Phase 1 Study of Neoadjuvant Short-Course Radiation Therapy Concurrent With Infusional 5-Fluorouracil for the Treatment of Locally Advanced Rectal Cancer.
To assess the safety and feasibility of neoadjuvant short-course radiation therapy (RT) concurrent with continuous infusion 5-fluorouracil (5-FU) for the treatment of locally advanced rectal cancer. Patients with cT3-4 or N + rectal adenocarcinoma based on ultrasound or magnetic resonance imaging were prospectively enrolled in this study. Study treatment consisted of continuous infusion 5-FU combined with short-course RT (5 Gy x 5 fractions) followed by 4 cycles of mFOLFOX, total mesorectal excision (TME), and 6 cycles of adjuvant mFOLFOX. To mitigate the potential added toxicity from concurrent 5-FU, intensity modulated RT was used. Using the continual reassessment method, the dose of 5-FU was escalated from 100 to a maximum-tolerated dose of 200 mg/m2/d. Fourteen patients were accrued. All patients completed continuous infusion 5-FU and short-course RT and the 5-FU dose was safely escalated to 200 mg/m2/d with no dose-limiting toxicity. Thirteen patients received the neoadjuvant mFOLFOX, and only 1 patient went straight to surgery after chemoradiation. Clinical response was 21% complete, 63% partial, 14% stable disease, and no patients had progression. Three patients with cCR had negative biopsies and did not have TME. Pathologic response was 64% partial response and 14% stable disease. No patients had pathologic progression. The most common grade 3 and 4 toxicities were cytopenias. The most common grade 1 and 2 toxicities were cytopenia, fatigue, diarrhea, and nausea. Our findings suggest that concurrent chemotherapy with neoadjuvant short-course RT is feasible and can be safely given with concurrent continuous infusion 5-FU. This works adds to the growing evidence that short-course RT is not only equivalent to long-course RT, but also may provide additional benefits, such as allowing for a transition to full dose systemic therapy in the neoadjuvant setting, selective organ preservation in complete responders, and providing a more convenient and cost-effective way of delivering pelvic RT.


Effect of saponin fraction from Ficus religiosa on memory deficit, and behavioral and biochemical impairments in pentylenetetrazol kindled mice.
In our previous study, the saponin-rich fraction (SRF) of adventitious root extract of Ficus religiosa L. (Moraceae) was shown to have an anticonvulsant effect in acute animal models of convulsions. The present study was envisaged to study the effect of SRF in the pentylenetetrazol (PTZ) kindling mouse model and its associated depression and cognition deficit. Treatment with the SRF (1, 2 and 4 mg/kg; i.p.) for 15 days in kindled mice significantly decreased seizure severity on days 5, 10 and 15 when challenged with PTZ (35 mg/kg; i.p.). Marked protection against kindling-associated depression was also observed on days 10 and 15 in the SRF-treated groups when tested using the tail-suspension test. However, the SRF treatment failed to protect kindling-associated learning and memory impairments in the passive shock avoidance paradigm. The observed behavioral effects were corroborated with modulation in the levels of noradrenaline, dopamine, serotonin, GABA and glutamate in discrete brain regions.


Nrf2 and oxidative stress in liver ischemia/reperfusion injury.
In response to stress signal, nuclear factor-erythroid 2-related factor 2 (Nrf2) induces the expression of target genes involved in antioxidant defense and detoxification. Nrf2 activity is strictly regulated through a variety of mechanisms, including regulation of Keap1-Nrf2 stability, transcriptional regulation (NF-ĸB, ATF3, ATF4), and post-transcriptional regulation (miRNA), evidencing that transcriptional responses of Nrf2 are critical for the maintenance of homeostasis. Ischemia-reperfusion (IR) injury is a major cause of graft loss and dysfunction in clinical transplantation and organ resection. During the IR process, the generation of reactive oxygen species (ROS) leads to damage from oxidative stress, oxidation of biomolecules, and mitochondrial dysfunction. Oxidative stress can trigger apoptotic and necrotic cell death. Stress factors also result in the assembly of the inflammasome protein complex and the subsequent activation and secretion of proinflammatory cytokines. After Nrf2 activation, the downstream antioxidant upregulation can act as a primary cellular defense against the cytotoxic effects of oxidative stress and help to promote hepatic recovery during IR. The complex crosstalk between Nrf2 and cellular pathways in liver IR injury and the potential therapeutic target of the Nrf2 inducers will be discussed in the present review.


