated immunologic derangement and HCC recurrence, which could be a promising target for reducing the HCC recurrence after hepatectomy. Liver IRI affects the balance of Th17/Treg cells by inhibiting the expression of FOXO1, and the increase of Th17 cells has the ability to induce HCC recurrence through EMT program, cancer stemness pathway, the formation of premetastatic microenvironment and angiogenesis.


Comparison of COVID-19 Preprint and Peer-Reviewed Versions of Studies on Therapies for Critically Ill Patients.
Significant increases in the volume of preprint articles due to the COVID-19 pandemic, we examined the reliability of preprint articles compared to their peer-reviewed publications. Preprint articles evaluating experimental studies of select treatment options (anticoagulation, dexamethasone, hydroxychloroquine, remdesivir, and tocilizumab) for COVID-19 in the critically ill, available in a peer-reviewed publication were screened for inclusion within Altmetric (n = 2040). A total of 40 articles met inclusion criteria, with 21 being randomly selected for evaluation. The primary outcome of this evaluation was a change in a study's reported primary outcome or statistical significance between preprint and peer-reviewed articles. Secondary outcomes included changes in primary/secondary outcome effect size and change in study conclusion. One article (4.8%, 95% CI 0.12%-23.8%) had a change in the primary outcome. Seven articles (33.3%, 95% CI 14.6%-57.0%) had a change in the primary outcome's effect measure. Five studies (23.8%, 95% CI 8.2%-47.2%) had changes in statistical significance of at least one secondary outcome. Four studies (19.0%, 95% CI 5.4%-41.9%) had a change in study conclusion. In preprint articles of COVID-19 treatments, the provided primary outcome is generally reliable, while interpretation of secondary outcomes should be made with caution, while awaiting completion of the peer-review process.


Surgical management of gynecologic rhabdomyosarcoma.
The multidisciplinary treatment strategy for rhabdomyosarcoma (RMS) of the female gynecologic system is evidence of the progress made in the management of many childhood cancers. Previously, initial radical surgery (eg, complete vaginectomy, hysterectomy, and pelvic exenteration) and less effective single-agent chemotherapeutic agents were used with suboptimal results. Over the past 30 years, there has been an increase in overall survival with gynecologic RMS and a significant decrease in the hysterectomy and vaginectomy rates. The usual recommended treatment strategy for gynecologic RMS is initial biopsy to establish the diagnosis, followed by neoadjuvant chemotherapy. The specific chemotherapy regimen is selected based on the risk stratification of the particular patient, and this will often allow a more conservative surgical approach to be used, with the goal of complete tumor resection. Radiation therapy is considered before definitive surgical resection with minimal response to chemotherapy or after definitive surgical resection with positive margins. Recurrent or persistent RMS, including RMS of the female gynecologic system, represents a very aggressive disease with poor outcome. In these cases, aggressive management, including experimental chemotherapy agents and organ-sacrificing surgery, is often indicated to afford any chance of long-term survival. Continued enrollment of a high proportion of these patients into ongoing prospective clinical trials should allow the outcomes to continue to improve.


Multicenter prospective study of stereotactic body radiotherapy for previously untreated solitary primary hepatocellular carcinoma: The STRSPH study.
To prospectively evaluate the efficacy and safety of stereotactic body radiotherapy (SBRT) for patients with previously untreated solitary primary hepatocellular carcinoma (HCC). The main eligibility criteria included the following: (1) primary solitary HCC; (2) no prior treatment for HCC; (3) Child-Turcotte-Pugh score of seven or less; and (4) unsuitability for or refusal of surgery and radiofrequency ablation (RFA). The prescribed dose of SBRT was 40 Gy in five fractions. The primary endpoint was 3-year overall survival (OS); the secondary endpoints included local progression-free survival (LPFS), local control (LC), and adverse events. The accrual target was 60 patients, expecting a 3-year OS of 70% with a 50% threshold. Between 2014 and 2018, 36 patients were enrolled; enrollment was closed early because of slow accrual. The median tumor size was 2.3 cm. The median follow-up at the time of evaluation was 20.8 months. The 3-year OS was 78% (95% confidence interval [CI]: 53%-90%). The 3-year LPFS and LC proportion were 73% (95% CI: 48%-87%) and 90% (95% CI: 65%-97%), respectively. Grade 3 or higher SBRT-related toxicities were observed in four patients (11%), and grade five toxicities were not observed. This study showed acceptably low incidence of SBRT-related toxicities. LC and OS after SBRT were comparable for previously untreated solitary HCC for patients unfit for resection and RFA. Although a definitive conclusion cannot be drawn by this study, the promising results indicate that SBRT may be an alternative option in the management of early HCC.


A model for implementing oral health-promoting school: Integration with dental students' educational curriculum: A protocol study.
Schools are ideal setting for children's oral health-promoting programs. It is an integrated model for oral health-promoting schools (OHPS) with the capacities of dental school's curriculum and dental students as workforces. In this protocol, the principle of planning and implementation of the oral health program is described. Based on the PRECEDE-Policy, Regulatory, and Organizational Constructs in Educational and Environmental Development (PROCEED) planning model, a framework for determining the potential predisposing, reinforcing, and enabling factors that could be intervening was diagnosed. To adapt the phases of the planning model for integration of the "OHPS" principles and the dental students' curriculum, the following steps are supposed to be considered: Phases 1-5 which are to assess the baseline data will include the assessment of children oral health status and parents and teachers' knowledge, attitude, and performance. Phase 6 or implementation phase will be allocated to oral health education interventions for students, parents, and teachers, professional screening, prevention, and referral. Phase 7 or the process assessment phase will be to record the number of screened students, the amount of fissure sealant and fluoride provision, and percentage of trained parents and teachers. Phase 8 or the impact assessment phase will assess the students' improvement in knowledge and practice, decayed, missing, and filled teeth scores, teachers and mothers' oral health attitudes and behaviors, and brushing and flossing behaviors. At the last, cost analysis of the program and long-term monitoring of the interventions is suggested. In case that the effectiveness of this model is proven, it can be implemented by other dental schools for the primary schools in their regions. Considering the number and distribution of dental schools in the country, this model is executable as targeted population oral health promotion approach in 6-12-year-old schoolchildren.


Root vertical spatial stress: A method for enhancing rhizosphere effect of plants in subsurface flow constructed wetland.
The depth of the substrate of subsurface flow (SSF) constructed wetlands (CWs) is closely related to their cost and operation stability. To explore the physiological regulation mechanism of wetland plants and pollutant removal potential of SSF CWs under "vertical spatial stress of roots" (by greatly reducing the depth of the substrate in SSF CWs to limit the vertical growth space of roots, VSSR), the physiological response and wetland purification effect of a 0.1 m Canna indica L. CW under VSSR were studied compared with conventional SSF CWs (0.6 m, 1.2 m). The results demonstrated that VSSR significantly enhanced the dissolved oxygen (DO) concentration (p < 0.05) within the SSF CWs, with the DO in 0.1 m CW remaining stable at over 3 mg/L. Under the same hydraulic retention time (HRT), VSSR significantly improved the removal effect of pollutants (p < 0.05). The removal rates of COD, NH4+-N, and total phosphorus (TP) remained above 87%, and the mean removal rates of total nitrogen (TN) reached 91.71%. VSSR promoted the morphological adaptation mechanisms of plants, such as significantly increased root-shoot ratio (p < 0.05), changed biomass allocation. Plants could maintain the stability of the photosynthetic mechanism by changing the distribution of light energy. The results of microbial community function prediction demonstrated that aerobic denitrification was the main mechanism of N transformation in the 0.1 m CW under VSSR. VSSR could induce the high root activity of plants, augment the concentration of root exudates, enhance the redox environment of the plant rhizosphere, further foster the enrichment of aerobic denitrifying bacteria, and strengthen the absorption efficiency of wetland plants and substrate, thus achieving an efficient pollutant removal capacity. Studies showed that VSSR was an effective means to enhance the rhizosphere effect of plants and pollutant removal in SSF CWs.


Prognostic significance of tumor deoxyribonucleic acid content in surgically resected small-cell carcinoma of lung.
The prognostic role of deoxyribonucleic acid flow cytometry was investigated in 53 cases of surgically resected small-cell lung cancer. Deoxyribonucleic acid aneuploidy was detected in 26 patients (49.1%), the remaining tumors being either diploid or tetraploid. Patients with aneuploid tumors had a significantly reduced 2-year survival (38.5%) when compared with patients with diploid or tetraploid tumors (70.3%; p less than 0.05). This finding was independent of tumor stage on multiple logistic regression analysis. Diploid or tetraploid deoxyribonucleic acid content was associated with a particularly good 2-year survival (85%) in N0 or N1 disease. Tumor deoxyribonucleic acid ploidy should be taken into account in planning of management and assessment of prognosis in small-cell lung cancer.