A Systematic Review of Ethnoracial Participation in Randomized Clinical Trials of Behavioral Activation.
As of the last available NIH report, people of color (POC) constituted 28.1% of enrollment across all U.S. domestic clinical trials. The literature on prevalence rates of depression among POC is mixed. While the prevalence rates of depression may vary across POC, it remains unknown to what degree POC have been included in outcome clinical trials of depression since NIH's mandates for inclusion of minorities in clinical outcome research. Following PRISMA guidelines, the present review identified randomized controlled trials of behavioral activation from 1989 to 2021 using the following search engines: PsycINFO, EMBASE, and Cochrane Central Register of Controlled Trials. We reviewed 5,247 articles and included 28 articles that met full inclusion criteria (n = 5,169 participants). Across studies included in this review, 70% were non-Latinx White, 14.1% were African American, 8.9% were Latinx, 0.5% were Asian, 2.9% were other, and 3.7% were unknown. Results indicated an increase in representation of ethnoracial inclusion rates across time and that recruitment method was not associated with adequate inclusion of POC. However, the university setting was associated with inadequate representation of POC.


A new sensitive assay for measurement of cell-mediated cytotoxicity to intact layers of cultured human keratinocytes.
A cytotoxicity assay for sensitive measurement of cell-mediated lympholysis (CML) of human cultured keratinocytes (cK) is described. The usage of 51Cr-labeled keratinocytes in intact layers as target cells in this assay allows objective and accurate determination of lysis of keratinocytes which have not undergone trypsin- and suspension-induced membrane changes. Furthermore, the problem of high spontaneous 51Cr release values encountered with suspended keratinocytes is overcome. The assay was applied to study antigen-specific CML of cK by cloned cytotoxic T cells (CTL) and to determine the effect of IFN-gamma on the susceptibility of cK to lysis. The results showed that HLA-A2 specific CTLs could reproducibly lyse cK of HLA-A2 positive healthy skin donors both with and without incubation of cK with IFN-gamma. Applications of this keratinocyte cytotoxicity assay lie in determining the antigenic expression of human cK, in analysis of effector cell/keratinocyte interactions in CML and of the modulatory effects of cytokines on these mechanisms. The assay thus may provide a helpful tool in gaining insight into the role of CML of keratinocytes in the destruction of inflamed skin.


Transanastomotic stents for dismembered pyeloplasty in children.
Among pediatric urologists, there is a debate whether to drain the upper system after pyeloplasty in children. In a prospective, randomized clinical study we compared the early and late results of patients operated upon for ureteropelvic junction obstruction (UPJO) with or without a transanastomotic stent. Anderson-Hynes pyeloplasty was performed in 31 children during a 5-year period. In 15 a transanastomotic stent with multiple holes was used; the upper system was not drained in 16. A Penrose drain was placed in the perinephritic area in all patients. Patients were evaluated in regard to the time of removal of the stent and the Penrose drain, duration of urine leakage, and duration of hospital stay in the early postoperative period, and favorable or unfavorable outcome during follow-up. The statistical analysis showed no significant difference in regard to the removal time of the stent and Penrose drain, duration of drainage, duration of hospitalization, and early or late complications between the groups. Although stenting does not increase morbidity, we believe that pyeloplasty can be performed in children without upper-tract drainage. A feeding tube with multiple holes at the tip is recommended.


Technology insight: PET and PET/CT in head and neck tumor staging and radiation therapy planning.
The evolving utilization of functional imaging, mainly 2-[18F]fluoro-2-deoxyglucose (18FDG) imaging, with positron emission tomography (PET) and PET/CT, is profoundly altering head and neck tumor staging approaches, radiation treatment planning, and follow-up management. Tumor-node-metastasis staging with PET/CT has improved the characterization of patient disease versus CT, MRI, or PET alone, thereby affecting patient disease management. Therefore, the utilization of PET/CT is appropriate for head and neck cancer staging in the initial presentation and in the recurrent setting. In the setting of radiation therapy treatment planning, PET-directed tumor volume contouring is not ready for clinical practice without further technological improvements in imaging specificity/sensitivity and resolution. Patient or organ motion might interfere with the accuracy of anatomical co-alignment, and variability in defining the threshold of imaging signals on PET images can affect the contour of the biological tumor volume. The use of PET/CT for staging and detecting both primary and recurrent head and neck cancer is valuable; however, its application in radiation treatment planning should be viewed as investigational.