Phillyrin attenuates norepinephrine-induced cardiac hypertrophy and inflammatory response by suppressing p38/ERK1/2 MAPK and AKT/NF-kappaB pathways.
Phillyrin, a well-known natural compound from the dried fruits of Forsythia suspensa (Thunb.) Vahl., has shown anti-inflammatory, antioxidant and anti-virus activities as well as renal protective effects on diabetic nephropathy. In this study, we investigated whether phillyrin attenuated cardiac hypertrophy induced by catecholamine in vivo and in vitro, and explored the underlying mechanisms. Cardiac hypertrophy was induced in C57BL/6 mice by subcutaneous injection of norepinephrine (NE, a key catecholamine), and in rat cardiomyoblasts (H9c2) by stimulation with NE in vitro. Our results showed that administration of phillyrin (100 mg/kg, i.p. for 15 days) significantly improved cardiac function, histopathological changes, cardiac hypertrophy and decreased the upregulated hypertrophic markers (ANP, BNP, and β-MHC). Moreover, treatment with phillyrin obviously reduced the infiltration of the CD68 positive macrophages and the mRNA expression of proinflammatory genes (IL-1β, IL-6, and TNF-α) in left ventricular tissue. In addition, treatment with phillyrin markedly inhibited the phosphorylation of p38 MAPK, ERK1/2, AKT, and NF-κB p65 in heart tissues. Furthermore, in NE-treated H9c2 cells, pretreatment with phillyrin clearly attenuated cardiomyocyte hypertrophy, reduced ROS production and inhibited the phosphorylation of p38 MAPK, ERK1/2, AKT, and NF-κB p65 in vitro. Collectively, our results demonstrate that phillyrin effectively alleviates NE-induced cardiac hypertrophy and inflammatory response by suppressing p38 MAPK/ERK1/2 and AKT/NF-κB signaling pathways.


Organization of contractile protein genes within the 88F subdivision of the D. melanogaster third chromosome.
We have investigated contractile protein gene arrangement within the 88F subdivision of the Drosophila melanogaster third chromosome. We show that at least five antigenically related myofibrillar proteins, three of which accumulate only within indirect flight muscles, are encoded by a 20 kilobase chromosome segment located 140 kilobases proximal to the act88F actin gene. The chromosome segment includes two transcribed regions, each of which directs the synthesis of multiple mRNAs. RNA blot-hybridization experiments and DNA sequencing suggest that overlapping transcripts are generated by differential RNA splicing. The nucleotide sequence also establishes that two of the encoded proteins are tropomyosin isoforms, and two are related to tropomyosin. The arrangement of myofibrillar genes parallels the distribution of third chromosome mutations that disrupt indirect flight muscle formation.


Injury of the Internal Carotid Artery During Dissection of a Craniopharyngioma via the Pterional Approach: Case Report.
Among the various causes of intraoperative neurosurgical complications, a major arterial injury is one of the most devastating. Herein, the authors present a case of a 76-year-old patient who underwent removal of a craniopharyngioma via the pterional approach and experienced severe damage of her sclerotic left internal carotid artery because it was retracted excessively by a brain spatula, which resulted in complete sacrifice of the vessel. Despite stable parameters on intraoperative monitoring of motor evoked potentials and sufficient collateral blood flow, confirmed by Doppler flowmetry, a large infarct in the left cerebral hemisphere was noted after surgery. Although retraction of movable arteries, veins, and cranial nerves can often be done safely during neurosurgical procedures for effective exposure of the operative field, forced displacement of a sclerotic internal carotid artery in its paraclinoid portion anchored to the fixed distal dural ring should definitely be avoided because it poses a significant risk of major vessel damage.


RNA from LPS-stirnulated macrophages induces the release of tumour necrosis factor-alpha and interleukin-1 by resident macrophages.
The effect of exogenous RNA on many cellular functions has been studied in a variety of eukaryotic cells but there are few reports on macrophages. In the present study, it is demonstrated that cytoplasmatic RNA extracted from rat macrophages stimulated with Escherichia coli lipopolysaccharide (LPS), referred to as L-RNA, induced the release of TNF-alpha and IL-1 from monolayers of peritoneal resident macrophages. The activity of L-RNA was not altered by polymyxin B but was abolished by ribonuclease (RNase) pretreatment, indicating the absence of LPS contamination and that the integrity of the polynucleotide chain is essential for this activity. Both the poly A(-) and poly A(+) fractions obtained from L-RNA applied to oligo(dT)-cellulose chromatography induced TNF-alpha and IL-1 release. The L-RNA-induced cytokine release was inhibited by dexamethasone and seemed to be dependent on protein synthesis since this effect was abolished by cycloheximide or actinomycin-D. The LPS-stimulated macrophages, when pre-incubated with [5-(3)H]-uridine, secreted a trichloroacetic acid (TCA) precipitable material which was sensitive to RNase and KOH hydrolysis, suggesting that the material is RNA. This substance was also released from macrophage monolayers stimulated with IL-1beta but not with TNF-alpha, IL-6 or IL-8. The substance secreted ((3)H-RNA) sediments in the 4-5S region of a 5-20% sucrose gradient. These results show that L-RNA induces cytokine secretion by macrophage monolayers and support the idea that, during inflammation, stimulated macrophages could release RNA which may further induce the release of cytokines by the resident cell population.


Improving the Fenton catalytic performance of FeOCl using an electron mediator.
FeOCl Fenton-like catalyst has drawn much attention due to its high catalytic activity. Nevertheless, the potential application of FeOCl is significantly hindered by the sluggish reduction kinetics of Fe3+ to active Fe2+. Here, we report that the incorporation of Fe - O-Mo electron mediator into FeOCl via forming a FeOCl/MoS2 composite can facilitate the Fe2+ regeneration through the oxidation of Mo4+ to Mo6+, which boosts the hydroxyl radicals yields, thus leading to a significantly improved catalytic performance. The removal efficiency of methylene blue (MB, 50 mg L-1) achieves ∼100% within 2 min. with low dosage of FeOCl/MoS2 (0.2 g L-1) and H2O2 (0.6 mM). FeOCl/MoS2 not only has broad working pH range (∼3 - 9) and high salinity tolerance (100 mM), but also capable to degrade various organic pollutants. For practical application, the fabricated FeOCl/MoS2 membrane effectively degrades continuous MB flow. This study demonstrates that incorporating an electron mediator is an effective way to improve the catalytic performance of heterogeneous Fenton-like catalysts.


Gastric volvulus in children: report of two cases.
Two cases of gastric volvulus in children are reported, one acute and one chronic. The diagnosis should be suspected as an unusual cause of chronic recurring upper abdominal pain or in acute gastric obstruction. The radiographic appearances of these patients are presented. Anterior gastropexy has produced good results in both the patients described.


Antibodies that block virus attachment to Vero cells are a major component of the human neutralizing antibody response against dengue virus type 2.
Epidemiological data strongly implicate a role for the host humoral immune response in both protection against and exacerbation of dengue virus-caused disease. In an effort to characterize elements of the normal human immune response against dengue virus we have addressed the issue of antibody-mediated neutralization of dengue virus. We show here the ability of both mouse monoclonal antibody 3H5 and human anti-dengue neutralizing sera to block binding of dengue-2 virus to monkey kidney (Vero) cells. Since Vero cells possess virus receptors but not Fc receptors we conclude that the major effect of host neutralizing antibodies is to block virus attachment to Vero cell dengue virus receptors. Analysis of 61 patient antisera yielded good correlation (Pearson's coefficient = 0.90; P < 0.001) between neutralizing activity and ability to block virus-cell attachment suggesting that antibody-mediated neutralization of dengue virus occurs primarily extracellularly and less by a postattachment mechanism as has been described for certain other viruses.


Probing the interaction of a quercetin bioconjugate with Bcl-2 in living human cancer cells with in-cell NMR spectroscopy.
In-cell NMR spectroscopy has emerged as a powerful technique for monitoring biomolecular interactions at an atomic level inside intact cells. However, current methodologies are inadequate at charting intracellular interactions of nonlabeled proteins and require their prior isotopic labeling. Herein, we describe for the first time the monitoring of the quercetin-alanine bioconjugate interaction with the nonlabeled antiapoptotic protein Bcl-2 inside living human cancer cells. STD and Tr-NOESY in-cell NMR methodologies were successfully applied in the investigation of the binding, which was further validated in vitro. In-cell NMR proved a very promising strategy for the real-time probing of the interaction profile of potential drugs with their therapeutic targets in native cellular environments and could, thus, open a new avenue in drug discovery.


Preparing for an epidemic of limited health literacy: weathering the perfect storm.
Empirical data collected over the past two decades have demonstrated strong links between low literacy skills and poor health outcomes, including mortality. Recently, the Educational Testing Service released a relevant report predicting that our nation is at great risk as a result of declining adult literacy, shifting demographics, and a changing economy. It is essential to understand how these educational and socioeconomic changes will impact health care and prepare for a likely epidemic of limited health literacy. A formative public health response should include seeking out new strategies for health systems to advance our public's health literacy, while working with the educational system to better equip younger generations with the knowledge and skills necessary to navigate health care.