Impact of tactile dysfunction on upper-limb motor performance in children with unilateral cerebral palsy.
To determine the relationship between tactile function and upper-limb function in children with unilateral cerebral palsy (CP). Cross-sectional study. Assessments were performed in community or hospital venues or in participants' homes. Recruitment information was sent to 253 possible participants with unilateral CP (aged 8-18 y), and N=52 participated (median age [interquartile range], 12 y [9-14 y]; Gross Motor Functional Classification System level I=34; II=18; Manual Abilities Classification Scale level I=36; II=16). Not applicable. Tactile assessment included 1 test of registration, 5 tests for spatial perception, and 1 test for texture perception. Upper-limb motor function was assessed using 2 unimanual tests, the Melbourne Unilateral Upper Limb Assessment (MUUL) and Jebsen-Taylor Test of Hand Function (JTTHF), and 1 bimanual test, the Assisting Hand Assessment (AHA). Tactile registration and all tests of spatial perception were moderately related to the MUUL, JTTHF, and AHA (P<.001). Texture perception was not related to upper-limb motor function. Regression analysis showed that single point localization, a unilateral tactile spatial perception test, contributed most strongly to unimanual capacity (29% explained variance in MUUL and 26% explained variance in JTTHF), whereas double simultaneous, a bilateral tactile spatial perception test, contributed most strongly to bimanual performance (33% for the AHA). Spatial tactile deficits account for approximately 30% of the variance in upper-limb motor function in children with unilateral CP. This emphasizes the need for routine tactile assessment and targeted treatment of tactile spatial deficits in this population.


Successful pembrolizumab treatment in a patient with metastatic urothelial carcinoma and underlying overlap syndrome involving systemic sclerosis and systemic lupus erythematosus.
The safety and efficacy of pembrolizumab administration in patients with urothelial carcinoma and underlying autoimmune disease (including overlap syndrome) is unknown. We present the case of a 67-year-old woman with cT3N2M0 metastatic renal pelvic cancer who had been treated with prednisolone for overlap syndrome involving systemic sclerosis and systemic lupus erythematosus for 20 years. She had a remarkable response to pembrolizumab as a third-line systemic therapy, wherein the tumor reduced in size and all regional lymph node and pulmonary metastases disappeared. She did not develop any immune-related adverse events or autoimmune disease flare-ups during the treatment. This case report suggests that pembrolizumab could be beneficial to patients with urothelial carcinoma and underlying well-controlled overlap syndrome.


Malignant mixed tumor of the nasal cavity.
Parotid gland is the most common location of malignant mixed tumors. Three different subtypes of these tumors exist: carcinoma ex pleomorphic adenoma, carcinosarcoma, and metastasizing mixed tumor. Carcinoma ex-pleomorphic adenoma is by far the most common subtype. Although unusual sites of these tumors have been published, we report an extremely rare case of a malignant mixed tumor located in the nasal cavity.


Defects in chondrocyte maturation and secondary ossification in mouse knee joint epiphyses due to Snorc deficiency.
The role of Snorc, a novel cartilage specific transmembrane proteoglycan, was studied during skeletal development using two Snorc knockout mouse models. Hypothesizing that Snorc, like the other transmembrane proteoglycans, may be a coreceptor, we also studied its interaction with growth factors. Skeletal development was studied in wild type (WT) and Snorc knockout mice during postnatal development by whole mount staining, X-ray imaging, histomorphometry, immunohistochemistry and qRT-PCR. Snorc promoter activity was studied by applying the LacZ reporter expressed by the targeting construct. Slot blot binding and cell proliferation assays were used to study the interaction of Snorc with several growth factors. Snorc expression was localized in the knee epiphyses especially to the prehypertrophic chondrocytes delineating the cartilage canals and secondary ossification center (SOC). Snorc was demonstrated to have a glycosaminoglycan independent affinity to FGF2 and it inhibited FGF2 dependent cell growth of C3H101/2 cells. In Snorc deficient mice, SOCs in knee epiphyses were smaller, and growth plate (GP) maturation was disturbed, but total bone length was not affected. Central proliferative and hypertrophic zones were enlarged with higher extracellular matrix (ECM) volume and rounded chondrocyte morphology at postnatal days P10 and P22. Increased levels of Ihh and Col10a1, and reduced Mmp13 mRNA expression were observed at P10. These findings suggest a role of Snorc in regulation of chondrocyte maturation and postnatal endochondral ossification. The interaction identified between recombinant Snorc core protein and FGF2 suggest functions related to FGF signaling.