Different Scores Predict the Value of Hemorrhagic Transformation after Intravenous Thrombolysis in Patients with Acute Ischemic Stroke.
To evaluate the value of the Alberta stroke project early CT score (ASPECTS), DRAGON score, SEDAN score, and HAT score in predicting hemorrhagic transformation (HT) after intravenous thrombolysis in patients with acute ischemic stroke (AIS). The clinical data of 248 AIS patients treated with intravenous thrombolysis in our hospital from December 2017 to December 2019 were analyzed. According to the prognosis, all patients were divided into the non-HT group (n = 200) and the HT group (n = 48). Univariate analysis and multivariate logistic regression models were used to analyze clinical data to determine the influencing factors of HT after intravenous thrombolysis in AIS patients. The receiver operating characteristic curve was used to evaluate the ASPECTS, DRAGON, SEDAN, and HAT scores to the value of predicting HT after intravenous thrombolysis in AIS patients. The lower the ASPECTS score and the higher the DRAGON, SEDAN, and HAT scores, the higher the incidence of HT after intravenous thrombolysis in AIS patients (P < 0.05). The results of multivariate logistic regression analysis showed that the patient's age, atrial fibrillation, baseline NIHSS score, early signs of infarction on admission with head CT, time from onset to thrombolytic therapy, and thrombolytic drugs were all independent factors affecting intravenous thrombolysis in AIS patients (P < 0.05). The area under the curve (AUC) of the predictive value of ASPECTS for HT is 0.895 (95% CI 0.813-0.977). When the optimal cutoff value is 0.607, the sensitivity is 100% and the specificity is 60.7%. The AUC of the predictive value of DRAGON for HT is 0.877 (95% CI 0.790-0.964). When the optimal cutoff value is 0.665, the sensitivity is 84.4% and the specificity is 82.1%. The AUC of the predictive value of SEDAN for HT is 0.764 (95% CI 0.638-0.890). When the optimal cutoff value is 0.474, the sensitivity is 78.6% and the specificity is 68.8%. The AUC of the predictive value of HAT for HT is 0.777 (95% CI 0.651-0.903). When the optimal cutoff value is 0.509, the sensitivity is 68.8% and the specificity is 82.1%. The lower the ASPECTS score and the higher the DRAGON, SEDAN, and HAT scores, the higher the incidence of HT in AIS patients. The patient's age, atrial fibrillation, baseline NIHSS score, early signs of infarction on admission with head CT, time from onset to thrombolytic therapy, and thrombolytic drugs are all independent factors affecting HT in AIS patients. The scores of ASPECTS, DRAGON, SEDAN and HAT have certain value in predicting HT after intravenous thrombolysis in AIS patients, and the predicted value of ASPECTS score is the best.


Detection of ankle fractures using deep learning algorithms.
Early and accurate detection of ankle fractures are crucial for optimizing treatment and thus reducing future complications. Radiographs are the most abundant imaging techniques for assessing fractures. Deep learning (DL) methods, through adequately trained deep convolutional neural networks (DCNNs), have been previously shown to faster and accurately analyze radiographic images without human intervention. Herein, we aimed to assess the performance of two different DCNNs in detecting ankle fractures using radiographs compared to the ground truth. In this retrospective case-control study, our DCNNs were trained using radiographs obtained from 1050 patients with ankle fracture and the same number of individuals with otherwise healthy ankles. Inception V3 and Renet-50 pretrained models were used in our algorithms. Danis-Weber classification method was used. Out of 1050, 72 individuals were labeled as occult fractures as they were not detected in the primary radiographic assessment. Single-view (anteroposterior) radiographs was compared with 3-views (anteroposterior, mortise, lateral) for training the DCNNs. Our DCNNs showed a better performance using 3-views images versus single-view based on greater values for accuracy, F-score, and area under the curve (AUC). The highest sensitivity was 98.7 % and specificity was 98.6 % in detection of ankle fractures using 3-views using inception V3. This model missed only one fracture on radiographs. The performance of our DCNNs showed that it can be used for developing the currently used image interpretation programs or as a separate assistant solution for the clinicians to detect ankle fractures faster and more precisely. III.


Manipulation of estrous cycle in dwarf goat (Capra hircus) using estrumate under different management conditions.
A study was conducted to elucidate the effectiveness of exogenous estrumate (prostaglandin F(2alpha)) treatment as a synchronizing agent for Dwarf goats and to establish the progesterone levels at different reproductive stages under two different environmental and nutritional conditions. Female Dwarf goats of various ages were raised, 10 each at two sites, viz. the Bio-Saline Research Substation (BSRS), Lahore and at the Nuclear Institute for Agriculture and Biology (NIAB), Faisalabad. The animals at the NIAB farm were reared on non-saline soil under normal grazing conditions, while the other animal lot was raised on salt-affected lands at the BSRS, Lahore and was fed on non-conventional fodders produced by salt-affected lands. The animals received two intramuscular doses (0.5 ml each) of estrumate (125 microg/ml) at 10 days interval. Nineteen of the 20 animals exhibited estrus after 56-72 h of the second injection of estrumate. The mean progesterone concentration in the NIAB and BSRS lots was 2.8 and 2.4 ng/ml, respectively, at the time of second injection and declined to the basal level (estrus) within 48 h. A gradual increase in the progesterone level occurred during the metestrus, reaching maximum during the luteal phase when it was 6.3 and 6.7 ng/ml in NIAB-lot and BSRS-lot, respectively. During the proestrous phase, the progesterone level decreased to the basal level (0.1 ng/ml) at the onset of the next estrus after 22 days. The length of the induced or natural estrous cycle (20+/-1 days) was not affected by the estrumate treatment, nor by the environmental and nutritional conditions. Breeding was allowed after the natural estrous cycle at the onset of third estrus and a high fertility rate (95%) was achieved. The progesterone concentrations remained at higher level (4.5-9.4 ng/ml) throughout the gestation period, declined gradually in the prepartum period, and dropped to the basal level at the completion of parturition. The results suggested that estrumate is an efficient synchronizing agent for the Dwarf goats kept under different environmental-nutritive conditions and that the progesterone profile is a useful indicator to assess the reproductive status of the goats.


CaMKII regulates neuromuscular activity and survival of the human blood fluke Schistosoma mansoni.
Calcium/calmodulin dependant protein kinase II (CaMKII), an important transducer of Ca2+ signals, orchestrates multiple cellular functions in animals. Here we investigated the importance of CaMKII to Schistosoma mansoni, a blood parasite that causes human schistosomiasis. We demonstrate that phosphorylated (activated) CaMKII is present in cercariae, schistosomula and adult worms, and show that striking activation occurs in the nervous tissue of these parasite life-stages; CaMKII was also activated in the tegument and muscles of adult worms and the vitellaria of females. Exposure of worms to the anti-schistosomal drug praziquantel (PZQ) induced significant CaMKII activation and depletion of CaMKII protein/activation in adult worms resulted in hypokinesia, reduced vitality and death. At medium confidence (global score ≥ 0.40), S. mansoni CaMKII was predicted to interact with 51 proteins, with many containing CaMKII phosphorylation sites and nine mapped to phosphoproteome data including sites within a ryanodine receptor. The CaMKII network was functionally enriched with mitogen-activated protein kinase, Wnt, and notch pathways, and ion-transport and voltage-dependent channel protein domains. Collectively, these data highlight the intricacies of CaMKII signalling in S. mansoni, show CaMKII to be an active player in the PZQ-mediated response of schistosomes and highlight CaMKII as a possible target for the development of novel anti-schistosome therapeutics.


Safety profile of prophylactic rescue dosing of immediate-release oral opioids in cancer patients.
Appropriate prophylactic rescue dosing of opioids is considered effective for cancer pain relief, but no study has reported the safety of such prophylactic rescue. We compared the safety of prophylactic rescue dosing of immediate-release oral opioids with that of regular rescue dosing. The study included 103 cancer patients who used either immediate-release morphine syrup or immediate-release oxycodone powder at Shizuoka Cancer Center between January and December 2016. Patients were divided into those who mostly used (prophylactic group) and those who never used (regular group) prophylactic rescue doses of opioids and compared the incidence of adverse events (AEs). We also investigated whether the prophylactic rescue dose negatively interfered with its objective activity, such as meals. Incidence of each AE in the prophylactic versus regular groups was as follows: somnolence, 20.6% versus 14.3%; nausea, 22.1% versus 17.1%; constipation, 19.1% versus 20.0%; urinary retention, 1.5% versus 2.9%; delirium, 4.4% versus 8.6%; and pruritus, 0% versus 2.9%. No serious AE associated with prophylactic rescue dosing was observed. No significant difference was observed in the incidence of any AE between the two groups (p > 0.05, Fisher's exact test). No AE interfered with the objective activity of the prophylactic rescue dose. Incidence of AEs associated with prophylactic rescue dosing is not different from that associated with regular rescue dosing. In addition, the prophylactic rescue dose did not adversely affect its objective activity, suggesting the safety of appropriate prophylactic rescue dosing was similar to that of regular rescue dosing. The study approval number in the institution; H29-J30-29-1-3. Registered June 5, 2017.


Late intracranial haemorrhage and subsequent carotid-cavernous sinus fistula after fracture of the facial bones.
Carotid-cavernous sinus fistula is an arteriovenous fistula between the internal carotid artery and the cavernous sinus, and is usually caused by a traumatic tear or a ruptured aneurysm of the cavernous segment of the internal carotid artery. We describe a rare case of delayed intracranial haemorrhage and carotid-cavernous sinus fistula that presented 3 weeks after fracture of the facial bones. The patient developed orbital apex syndrome including ptosis of upper eyelid, pulsatile exophthalmos, chemosis, loss of ocular motility, monocular blindness on the right, and numbness of the right infraorbital region. After transcatheter intra-arterial embolisation, the ptosis and chemosis improved.


Expanding the Pipeline to Teach: Recruiting Future Urban Teachers of Color Through a Dual Enrollment Program.
This qualitative case study explores the perceptions of schools, schooling, and teaching prior to and after engagement in a dual enrollment program. Data from nine participants revealed insights into the ways pre-college students thought about careers in teaching, how experiences in the dual enrollment program shaped their interest in teaching, and their perceptions of the pathways to and aspirations for teaching. Pre-college students envisioned teaching as a career possibility due to intrinsic factors, such as intellectual interests and racial identity; these factors were reinforced by family and salient schooling experiences. The dual enrollment program confirmed prior interests in teaching through its focus on the education major, mentoring, and the opportunity to take college coursework at the host university.