Comparative assessment of intrinsic mechanical stimuli on knee cartilage and compressed agarose constructs.
A well-established cue for improving the properties of tissue-engineered cartilage is mechanical stimulation. However, the explicit ranges of mechanical stimuli that correspond to favorable metabolic outcomes are elusive. Usually, these outcomes have only been associated with the applied strain and frequency, an oversimplification that can hide the fundamental relationship between the intrinsic mechanical stimuli and the metabolic outcomes. This highlights two important key issues: the firstly is related to the evaluation of the intrinsic mechanical stimuli of native cartilage; the second, assuming that the intrinsic mechanical stimuli will be important, deals with the ability to replicate them on the tissue-engineered constructs. This study quantifies and compares the volume of cartilage and agarose subjected to a given magnitude range of each intrinsic mechanical stimulus, through a numerical simulation of a patient-specific knee model coupled with experimental data of contact during the stance phase of gait, and agarose constructs under direct-dynamic compression. The results suggest that direct compression loading needs to be parameterized with time-dependence during the initial culture period in order to better reproduce each one of the intrinsic mechanical stimuli developed in the patient-specific cartilage. A loading regime which combines time periods of low compressive strain (5%) and frequency (0.5Hz), in order to approach the maximal principal strain and fluid velocity stimulus of the patient-specific cartilage, with time periods of high compressive strain (20%) and frequency (3Hz), in order to approach the pore pressure values, may be advantageous relatively to a single loading regime throughout the full culture period.


Diabetes management: utilizing community health workers in a Hawaiian/Samoan population.
Although not widely utilized, community health workers (CHWs) have been shown to enhance diabetes education and management efforts among racial/ethnic minority populations. To examine the effectiveness of CHWs on diabetes management among a population with primarily Native Hawaiian and Samoan ethnic minority participants with HbA1c greater than 10%. Descriptive study comparing HbA1c readings of participants with diabetes with and without CHW intervention. Of 116 eligible participants, 74% were either Native Hawaiian or Samoan. The mean baseline HbA1c for all eligible participants was 10.9+/-0.8%. The 80 participants who completed CHW intervention had a 2.2+/-1.8% (p.<.01, compared with baseline) mean reduction in HbA1c, compared with a 0.2+/-1.5% reduction for those without CHW intervention. Community health workers had a positive impact on diabetes management defined in terms of improved HbA1c amongst this predominantly Native Hawaiian and Samoan population.


The pharmacokinetics of atracurium isomers in vitro and in humans.
Atracurium is a mixture of ten isomers. By high-performance liquid chromatography, using acidified methanol as the mobile phase and silica support, it was separated into its three geometrical isomer groups, cis-cis, cis-trans, and trans-trans, which contain three, four, and three isomers, respectively. The clinically available form of atracurium was made up of 58% cis-cis, 36% cis-trans, and 6% trans-trans isomers. In buffered saline, pH 7.4, at 37 degrees C, the half-lives of the three isomer groups were 57.1 +/- 0.9, 59.7 +/- 0.9, and 66.4 +/- 2.7 min, respectively, for the cis-cis, cis-trans, and trans-trans groups. In whole blood, under similar conditions, the three groups showed different behavior. The cis-cis group broke down in a monoexponential manner with a half-life of 23.3 +/- 2.8 min. The cis-trans group showed bi-exponential breakdown with a rapid phase of 2.3 +/- 0.4 min and a slow phase of 22.1 +/- 2.9 min. The trans-trans group decayed rapidly, but, because of the low concentration of this group in the mixture, kinetic parameters could not be obtained. In eight patients, the mean elimination half-life and apparent clearance of the cis-cis group were 20.6 +/- 1.5 min and 5.3 +/- 0.4 ml.kg-1.min-1, respectively. For the cis-trans group, the apparent elimination half-life and clearance were 17.7 +/- 1.8 min and 9.0 +/- 1.0 ml.kg-1.min-1, but these figures require care in interpretation, as this isomer group contains isomers of widely varying rates of decomposition.(ABSTRACT TRUNCATED AT 250 WORDS)


Purification of influenza A virus and preliminary characterization of virus proteins by polyacrylamide gel electrophoresis (PAGE).
Influenza A/ZSSR/053/74 (H3N2) from egg ellantoic fluid was partially purified by absorption and elution on chick erythrocytes and chromatography on Sepharose 2B. Concentrated and partially purified preparation of virus containing 5000 HAV and 80 micrograms of protein per ml was subjected to PAGE in 0.1% SDS. Eleven protein bands were selected of which three were identified as NA, NP and HA.


Risk of stillbirth among Zambian women with a prior cesarean delivery.
Cesarean delivery (CD) may be associated with stillbirth in future pregnancies. We investigated prior CD as a risk factor for stillbirth in Lusaka, Zambia. We conducted a retrospective cohort analysis of women with only one prior pregnancy who delivered between February 1, 2006, and May 31, 2013. We analysed data from the Zambia Electronic Perinatal System. Maternal and infant characteristics were analyzed for association with stillbirth using Pearson's χ2 test or the Wilcoxon rank-sum test. We calculated risk ratios for the relationship between stillbirth (antepartum vs intrapartum) and prior CD, with a log Poisson model to adjust for confounding. Of 57 320 women in our cohort, 1933 (3.4%) reported a prior CD. There were 1012 (1.8%) stillbirths in the no prior CD group and 81 (4.2%) in the prior CD group (P<0.001). In multivariate models adjusting for stillbirth risk factors, prior CD was associated with antepartum (adjusted risk ratio 1.56, 95% confidence interval 1.08-2.24) and intrapartum (adjusted risk ratio 3.26, 95% confidence interval 2.40-4.42) stillbirth compared with no prior CD. The difference between groups was most apparent at 36-37 weeks' gestation (log-rank P<0.001). Prior CD was associated with increased risk of stillbirth. Improved monitoring during labor and safe methods for induction are urgently needed in low-resource settings.


Advances of research of Fc-fusion protein that activate NK cells for tumor immunotherapy.
The rapid development of bioengineering technology has introduced Fc-fusion proteins, representing a novel kind of recombinant protein, as promising biopharmaceutical products in tumor therapy. Numerous related anti-tumor Fc-fusion proteins have been investigated and are in different stages of development. Fc-fusion proteins are constructed by fusing the Fc-region of the antibody with functional proteins or peptides. They retain the bioactivity of the latter and partial properties of the former. This structural and functional advantage makes Fc-fusion proteins an effective tool in tumor immunotherapy, especially for the recruitment and activation of natural killer (NK) cells, which play a critical role in tumor immunotherapy. Even though tumor cells have developed mechanisms to circumvent the cytotoxic effect of NK cells or induce defective NK cells, Fc-fusion proteins have been proven to effectively activate NK cells to kill tumor cells in different ways, such as antibody-dependent cell-mediated cytotoxicity (ADCC), activate NK cells in different ways in order to promote killing of tumor cells. In this review, we focus on NK cell-based immunity for cancers and current research progress of the Fc-fusion proteins for anti-tumor therapy by activating NK cells.


[Magnetically-guided anesthetics based on highly dispersed iron powders coated by polyacrylamide].
The effect of external magnetic field (direct and alternating) on the targeted delivery and distribution in body tissues of experimental animals of anesthetics (novocain, lidocaine, and trimecaine) immobilized on highly dispersed ferromagnetics with biocompatible coating was studied by the method of emission spectral analysis. The results are compared with the results obtained earlier on highly dispersed iron powders with dextran coating. The parameters for the powders with dextran coating are considerably lower than those for the magnetic carriers with the polyacrylamide coating.


Impact of corporate motives for sustainable sourcing: key moderating role of regulatory pressure.
Organizational decisions and their motivations are crucial for successfully implementing sustainable sourcing practices (SSP). Still, there is scant research on how SSPs are impacted by corporate motives (CM). To fill this research gap, we formed a three-tiered stakeholder theory (ST) based paradigm that accounts for the moderating impact of regulatory pressure (RP) while examining the relationship between different types of corporate motives (instrumental, relational, and moral) and SSP. Partial least squares structural equation modeling (PLS-SEM) was used to examine data collected from 248 respondents in the Pakistani manufacturing industry. The outputs of SEM disclosed that all CMs affect SSP. RP also confoundedly moderated these targeted relationships. Importance performance map analysis (IPMA) showed that regulatory pressure (0.319) and relational motives (67.38) are more important and perform better than all other exogenous variables. This study sheds light on corporate strategies and decision-making in multi ways. All dimensions of CM greatly enhance SSP directly and through RP, as RP firmly moderates these associations, indicating the relevance of ST. Finally, this empirical investigation ends with a framework of testable assertions and many future research endeavors on environmental sustainability.


Local anesthesia with sedation for vaginal reconstructive surgery.
To evaluate local anesthesia with sedation for vaginal reconstructive surgery. All cases of vaginal surgery performed by the primary author for correction of pelvic organ prolapse with and without urinary incontinence between February 2000 and October 2004 were identified. From the medical record, data on age, duration of surgery, amount of local anesthetic used, estimated blood loss, hospital stay, urinary retention, and need for conversion to general anesthesia were recorded. Among 127 potential candidates, 98 (77.2%) opted for local with sedation. These cases included 18 anterior colporrhaphies, 47 posterior colporrhaphies with perineoplasties, 9 enterocele repairs, 32 total colpocleises, and 9 LeFort procedures. Tension-free vaginal tape (TVT) were concomitantly placed in 37 of the cases; 121 TVT-only cases done under local were not included. No cases were converted to general anesthesia. Surgical time ranged from 20 to 195 min (mean 99 min). Most patients were discharged within 24 h of surgery. Traditionally, local anesthesia with sedation has been reserved for superficial vaginal procedures. However, it can be successfully employed for more invasive vaginal reconstructive surgeries. Duration of surgery and patient acceptance have not been limiting factors. The advantages of local anesthesia include minimal interference with homeostasis and rapid recovery with patients often bypassing the recovery unit.