An overnight sedimentation method: improving the diagnosis of tuberculosis when electrical centrifuge is not available.
An experimental comparative study was conducted in order to compare the positivity pattern of sputum microscopy using the direct and overnight sedimentation Ziehl-Neelsen (ZN) smears, direct and NaOCl pretreated centrifuged ZN smears and overnight sedimentation and NaOC1 pretreated centrifuged ZN smears methods. We examined 660 sputum smeared slides for the presence of acid-fast bacillus from 220 sputum samples. Compared with the direct microscopy method, positivity increased by 91.1% after centrifugation (P < 0.001, chi(2) = 18.27) and by 71.1% after overnight sedimentation (P < 0.001, chi(2) = 11.61). No statistical significant difference was observed between the results of two different concentration techniques (P > 0.05, chi(2) = 0.789). The application of overnight sedimentation (in a laboratory without electricity) and/or the centrifugation technique could make a positive impact on the effectiveness of national tuberculosis control programmes.


The heat shock protein antagonist 17-AAG potentiates the activity of enzastaurin against malignant human glioma cells.
Recent studies have suggested that the proliferation of malignant gliomas may result from activation of protein kinase C (PKC)-mediated pathways. Enzastaurin (LY317615), an acyclic bisindolylmaleimide, is an oral inhibitor of PKCbeta as well as other isoforms. The initial objective of this study was to assess the efficacy of enzastaurin in a series of malignant human glioma cell lines with diverse genomic alterations. Although enzastaurin independently produced a dose-dependent inhibition of cellular proliferation and decreased cell viability in each of the glioma cell lines examined, and partially down-regulated Akt and GSK3beta phosphorylation, median effective concentrations were at the upper limits of, or above, the clinically achievable range in all cell lines tested. We therefore examined whether the efficacy of enzastaurin could be enhanced by combination with the HSP90 antagonist, 17-AAG, which inhibits Akt and other signaling intermediates by a distinct mechanism. In comparison to the effect of enzastaurin alone, combination of enzastaurin with 17-AAG led to marked enhancement of antiproliferative and cytotoxic effects. Simultaneous exposure to both agents significantly increased the release of cytochrome c, as well as caspase 3 activation, Bax cleavage, and inhibition of Akt phosphorylation. Cells exposed to enzastaurin and 17-AAG also displayed a significant reduction in cell cycle regulatory proteins, such as CDK4 and CDK6. Taken together, these findings suggest that the efficacy of enzastaurin can be potentiated by the addition of 17-AAG, and indicate that combining molecularly targeted therapies may provide a more effective strategy than single-agent therapy to treat patients with malignant gliomas.


Iron-mediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis.
Previous phenotyping of glucose homeostasis and insulin secretion in a mouse model of hereditary hemochromatosis (Hfe(-/-)) and iron overload suggested mitochondrial dysfunction. Mitochondria from Hfe(-/-) mouse liver exhibited decreased respiratory capacity and increased lipid peroxidation. Although the cytosol contained excess iron, Hfe(-/-) mitochondria contained normal iron but decreased copper, manganese, and zinc, associated with reduced activities of copper-dependent cytochrome c oxidase and manganese-dependent superoxide dismutase (MnSOD). The attenuation in MnSOD activity was due to substantial levels of unmetallated apoprotein. The oxidative damage in Hfe(-/-) mitochondria is due to diminished MnSOD activity, as manganese supplementation of Hfe(-/-) mice led to enhancement of MnSOD activity and suppressed lipid peroxidation. Manganese supplementation also resulted in improved insulin secretion and glucose tolerance associated with increased MnSOD activity and decreased lipid peroxidation in islets. These data suggest a novel mechanism of iron-induced cellular dysfunction, namely altered mitochondrial uptake of other metal ions.


Jianqu fermentation with the isolated fungi significantly improves the immune response in immunosuppressed mice.
Jianqu, a classical formula of traditional Chinese medicine, is used clinically to treat symptoms like chill and fever headache, diarrhea and loss of appetite and act on patients with low immunity. However, the quality control of Jianqu fermentation is not well established, and its function in regulating the body's immunity still remains unclear. The present study firstly assesses the structure and diversity of fungal community during Jianqu fermentation and then investigates the immune regulating function of Jianqu extract in mouse model. The high-throughput sequencing is conducted to analyze the diversity and distribution of fungal community during the fermentation process of Jianqu, and then fungi with a high frequency and relative abundance are isolated. The immunosuppressed mice are induced by using cyclophosphamide (CTX) and used to evaluate the immune regulating function of Jianqu extract from natural fermentation or directed fermentation, respectively. With the fermentation, the diversity and distribution of fungal community significantly changed. The number of OTU (operational taxonomic unit) was gradually decreased from 223 ± 1 in the early phase to 201 ± 11 in the middle phase and to 175 ± 32 in the later phase of Jianqu fermentation. Generally, in genus level, Millerozyma, Debaryomyces and Rhizomucor showed a significant increase and became dominant in the mid or later phase of fermentation, while the Aspergillus displayed a decrease following the fermentation. However, Saccharomycopsis is a dominate species in surveyed samples. Next, six fungi strains with a high frequency and relative abundance, including Saccharomycopsis fibuligera, Millerozyma farinose, Hyphopichia burtonii, Rhizomucor pusillus, Lichtheimia ramosa, and Monascus purpureus, are isolated successfully. Interestingly, directed fermentation for Jianqu with the six isolated fungi strains could achieve similar morphological characteristics with the natural fermentation. Consistently, Jianqu extract from directed fermentation demonstrated a similar therapeutic effect on immune response as that of naturally fermented Jianqu. We firstly showed the significant change of structural profiles of fungal communities during Jianqu fermentation, and successfully isolated six dominate fungi strains in Jianqu. Interestingly, directed fermentation for Jianqu with these isolated strains could achieve a similar morphological characteristics and immune-modulating function as natural fermentation. It was suggested that Jianqu fermentation with functional fungi instead of natural microbes provide a new approach for the improvement of the production and quality control of the traditional Chinese medicine of Jianqu.


Tremulous jaw movements in rats: a model of parkinsonian tremor.
Several pharmacological and neurochemical conditions in rats induce 'vacuous' or 'tremulous' jaw movements. Although the clinical significance of these movements has been a subject of some debate, considerable evidence indicates that the non-directed, chewing-like movements induced by cholinomimetics, dopamine antagonists and dopamine depletions have many of the characteristics of parkinsonian tremor. These movements occur within the 3-7 Hz peak frequency range that is characteristic of parkinsonian tremor. Tremulous jaw movements are induced by many of the conditions that are associated with parkinsonism, and suppressed by several different antiparkinsonian drugs, including scopolamine, benztropine, L-DOPA, apomorphine, bromocriptine, amantadine and clozapine. Striatal cholinergic and dopaminergic mechanisms are involved in the generation of tremulous jaw movements, and substantia nigra pars reticulata appears to be a major basal ganglia output region through which the jaw movements are regulated. Future research on the neurochemical and anatomical characteristics of tremulous jaw movements could yield important insights into the brain mechanisms that generate tremulous movements.


Two new metabolites with cytotoxicities from deep-sea fungus, Aspergillus sydowi YH11-2.
Two new compounds, 2, 3, 5-trimethyl-6-(3-oxobutan-2-yl)-4H-pyran-4-one (1) and (2R)-2, 3- dihydro-7-hydroxy-6, 8-dimethyl-2-[(E)-prop-1-enyl] chromen-4-one (2), together with six known compounds (3-8), were isolated from a deep-sea fungus, identified as Aspergillus sydowi, by a bioassay-guided method. Their structures were elucidated by spectroscopic methods and the cytotoxicities were evaluated by SRB method.


Immunogenicity and effector functions of glutaraldehyde-treated rabbit and mouse immunoglobulin G.
Rabbit and mouse IgG treated with glutaraldehyde (GA) were immunogenic in homologous species. Glutaraldehyde treatment induced in the IgG molecule two types of antigenic determinants. One of them was found on the monomeric fraction of GA-treated rabbit IgG (haptenic determinant) and the other on the polymeric fraction (structural determinant). The haptenic determinants were found also on monoaldehyde-treated rabbit IgG and GA-treated Fab and Fc fragments. It was demonstrated that rabbit and mouse antibodies are specific for GA-treated IgG and have species specificity. While GA treatment did not alter the antigen binding capacity of rabbit IgG antibody, its effector functions (except protein A binding) were much affected. Thus it was found that GA treatment enhances IgG ability to react with rheumatoid factor, reduces drastically its capacity to activate the complement system, abolishes the cytophilic properties of IgG and accelerates its catabolic rate. The possible blocking effect of GA on the amino acid residues (mainly Lys) situated in or very close to the effector sites of the IgG molecule is suggested.