Low-cost fabrication of flexible tactile sensor arrays.
While for vision and audio the same mass-produced units can be embedded in many different systems from smartphones to robots, tactile sensors have to be built in application-specific shapes and sizes. To use a commercially available tactile sensor, it can be necessary to develop the entire system around an existing sensor model. We present a set of open-source solutions for designing, manufacturing, reading and integrating custom application-specific tactile matrix sensors. Our manufacturing process only requires an off-the-shelf cutting plotter and widely available plastic and metal foils. This allows creating sensors of diverse sizes, shapes, and layouts, which can be adapted to various specific use cases as demonstrated with exemplary robot integrations. For interfacing and readout, we develop an Arduino-like prototype board (Tacduino) with amplifier circuits to ensure good resolution and to suppress crosstalk. As an example, we give step-by-step instructions to build tactile fingertips for the RobotiQ 3-Finger Gripper, and we provide design files for the readout circuit board together with Arduino firmware and driver software. Both, wired and wireless communication between the sensors and a host PC are supported by this system. The hardware was originally presented and investigated in [1].


Ethanol extract of Pharbitis nil ameliorates liver fibrosis through regulation of the TGFβ1-SMAD2/3 pathway.
Pharbitis nil (L.) Choisy is a medicinal herb, and herbal remedies based on its seeds have been used to treat of obesity and liver diseases, including fatty liver and liver cirrhosis in East Asia. Liver fibrosis is a major cause of morbidity and mortality in patients with chronic liver inflammation such as that caused by non-alcoholic steatohepatitis. However, no effective pharmaceutical treatment for liver fibrosis has been approved. In this study, we aimed to investigate that ethanol extract of pharbitis nil (PNE) alleviates the liver fibrosis. We studied the effects of PNE on two preclinical models. Six-week-old male C57BL/6 mice were intraperitoneally injected with CCl4 twice weekly for 6 weeks and then treated with 5 or 10 mg/kg PNE daily from week 3 for weeks. Secondly, mice were fed HFD for 41 weeks and at 35 weeks treated with 5 mg/kg PNE daily for the remaining 6 weeks. In addition, we examined the antifibrotic effects of PNE in primary mouse hepatic stellate cells and LX-2 cells. PNE treatment ameliorated hepatocyte necrosis, inflammation, and liver fibrosis in CCl4-treated mice and inhibited the progression of liver fibrosis in mice with HFD-induced fibrosis. PNE reduced the expressions of fibrosis markers and SMAD2/3 activations in mouse livers and in TGFβ1-treated primary mouse hepatic stellate and LX-2 cells CONCLUSIONS: This study demonstrates that PNE attenuates liver fibrosis by downregulating TGFβ1-induced SMAD2/3 activation.


Thiopurine Therapy for Inflammatory Bowel Disease During Pregnancy Is Not Associated with Anemia in the Infant.
Thiopurine exposure throughout pregnancy in patients with inflammatory bowel diseases (IBD) is common and teratogenically safe. Late consequences of in utero exposure to thiopurines and its metabolite, 6-thioguanine nucleotides (6-TGN), such as neonatal and infant anemia are still disputed. To evaluate whether 6-TGN exposure during pregnancy influences anemia in infants at 1 year of life. A comparative observational study was performed between 2009 and 2015 at a multidisciplinary IBD clinic dedicated to pregnant women. The hemoglobin level and signs of anemia between 9 and 15 months after birth of infants born to women exposed to thiopurines throughout the entire pregnancy was compared to infants of women with no thiopurine exposure during pregnancy. Altogether, 34 patients, 21 in the study group and 13 in the control group, were included. The median duration of maternal thiopurine exposure prior to pregnancy was 24 months (range 12-72 months), and median dosage was 100 mg (range 50-175 mg). Maternal IBD activity, infants' iron supplementation, and iron deficiency diagnoses were similar between both groups. The infants' mean hemoglobin level (gr/dL) in the thiopurine-exposed women versus the control group was 11.48 ± 0.8 versus 11.54 ± 0.6, respectively, p = 0.81. The composite risk of any sign of infant anemia was numerically higher in the thiopurine-exposed women, 10 (47%), compared to non-exposed women, 3 (23%), p = 0.17. The mean corpuscular volume, red cell distribution width, white blood cell, and platelet counts were similar among groups. Thiopurine therapy during pregnancy in women with IBD is safe for long-term neonatal outcomes; still large-scale confirmatory studies are required.


Phosphorylation of molluscan paramyosin.
1. In Mytilus edulis two proteins of the contractile apparatus can be phosphorylated by cyclic AMP dependent protein kinases: a 295,000 d protein of unknown function, and paramyosin. 2. Paramyosin isolated from thick filaments by the selective extraction method contains the 106,000 d monomer only, whereas paramyosin extracted from ethanol ether dried powder contains equal amounts of the 108,000 d, and the 106,000 d monomers, and traces of the 104,000 d monomer. 3. Paramyosin isolated from ethanol ether dried powder incorporates up to four times the amount of 32P than paramyosin isolated by the selective extraction method. 4. Cytoplasmatic protein kinases show a higher affinity towards paramyosin as a phosphoryl acceptor than protein kinases associated with paramyosin. 5. Paramyosin of 5-HT treated catch muscles is phosphorylated 2 to 4 times better than paramyosin of ACh treated or untreated catch muscles.


Atypical presentation of cardiomyopathy in a case of maternal mortality that was demonstrated as hypovolemic shock.
Periconceptional and prenatal care should be continued even during COVID-19 pandemics. Indeed, prevention and intervention programs for managing heart failure with aggressive resuscitation and invasive monitoring help to provide the best outcomes in cardiomyopathies. PPH may be associated with cardiac diseases and the resuscitation measures need modification to prevent maternal mortality.


Adaptive interaction torque-based AAN control for lower limb rehabilitation exoskeleton.
In this paper, an adaptive interaction torque-based assist-as-needed (AITAAN) control method for the lower limb rehabilitation exoskeleton is proposed. Firstly, a desired input torque for the wearer's lower limb is designed based on computed torque control (CTC). A nonlinear disturbance observer (NDO) is used to assess the lower limb muscle torque. Subtract the estimated muscle torque from the desired input torque, the exoskeleton only provides the remaining torque through interaction torque. Then, the interaction torque tracking problem can be converted to the exoskeleton trajectory tracking problem by using the spring-damper like dynamics model of the interaction force. A flexible boundary prescribed performance controller (PPC) is designed for the exoskeleton to achieve fast and accurate trajectory tracking. The coupled wearer-exoskeleton system is established in SolidWorks and imported to MATLAB/Simulink with SimMechanics. The AITAAN controller's effectiveness and superiority were then verified through co-simulations.


Pharmacotherapeutic Management of Chronic Lymphocytic Leukaemia in Patients with Comorbidities: New Agents, New Hope.
Chronic lymphocytic leukaemia (CLL) is mostly considered a disease of the elderly. As such, many patients present with comorbidities. Several scores allow for a qualitative and quantitative assessment of comorbidity in patients with CLL. Although our knowledge about the impact of comorbidity on outcomes in patients with CLL is still incomplete, it is becoming increasingly apparent that comorbidities could negatively interfere with CLL treatment. Recently, a number of new agents have been approved for use in patients with previously untreated CLL and comorbidities (i.e. obinutuzumab, ofatumumab), as well as in patients with previously treated or high-risk CLL (i.e. idelalisib, ibrutinib). This review discusses the role of comorbidity in patients with CLL, together with the changing treatment landscape for CLL in this patient population.


Third-generation progestogen type influences hemostatic changes caused by oral contraceptives in Brazilian women.
We compared the effects of two third-generation progestogens, desogestrel (DSG) and gestodene (GSD), on coagulation and fibrinolysis in Brazilian users of oral contraceptives (OCs). Forty-six women were evaluated before treatment and after six cycles of treatment. The coagulation, anticoagulant, and fibrinolytic systems were investigated. During the use of the DSG-containing OC, the activity of factors VII, VIII, IX, X, and XII increased significantly whereas the GSD-containing OC caused no changes in coagulation parameters. Concerning the anticoagulant pathways, the DSG-containing OC increased protein C levels and decreased total protein S levels, and the GSD-containing OC only decreased total protein S. Both OCs increased plasminogen activity, although the DSG-containing OC increased fibrin degradation products levels and decreased the tissue plasminogen activator antigen. In conclusion, we have found that in Brazilian women the effects of DSG and GSD on hemostatic parameters are different and, therefore, third-generation progestogens may not contribute equally to the thrombotic risk.


Retraction: Deficits of learning and memory in Hemojuvelin knockout mice.
This article has been retracted at the request of the authors.