Effect of an external resistance to airflow on the inspiratory flow curve.
Inhalation is a convenient way to deliver drugs to the respiratory tract in the treatment of respiratory diseases. For dry powder inhalers (DPI's), the principle of operation is to use the patient-generated inspiratory flow as energy source for emptying of the dose system and the delivery of fine drug particles into the respiratory tract. Resistance to airflow of the inhaler device is a major determinant for the inspiratory flow profile through the dry powder inhaler that can be generated by the patient. Therefore, resistance to airflow is one of the design parameters for DPI's, that could be used to control the inspiratory flow profile, and is one of the parameters to optimise particle deposition in the airways. In this study the effect of resistance to airflow on different parameters of the inspiratory flow curves as generated by healthy subjects, asthmatics and COPD patients was determined. As a result of increased resistance to airflow, the peak inspiratory flow (PIF), the flow increase rate (FIR) and the inhaled volume to reach PIF is decreased. On the other hand, the total inhalation time as well as the 80% dwell time is increased. In general, tuning of the resistance to airflow in the design of a dry powder inhaler may improve the drug deposition in the respiratory tract.


Author Correction: Long non-coding RNA HEIH modulates CDK8 expression by inhibiting miR-193a-5p to accelerate nasopharyngeal carcinoma progression.
Correction to: European Review for Medical and Pharmacological Sciences 2021; 25 (2): 770-778-DOI: 10.26355/eurrev_202101_24638-PMID: 33577031, published online 31 January 2021. After publication, the authors found some mistakes in the article. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/24638.


Ketamine for depression - evidence and proposals for practice.
Current treatment for serious depression is unsatisfactory, and many patients fail to achieve the desired effect. Ketamine represents a new treatment option, and randomised trials show a rapid effect of intravenous ketamine. Although knowledge about adverse effects and the duration of the effect is somewhat deficient, we believe that the time has come to start clinical treatment in Norway.


Chemosensitization by lipophilic nitroimidazoles.
We have carried out experiments to determine the response of tumours and normal tissues in the C3H mouse to the combination of lipophilic nitroimidazoles and CCNU, cyclophosphamide or melphalan. The nitroimidazoles studied were Ro 07-1902 (1902) and benznidazole (Ro 07-1051, BENZO). Maximum enhancement of CCNU response in the KHT sarcoma by 2.5 mmol kg-1 1902 or 0.3 mmol kg-1 BENZO occurred at low doses of CCNU where dose modifying factors (DMF) of 2.5-3.0 and 1.5-2.0 respectively were found. The DMFs for depression of white cell count at day 3 were 1.6 and 1.2 respectively whilst the DMFs for LD50/30 were 1.5 and 1.3. There appears, therefore, to be a therapeutic gain at low doses of CCNU of about the same magnitude as produced by 2.5 mmol kg-1 misonidazole. The production of this gain at relatively low doses of BENZO is of possible clinical significance. Some sensitization of the KHT tumour to CCNU by 0.3 mmol kg-1 BENZO was maintained even with an interval of 25 h between BENZO and CCNU injection. A multiple injection regime of BENZO administration designed to maintain plasma concentrations for prolonged periods was, however, no more effective than a single dose. The response of the RIF-1 sarcoma to cyclophosphamide was not enhanced by the lipophilic sensitizers at the doses previously stated. Considerable enhancement of tumour response to melphalan (DMF 2.0) was produced by both lipophilic sensitizers. Enhancement of acute LD50 was similar in magnitude but no large enhancement by BENZO of melphalan induced white blood cell depression was observed. The evidence regarding the therapeutic potential of this combination is, therefore, equivocal.


Challenges encountered by local health volunteers in early diagnosis and prompt treatment of malaria in Myanmar artemisinin resistance containment zones.
After artemisinin resistance was reported, the Myanmar artemisinin resistance containment (MARC) project was initiated in 2011. One of the activities of MARC is to train volunteers for early diagnosis and prompt treatment by providing rapid diagnostic tests (RDT) and artemisinin combination therapy. This study aimed to fulfil the gap of information on the challenges faced by malaria volunteers in artemisinin-containment areas. A cross-sectional, descriptive study was conducted in 11 townships in MARC areas to assess the challenges in early diagnosis of malaria and treatment by malaria volunteers using qualitative and quantitative approaches. Altogether 405 volunteers participated in the study. Although 97.5 % of volunteers can interpret a positive result for malaria, only 41.2 % correctly stated the persistence of a positive result in recently infected cases. Over 80 % knew the effects of temperature and humidity on performance of the malaria RDT. Unexpectedly, 15.1 % perceived that expired RDTs can still be useful for diagnosis although 98.3 % of respondents cited that the overall results of RDTs were reliable. Although most of them knew the treatment for malaria based on RDT results, some could not give the correct answer, while a few (2 %) mentioned artesunate monotherapy for RDT-negative cases. Training received by volunteers was also varied in study sites and 92.1 % believed that it was not sufficient. A certain portion of them faced the problem of regular supply of RDTs (9.9 %) and drugs (47.5 %), interpretation of result of RDTs (30 %), and performing blood test (20 %). The median RDT tested per month (25th, 75th percentile) was 6.0 (2.0, 15.0) indicating the need for prioritization based on endemicity. Regular reporting, supervision, monitoring system, and proper refresher training using uniform content of guideline to correct misconception of the volunteers, were needed to be strengthened. Moreover, the reliable and regular supply of materials and exchange system for expired RDTs and anti-malarials was important in the effectiveness of volunteers in MARC zones. Adequate refresher training, monitoring, supervision, and regular reliable supply of RDTs and anti-malarials were needed for capacity strengthening of volunteers in MARC zones.


Gene Expression Profiling Studies Using Microarray in Osteoarthritis: Genes in Common and Different Conditions.
Osteoarthritis (OA), which is characterized mainly by cartilage degradation, is the most prevalent joint disorder worldwide. Although OA is identified as a major cause of joint pain, disability, and socioeconomic burden, the etiology of OA is still not clearly known. Recently, gene microarray analysis has become an efficient method for the research of complex diseases and has been employed to determine what genes and pathways are involved in the pathological process of OA. In this review, OA study results over the last decade are summarized for gene expression profiling of various tissues, such as cartilage, subchondral bone, and synovium in human OA and mouse OA models. Many differentially expressed genes, which mainly involve matrix metabolism, bone turnover, and inflammation pathways, were identified in diseased compared with "normal" tissues. Nevertheless, rare common genes were reported from studies using different tissue sources, microarray chips, and research designs. Thus, future novel and carefully designed microarray studies are required to elucidate underlying genetic mechanisms in the pathogenesis of OA as well as new directions for potential OA-targeted pharmaceutical therapies.


Serum antibodies to a normal cellular protein (P-65) in patients with Hodgkin's disease.
Samples from the L-428 Hodgkin's cell line and from several other lymphoma cell lines were lysed and the soluble proteins were subjected to one- or two-dimensional gel electrophoresis. The separated proteins were transferred to nitrocellulose by the Western Blot technique; antibody reactivity was detected by an immunoperoxidase reaction. Of 152 sera from patients with Hodgkin's disease (HD) 26 (17%) reacted with protein P-65 whereas in the control group, consisting of 35 healthy persons and 20 patients with other malignant diseases only 1 serum was reactive. Thus, the difference between the two groups was highly significant (P less than 0.01). These antibodies were most common in stage III HD. Splenectomy had no effect on the incidence of these antibodies, and there seemed to be no correlation with B-symptoms or with the histological subtype.


Extensive protein carbonylation precedes acrolein-mediated cell death in mouse hepatocytes.
Allyl alcohol hepatotoxicity is mediated by an alcohol dehydrogenase-derived biotranformation product, acrolein. This highly reactive alpha,beta-unsaturated aldehyde readily alkylates model proteins in vitro, forming, among other products, Michael addition adducts that possess a free carbonyl group. Whether such damage accompanies acrolein-mediated toxicity in cells is unknown. In this work we established that allyl alcohol toxicity in mouse hepatocytes involves extensive carbonylation of a wide range of proteins, and that the severity of such damage to a subset of 18-50 kDa proteins closely correlated with the degree of cell death. In addition to abolishing cytotoxicity and glutathione depletion, the alcohol dehydrogenase inhibitor 4-methyl pyrazole strongly attenuated protein carbonylation. Conversely, cyanamide, an aldehyde dehydrogenase inhibitor, enhanced cytotoxicity and protein carbonylation. Since protein carbonylation clearly preceded the loss of membrane integrity, it may be associated with the toxic process leading to cell death.


Do reduction and healing of the bony fragment really matter in arthroscopic bony Bankart reconstruction?: a prospective study with clinical and computed tomography evaluations.
Bony Bankart lesions can be treated with arthroscopic repair. However, few studies have evaluated the importance of bony fragment reduction and healing to stability of the glenohumeral joint after arthroscopic bony Bankart repair. To evaluate functional results after surgery and determine the correlation between reduction and healing of the fracture and postoperative stability of the glenohumeral joint. Case series; Level of evidence, 4. A total of 50 patients (47 men, 3 women; average age, 27.6 years; range, 16.5-50.1 years) with bony Bankart lesions and recurrent anterior shoulder dislocations were treated with arthroscopic reduction and internal fixation with suture anchors. The average follow-up period was 32.5 months (range, 24.3-61.2 months). Preoperative and postoperative range of motion and American Shoulder and Elbow Surgeons (ASES), Constant-Murley, and Rowe scores were compared to evaluate the results of the surgeries. Sequential 3-dimensional computed tomography (CT) scans were available for 37 patients and were analyzed to investigate the effect of the bony defect of the glenoid and the correlation between the success of the surgery and reduction and healing of the bony fragment. After surgery, active forward elevation was significantly improved (P < .05). No significant differences were found regarding external and internal rotations after surgery. The ASES, Constant-Murley, and Rowe scores improved significantly after surgery. Redislocations occurred in 3 patients, and a positive anterior apprehension sign was detected in 1 patient during follow-up. The overall failure rate was 8.0% (4/50). The CT scans during the follow-up period showed a nonunion of the bony fragment in 13.5% of cases (5/37). The reconstructed size of the glenoid was <80% in 3 of the 4 failure cases but >80% in all of the successful cases. Arthroscopic reduction and fixation of a bony Bankart lesion can achieve good results in selected cases. The size of the reconstructed glenoid is crucial to the success of the surgery.


Bifunctional Platinum(II) Complexes with Bisphosphonates Substituted Diamine Derivatives: Synthesis and In vitro Cytotoxicity.
A series of N,N'-dibisphosphonate-containing 1,3-propanediamine derivatives (L1 - L6) and their corresponding dichloridoplatinum(II) complexes (1 - 6) have been synthesized and characterized by elemental analysis, 1 H-NMR, 13 C-NMR, 31 P-NMR and HR-MS spectra. The in vitro antitumor activities of compounds L1 - L6 and 1 - 6 were tested by WST-8 assay with Cell Counting Kit-8, indicating that platinum-based complexes 1 - 6 showed higher cytotoxicity than corresponding ligands L1 - L6 against A549 and MG-63, especially complex 2 which displayed comparable cytotoxicity to those of cisplatin and zoledronate after 48 h incubation. In addition, complexes 1 - 6 were more active in vitro on osteosarcoma cell line MG-63 than normal osteoblast cell line hFOB 1.19. The structure-activity relationship has been summarized based on the in vitro cytotoxicity of three series of platinum complexes from this and our previous studies. The in vitro bone affinity of platinum complexes was also tested by hydroxyapatite (HAP) chromatography in terms of capacity factor K'. Besides, in this paper, representative complex 2, which has been proved to be a promising antitumor agent with high cytotoxicity and bone HAP binding property, was investigated for its mechanism of action producing cell death against MG-63.


Growth factor release during preparation and storage of platelet concentrates.
The platelet content of platelet-derived growth factor (PDGF), a mitogen stored in the alpha-granules, was studied during preparation and storage of platelet concentrates (PC) and compared to the growth-promoting activity of platelets, beta-thromboglobulin (beta-TG) and lactate dehydrogenase (LD). We compared PC prepared from platelet-rich plasma (PRP-PC; n = 10) and from buffy coat. Two different pre-preparation storage periods of the buffy coat were used: 4 h (BC-PC:4h; n = 10) and 24 h (BC-PC:24h; n = 5). The platelet content of PDGF and beta-TG was measured by a RIA technique and the growth-promoting activity by incorporation of 3H-thymidine in stimulated fibroblasts. The platelet content of PDGF, beta-TG and the growth-promoting activity of the platelets decreased in a similar way during preparation and storage of PRP-PC (31 +/- 2, 35 +/- 2 and 33 +/- 7%, respectively, at day 5 of storage; mean +/- SEM). The release of LD was minor (3.9 +/- 0.5% at day 5). At day 1 of storage the platelet content of PDGF was significantly better preserved in BC-PC:4h than in BD-PC:24h (88 +/- 2 and 81 +/- 3%, respectively; p = 0.03). Comparing BC-PC:4h and PRP-PC we found a significantly better preservation of PDGF in BC-PC:4h until day 3 of storage (80 +/- 2 and 75 +/- 1%, respectively at day 3; p = 0.046). In conclusion the preparation of PC according to the PRP method initially induces a higher loss of PDGF, and hence of the growth-promoting activity, than the BC method.


Host DNA released by NETosis in neutrophils exposed to seasonal H1N1 and highly pathogenic H5N1 influenza viruses.
Neutrophil is of the most abundant number in human immune system. During acute influenza virus infection, neutrophils are already active in the early phase of inflammation - a time in which clinical biopsy or autopsy material is not readily available. However, the role of neutrophil in virus infection is not well understood. Here, we studied the role of neutrophil in host defense during influenza A virus infection, specifically assessing if it contributes to the differential pathogenesis in H5N1 disease. Neutrophils were freshly isolated from healthy volunteers and subjected to direct influenza H1N1 and H5N1 virus infection in vitro. The ability of the naïve neutrophils to infiltrate from the basolateral to the apical phase of the influenza virus infected alveolar epithelium was assessed. The viral replication, innate immune responses and Neutrophil extracellular trap (NET) formation of neutrophils upon influenza virus infection were evaluated. Our results demonstrated that influenza virus infected alveolar epithelium allowed neutrophil transmigration. Significantly more neutrophils migrated across the H5N1 influenza virus infected the epithelium than the counterpart infected by the seasonal influenza H1N1 virus infected. Neutrophils were equally susceptible to H5N1 and H1N1 virus infection with similar viral gene transcription. Productive replication was observed in H5N1 infected neutrophils. H5N1 induced higher cytokine and chemokine gene transcription than H1N1 infected neutrophils, including TNF-α, IFN-β, CXCL10, MIP-1α and IL-8. This inferred a more intense inflammatory response posed by H5N1 than H1N1 virus. Strikingly, NADPH oxidase-independent NET formation was only observed in H1N1 infected neutrophils at 6 hpi while no NET formation was observed upon H5N1 infection. Our data is the first to demonstrate that NET formation is abrogated in H5N1 influenza virus infection and might contribute to the severity of H5N1 disease.


Effect of indomethacin on UVB- and UVA-induced erythema in polymorphic light eruption.
The effect of topical indomethacin on the intensity of UVB- and UVA-induced erythema was measured by reflectance spectrophotometry in 23 patients with polymorphic light eruption. Thirteen patients showed a response to indomethacin that was identical to that seen in normal subjects (i.e., inhibition of UVB-induced erythema; no effect on the intensity of UVA-induced erythema). In the remaining 10 patients indomethacin caused abnormal augmentation of UVB- and UVA-induced erythema. These results show for the first time that the term polymorphic light eruption embraces at least two disease states that have different mechanisms of photosensitivity and that can be distinguished on the basis of clinical features and results of photobiologic investigation.


N-hydroxypropyltrimethylammonium polydimethylaminoethylmethacrylate sub-microparticles for oral delivery of insulin--an in vitro evaluation.
The present study describes the synthesis and in vitro evaluation of quaternised polydimethylaminoethylmethacrylate for oral delivery of insulin. Quaternisation of the polymer was carried out by conjugating N-hyroxypropyltrimethylammonium chloride to aminoterminated polydimethylaminoethylmethacrylate. Quaternised particles were characterised by particle size, zeta potential measurements, nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), differential scanning calorimetry (DSC) and atomic force microscopy (AFM). In addition, in vitro insulin release experiments, cytotoxic evaluation on L929 & Caco-2 cells, mucoadhesion, enzymatic degradation and tight junction visualisation studies were also performed to evaluate the potential of this matrix for oral delivery of insulin. Results suggest that the quaternised particles exhibited positive zeta potential with a particle size of 513.6±17 nm. Dose-dependent cytotoxic evaluation of quaternised particles on L929 & Caco-2 cells confirmed the nontoxic nature of the matrix. Quaternised particles were more mucoadhesive compared to parent polymer. Adhesive behaviour of mucin with quaternised particles were confirmed by DSC. Moreover these particles exhibited calcium chelating ability and displayed significant inhibitory effect towards trypsin and chymotrypsin. These particles also helped in the opening of tight junctions by disruption of actin filaments and binding to Zona Occludens (ZO-1) proteins. Preliminary studies suggest that the quaternised particles can act as suitable candidates for oral delivery of insulin.


Glucose metabolism of the midline nuclei raphe in the brainstem observed by PET-MRI fusion imaging.
The brainstem contains various important monoaminergic neuronal centers, including the raphe nuclei which contain serotonergic neurons. The raphe nuclei, however, are not easily identifiable and located by conventional neuroimaging. Fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance imaging (MRI) were performed in seven healthy subjects using a new PET-MRI, which consists of a high-resolution research tomograph (HRRT) PET and 7.0 T-MRI. Glucose metabolism of raphe nuclei was semiquantitatively measured and identified along the midline brainstem region in vivo. Midline nuclei clustered in four groups appeared to be the raphe nuclei and could be clearly visualized; specifically, we identified the groups as the dorsal raphe, raphe reticularis centralis superior, raphe pontis, and raphe magnus group. FDG imaging of the midline raphe nuclei in vivo could potentially be an important tool for investigating brain diseases as well as conducting functional brain studies in the context of sleep disorders, depression, and neurodegenerative disease.


Electroretinographic Responses in Retinopathy of Prematurity Treated Using Intravitreal Bevacizumab or Laser.
Intravitreal injection of bevacizumab (IVB) offers advantages over laser photoablation for treatment of type 1 retinopathy of prematurity (ROP). However, retinal function has not, to date, been quantitatively compared following these interventions. Therefore, electroretinography (ERG) was used compare retinal function among eyes treated using IVB or laser, and control eyes. In addition, among the IVB-treated eyes, ERG was used to compare function in individuals in whom subsequent laser was and was not required. Prospective clinical cohort study. ERG was used to record dark- and light-adapted stimulus/response functions in 21 children treated using IVB (12 of whom required subsequent laser in at least 1 eye for persistent avascular retina [PAR]). Sensitivity and amplitude parameters were derived from the a-wave, b-wave, and oscillatory potentials (OPs), representing activity in photoreceptor, postreceptor, and inner retinal cells, respectively. These parameters were then referenced to those of 76 healthy, term-born controls and compared to those of 10 children treated using laser only. In children with treated ROP, every ERG parameter was significantly below the mean in controls. However, these significant ERG deficits did not differ between IVB- and laser-treated eyes. Among children treated using IVB, no ERG parameter was significantly associated with dose or need for subsequent laser. Retinal function was significantly impaired in treated ROP eyes. Function in IVB-treated eyes did not differ from that in laser-treated eyes. Functional differences also did not distinguish those IVB-treated eyes that would subsequently need laser for PAR.


Transverse femoral arteriotomy for intraaortic balloon insertion.
A technique for intraaortic balloon placement employing a transverse femoral arteriotomy is described. After balloon removal, the arteriotomy can be closed primarily. Avoidance of retained graft material or use of a vein patch reduces the likelihood of vascular complications.


Superior clinical response and survival rates with initial bolus of cisplatin and 120 hour infusion of 5-fluorouracil before definitive therapy for locally advanced head and neck cancer.
One hundred ninety-one patients were treated by one of three cisplatin-containing multidrug protocols. The initial 77 patients received two courses of cisplatin and vincristine plus bleomycin. The next 26 patients received two courses of 5-fluorouracil and cisplatin, and the final 88 patients were placed on a three course 5-fluorouracil and cisplatin protocol. Overall response rates were similar for each of the three protocols. The complete response rate, however, was much better (54 percent) for three course 5-fluorouracil and cisplatin versus cisplatin vincristine, and bleomycin (29 percent) and two course 5-fluorouracil and cisplatin (19 percent). Survival curves were also better for the three course 5-fluorouracil and cisplatin segment of this nonrandomized pilot study.


Prescription of panoramic radiographs in children using age-based prevalence of dental anomalies and pathologies.
Panoramic radiographs (PRs) are used in the detection and diagnosis of developmental dental anomalies and pathologies (DDAPs) in children. The primary objective of this observational cohort study was to evaluate the age-based prevalence of DDAP on PRs, whereas the secondary objective was to determine a threshold age for the detection of DDAP to provide supportive evidence for the prescription of PR in paediatric dental practice. The study examined diagnostic PRs from 581 subjects aged 6 to 19 years. All PRs were reviewed by experienced, calibrated, masked examiners for the identification or presence of anomalies in size, shape, position, structure, and other developmental anomalies and pathologies (ODAP) of the face-neck region in a standardized condition. The data were statistically analyzed for interpretation. Overall, 74% (n = 411) of the cohort had at least one anomaly (shape anomaly: 12%, number anomaly: 17%, positional anomaly: 28%, structural anomaly: 0%, and ODAP: 63%). The optimal Youden index cutoff for any anomaly was 9 years. Twelve and 15 years also showed predictive ability. The results suggest that PRs should be prescribed at ages 9, 12, and 15 years for the diagnosis of DDAP.


The contribution of physical and social activity participation to social support and happiness among people with physical disabilities.
Prior studies have suggested that certain leisure activities provide health benefits to people with physical disabilities. Participation in social activities has been identified as a strong predictor of active coping strategies and social support from others. In addition, leisure-time physical activity (LTPA) has been found to be positively associated with health perceptions and quality of life. The purpose of this study was to investigate the relationships between social activity and LTPA to social support and life satisfaction among people with physical disabilities. Data were collected from Korean Association of Persons with Physical Disabilities. A total of 351 surveys were used. Results indicated that social activity, emotional and informational support, and tangible and affectionate support were significantly associated with happiness. However, there were no direct effects of LTPA and positive social interaction support on happiness. The study results showed significant direct effects of LTPA on emotional and informational support and positive social interaction. This study shows that it is important for people with physical disabilities not only to participate in LTPA, but also to be provided with opportunities for social activities. In particular, the importance of social activity to Korean people with physical disabilities as a means of receiving social support and increasing happiness was confirmed. The results suggest that practitioners need to create a variety of social activity opportunities, such as online social participation programs, community-based social programs, and social events for health.


Report of an outbreak of Clostridium difficile infection caused by ribotype 053 in a neurosurgery unit.
We describe an outbreak of Clostridium difficile infection (CDI) with ribotype 053, a possible hypervirulent strain that causes outbreaks, in a neurosurgical unit. The outbreak was investigated by creating a timeline of all toxin positive patients with root cause analysis, supplemented with ribotyping results, hand hygiene and environmental audits. There were five cases of CDI, three caused by ribotype 053 indicating transmission. These included a short period of ward closure to allow enhanced cleaning, including use of vaporised hydrogen peroxide, isolation of infected patients, reinforcement of hand hygiene, education of all staff on C. difficile, reduction of shared bay occupancy from six to four, and addressing staffing levels. The patients with ribotype 053 all had long inpatient stays and had required several courses of broad-spectrum antibiotics for aspiration pneumonia. They also required enteral feeding, which can cause diarrhoea, and during long inpatient stays they had multiple toxin negative faecal samples making clinical diagnosis of CDI difficult. Hence they were not isolated promptly, leading to transmission. This is the first reported outbreak of C. difficile ribotype 053 in the UK and highlights the unique aspects of an outbreak in neurosurgical patients.


The genomically mosaic brain: aneuploidy and more in neural diversity and disease.
Genomically identical cells have long been assumed to comprise the human brain, with post-genomic mechanisms giving rise to its enormous diversity, complexity, and disease susceptibility. However, the identification of neural cells containing somatically generated mosaic aneuploidy - loss and/or gain of chromosomes from a euploid complement - and other genomic variations including LINE1 retrotransposons and regional patterns of DNA content variation (DCV), demonstrate that the brain is genomically heterogeneous. The precise phenotypes and functions produced by genomic mosaicism are not well understood, although the effects of constitutive aberrations, as observed in Down syndrome, implicate roles for defined mosaic genomes relevant to cellular survival, differentiation potential, stem cell biology, and brain organization. Here we discuss genomic mosaicism as a feature of the normal brain as well as a possible factor in the weak or complex genetic linkages observed for many of the most common forms of neurological and psychiatric diseases.


Learning curve for laparoscopic Roux-en-Y gastric bypass based on the experience of a newly created bariatric center.
 Introduction: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is one of the most common treatments for morbid obesity. The learning curve for this procedure is 50-75 cases for an independent surgeon, and it is considered the most important factor in decreasing complications and mortality. We present our experience and learning curve with LRYGB for a newly established bariatric center in Poland.
Material and methods: A prospectively collected database containing 285 LRYGB procedures performed in the II Department of General Surgery of the Jagiellonian University MC in Krakow between 06.2010 and 03.2019 was retrospectively reviewed. Patients were divided into groups of 30 (G1-G10) in the order of the procedures performed by each surgeon. The study analyzed the course of the operation and patient hospitalization, comparing those groups. Learning curve for the newly created bariatric center was established.
Results: Operative time in G1-G3 differed significantly from G4-G10 (P < 0.0001). The stabilization point was the 90th procedure. Perioperative complications were observed in 36 (12.63%) patients. Perioperative complications, intraoperative difficulties and adverse events did not differ importantly among groups. Liberal use of "conversions of the operator" from a surgeon to a senior surgeon provides reasonable safety and prevents complications.
Conclusions: The institutional learning process stabilization point for LRYGB in a newly established bariatric center is around the 90th operation. LRYGB can be a safe procedure from the very beginning in newly established bariatric centers. Specific bariatric training with active proctoring by an experienced surgeon in a bariatric centre can improve the laparoscopic gastric bypass outcome during the learning curve.


Anti-Inflammatory, Antioxidant, Metabolic and Gut Microbiota Modulation Activities of Probiotic in Cardiac Remodeling Condition: Evidence from Systematic Study and Meta-Analysis of Randomized Controlled Trials.
Heart failure (HF) is a global pandemic with increasing prevalence and mortality rates annually. Its main cause is myocardial infarction (MI), followed by rapid cardiac remodeling. Several clinical studies have shown that probiotics can improve the quality of life and reduce cardiovascular risk factors. This systematic review and meta-analysis aimed to investigate the effectiveness of probiotics in preventing HF caused by a MI according to a prospectively registered protocol (PROSPERO: CRD42023388870). Four independent evaluators independently extracted the data using predefined extraction forms and evaluated the eligibility and accuracy of the studies. A total of six studies consisting of 366 participants were included in the systematic review. Probiotics are not significant in intervening left ventricular ejection fraction (LVEF) and high-sensitivity C-reactive protein (hs-CRP) when compared between the intervention group and the control group due to inadequate studies supporting its efficacy. Among sarcopenia indexes, hand grip strength (HGS) showed robust correlations with the Wnt biomarkers (p < 0.05), improved short physical performance battery (SPPB) scores were also strongly correlated with Dickkopf-related protein (Dkk)-3, followed by Dkk-1, and sterol regulatory element-binding protein 1 (SREBP-1) (p < 0.05). The probiotic group showed improvement in total cholesterol (p = 0.01) and uric acid (p = 0.014) compared to the baseline. Finally, probiotic supplements may be an anti-inflammatory, antioxidant, metabolic, and intestinal microbiota modulator in cardiac remodeling conditions. Probiotics have great potential to attenuate cardiac remodeling in HF or post-MI patients while also enhancing the Wnt signaling pathway which can improve sarcopenia under such conditions.


A molecular approach integrating genomic and DNA methylation profiling for tissue of origin identification in lung-specific cancer of unknown primary.
Determining the tissue of origin (TOO) is essential for managing cancer of unknown primary (CUP). In this study, we evaluated the concordance between genome profiling and DNA methylation analysis in determining TOO for lung-specific CUP and assessed their performance by comparing the clinical responses and survival outcomes of patients predicted with multiple primary or with metastatic cancer. We started by retrospectively screening for CUP patients who presented with both intra- and extrathoracic tumors. Tumor samples from included patients were analyzed with targeted sequencing with a 520-gene panel and targeted bisulfite sequencing. TOO inferences were made in parallel via an algorithm using genome profiles and time interval between tumors and via machine learning-based classification of DNA methylation profiles. Four hundred patients were screened retrospectively. Excluding patients definitively diagnosed with conventional diagnostic work-up or without available samples, 16 CUP patients were included. Both molecular approaches alone enabled inference of clonality for all analyzed patients. Genome profile enabled TOO inference for 43.8% (7/16) patients, and the percentage rose to 68.8% (11/16) after considering inter-tumor time lag. On the other hand, DNA methylation analysis was conclusive for TOO prediction for 100% (14/14) patients with available samples. The two approaches gave 100% (9/9) concordant inferences regarding clonality and TOO identity. Moreover, patients predicted with metastatic disease showed significantly shorter overall survival than those with multiple primary tumors. Genome and DNA methylation profiling have shown promise as individual analysis for TOO identification. This study demonstrated the feasibility of incorporating the two methods and proposes an integrative scheme to facilitate diagnosing and treating lung-specific CUPs.


Production and characterization of partially purified extracellular thermostable α-amylase by Bacillus subtilis in submerged fermentation (SmF).
A Bacillus strain was isolated from soil samples from the campus area of Dicle University. Based on 16S ribosomal RNA sequencing, the microorganism was closely related to Bacillus subtilis. Effects of different culture medium, incubation time, carbon and nitrogen sources, and various starches, flours, and chemicals on α-amylase production were examined. Maximum enzyme production (7516 U/mL) was obtained in a basal medium A containing 0.05% Tween 40 in 24 h. Partially purified enzyme showed maximum activity at 60 °C with an optimum pH of 6.0. The effects of 0.2% detergents (sodium dodecyl sulfate [SDS], CHAPS [3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate], and commercial detergent Omo Matic) on partially purified enzyme activity over a period of time (15-150 min) were examined and the order of inhibition effect from the most to the least was found as SDS > Omo Matic > CHAPS. Different metal ions inhibited α-amylase activity at low concentrations (1.5 mM). Co²⁺ was a mild inhibitor and Hg²⁺ and Cd²⁺ were potent inhibitors, whereas Ca²⁺ and Mg²⁺ increased the enzyme activity. At 20 mM, Ca²⁺ enhanced enzyme activity, and different Ca²⁺ concentrations (10-300 mM) were studied.


Downregulation of osteopontin contributes to metastasis suppression by breast cancer metastasis suppressor 1.
Breast cancer metastasis suppressor 1 (BRMS1) inhibits the ability of multiple human and murine cancer cell lines to metastasize to lymph nodes, bones and lungs. Comparison of mRNA expression in metastatic MDA-MB-435 human carcinoma cells (435) and metastasis-suppressed BRMS1 transfectants (435/BRMS1) showed a marked (>90%) reduction of osteopontin (OPN) mRNA and protein expression in BRMS1-overexpressing cells. OPN expression is associated with disease progression in patients, with higher levels of OPN produced by cancer cells associated with poorer patient survival. Furthermore, OPN has been suggested to promote survival of cancer cells in response to stress, although the mechanisms by which this may occur remain poorly understood. This study tested the hypothesis that re-expression of OPN in metastasis-suppressed 435/BRMS1 cells would reverse metastasis suppression and confer protection from stress-induced apoptosis. A stable pooled population of OPN overexpressing 435/BRMS1 cells was created (435/BRMS1/OPN). OPN re-expression did not affect in vitro cell growth rates; however, increased anchorage independent growth/survival and protection from hypoxia-induced apoptosis was observed (p < 0.05). In vivo, OPN re-expression in BRMS1 transfected cells did not affect in vivo primary tumor growth but did increase the incidence of spontaneous metastasis to lymph nodes and lungs in mice. These novel findings suggest that OPN downregulation by BRMS1 may be responsible, at least in part, for BRMS1-mediated metastasis suppression by sensitizing cancer cells to stress induced apoptosis. These studies clarify one mechanism by which BRMS1 can suppress metastasis.


Comparison of estimated norovirus infection risk reductions for a single fomite contact scenario with residual and nonresidual hand sanitizers.
The purpose of this study was to relate experimentally measured log10 human norovirus reductions for a nonresidual (60% ethanol) and a residual (quaternary ammonium-based) hand sanitizer to infection risk reductions. Human norovirus log10 reductions on hands for both sanitizers were experimentally measured using the ASTM International Standard E1838-10 method, with modification. Scenarios included product application to: (1) inoculated fingerpads with 30- and 60-second contact times, and (2) hands followed by inoculation with human norovirus immediately and 4 hours later. Hand sanitizer efficacies were used in a mathematical model estimating norovirus infection risk from a single hand-to-fomite contact under low and high environmental contamination conditions. The largest log10 reductions for the residual and nonresidual hand sanitizers were for a 60-second contact time, reducing infection risk by approximately 99% and 85%, respectively. Four hours after application, the residual hand sanitizer reduced infection risks by 78.5% under high contamination conditions, whereas the nonresidual hand sanitizer offered no reduction. Log10 virus and infection risk reductions were consistently greater for the residual hand sanitizer under all scenarios. Further data describing residual hand sanitizer efficacy with additional contamination or tactile events are needed. Residual antinoroviral hand sanitizers may reduce infection risks for up to 4 hours.


A Permutation Test for Unbalanced Paired Comparisons of Global Field Power.
Global field power is a valuable summary of multi-channel electroencephalography data. However, global field power is biased by the noise typical of electroencephalography experiments, so comparisons of global field power on data with unequal noise are invalid. Here, we demonstrate the relationship between the number of trials that contribute to a global field power measure and the expected value of that global field power measure. We also introduce a statistical testing procedure that can be used for multi-subject, repeated-measures (also called within-subjects) comparisons of global field power when the number of trials per condition is unequal across conditions. Simulations demonstrate the effect of unequal trial numbers on global field power comparisons and show the validity of the proposed test in contrast to conventional approaches. Finally, the proposed test and two alternative tests are applied to data collected in a rapid serial visual presentation target detection experiment. The results show that the proposed test finds global field power differences in the classical P3 range; the other tests find differences in that range but also at other times including at times before stimulus onset. These results are interpreted as showing that the proposed test is valid and sensitive to real within-subject differences in global field power in multi-subject unbalanced data.


Thermodynamic compensation process in interacting protein systems: definition of thermodynamic compensatory temperature, (Tc).
In our thermodynamic analysis of the non-linear Van't Hoff expression as applied to several self-associating systems -- specifically in the cases of bovine liver L-glutamate dehydrogenase (GDH), glucagon and S-carboxymethylated apo A-II protein from human high density lipoprotein -- we have examined the interrelationships of a number of thermodynamic temperatures as they affect the association process. We found the principal determinants of the linear thermodynamic compensation process to be delta S0(T)/delta C0p(T) = (delta T'C)/(Texp), where (delta T'C) = Texp). We have defined the unique compensatory temperature, (TC), for any interacting system, at which the contributions of enthalpy and entropy to the association process are balanced.


Computing likelihoods for coalescents with multiple collisions in the infinitely many sites model.
One of the central problems in mathematical genetics is the inference of evolutionary parameters of a population (such as the mutation rate) based on the observed genetic types in a finite DNA sample. If the population model under consideration is in the domain of attraction of the classical Fleming-Viot process, such as the Wright-Fisher- or the Moran model, then the standard means to describe its genealogy is Kingman's coalescent. For this coalescent process, powerful inference methods are well-established. An important feature of the above class of models is, roughly speaking, that the number of offspring of each individual is small when compared to the total population size, and hence all ancestral collisions are binary only. Recently, more general population models have been studied, in particular in the domain of attraction of so-called generalised Lambda-Fleming-Viot processes, as well as their (dual) genealogies, given by the so-called Lambda-coalescents, which allow multiple collisions. Moreover, Eldon and Wakeley (Genetics 172:2621-2633, 2006) provide evidence that such more general coalescents might actually be more adequate to describe real populations with extreme reproductive behaviour, in particular many marine species. In this paper, we extend methods of Ethier and Griffiths (Ann Probab 15(2):515-545, 1987) and Griffiths and Tavaré (Theor Pop Biol 46:131-159, 1994a, Stat Sci 9:307-319, 1994b, Philos Trans Roy Soc Lond Ser B 344:403-410, 1994c, Math Biosci 12:77-98, 1995) to obtain a likelihood based inference method for general Lambda-coalescents. In particular, we obtain a method to compute (approximate) likelihood surfaces for the observed type probabilities of a given sample. We argue that within the (vast) family of Lambda-coalescents, the parametrisable sub-family of Beta(2 - alpha, alpha)-coalescents, where alpha in (1, 2], are of particular relevance. We illustrate our method using simulated datasets, thus obtaining maximum-likelihood estimators of mutation and demographic parameters.