On the role of fronto-striatal neural synchronization processes for response inhibition--evidence from ERP phase-synchronization analyses in pre-manifest Huntington's disease gene mutation carriers.
Fronto-striatal loops play an important role action selection processes, especially when discordant sensory and contextual information has to be integrated to allow adequate selection of actions. Neurodegeneration weakens neural inter-connectivity, which compromises the precision of neural synchronization processes. Yet, it is widely unknown how far changes in the precision of neural synchronization processes are induced by only slight dysfunctions of striatal neural inter-connectivity and in how far such slight changes may affect action selection processes. We investigated these processes in a sample of 25 pre-HDs and case-matched controls in a modified Go/Nogo task, while assessing neural synchronization processes by means of phase-locking factors (PLFs) as derived from event-related potentials (ERPs). The results show that pre-HDs only encounter problems in response inhibition, when discordant contextual information and sensory input have to be integrated. No deficits were evident, when response inhibition can be based on more habitual stimulus-response mappings, i.e., when contextual and sensory information were congruent. While 'habitual' action selection is unaffected by changes in striatal structures influencing reliability of neural synchronization processes, efficient 'controlled' processes of action seem to be closely dependent upon highly reliable neural synchronization processes. The neurophysiological analysis suggests that especially pre-motor inhibition processes (Nogo-N2) are affected. This was most strongly reflected in a decline in the degree of phase-locking in the Nogo-N2 range. Deficits in pre-HDs seem to emerge as a consequence of phase-locking-behavioural decoupling. Of clinical interest, declines in the precision of phase-locking depended on the amount of the individual's mutant huntingtin exposure and predicted the probability of disease manifestation in the next five years. This suggests that phase-locking parameters may prove useful in future studies evaluating a possible function as a biomarker in Huntington's disease.


Lentinula Edodes Mycelia extract regulates the function of antigen-presenting cells to activate immune cells and prevent tumor-induced deterioration of immune function.
Immune cell activation is essential for cancer rejection; however, the tumor microenvironment leads to deterioration of immune function, which enables cancer cells to survive and proliferate. We previously reported that oral ingestion of Lentinula Edodes Mycelia (L.E.M.) extract enhances the tumor antigen-specific T-cell response and exerts an antitumor effect in a tumor-bearing mouse model. In this study, we focused on antigen-presenting cells (APCs) located upstream of the immune system, induced a T-cell response, then examined the impact of L.E.M. extract on the APCs. L.E.M. extract enhanced the expression of MHC-I, MHC-II, CD86, CD80, and CD40 in bone marrow-derived dendritic cells (DCs) and strongly induced the production of IL-12. L.E.M.-stimulated DCs enhanced IFN-γ production from CD8+ T cells and induced their differentiation into effector cells. Furthermore, L.E.M. extract promoted IL-12 production and suppressed the production of IL-10 and TGF-β by transforming bone marrow-derived macrophages into M1-like macrophages. Furthermore, in a B16F10 melanoma inoculation model, DCs in the spleen were decreased and their activation was suppressed by the presence of cancer; however, ingestion of L.E.M. extract prevented this functional deterioration of DCs. In the spleen of cancer-bearing mice, the number of CD11b- F4/80+ macrophages in a hypoactivated state was also increased, whereas L.E.M. extract suppressed the increase of such macrophages. These findings suggest that L.E.M. extract may exhibit an antitumor immune response by regulating the function of APCs to induce cytotoxic T lymphocytes, as well as by suppressing the decline in antigen-presenting cell activity caused by the presence of cancer.


Efficacy of oxfendazole against inhibited Ostertagia ostertagi in naturally infected cattle.
Oxfendazole was administered to pregnant cows at 2.5 and 5 mg/kg body weight to determine the anthelmintic efficacy against naturally acquired larvae which became inhibited at the early 4th stage. The experimental design included three groups of orally-treated cows, that is, 10 placebo treated control cows, 11 cows treated with 2.5 mg/kg of oxfendazole and 10 cows treated with 5.0 mg/kg of oxfendazole. Oxfendazole at 2.5 mg/kg body weight was 82 and 94% effective against EL-4 and adult O. ostertagi, respectively. At 5 mg/kg, Oxfendazole was 95 and 99% effective against EL-4 And adult O. ostertagi, respectively. The results suggested the use of a field dosage level of 5 mg/kg body weight oxfendazole where inhibited larvae may be encountered.


Genomic landscape of microsatellite instability in Chinese tumors: A comparison of Chinese and TCGA cohorts.
Microsatellite instability (MSI) is an important biomarker for predicting the response to immunotherapy and prognosis that mainly results from a defective DNA mismatch repair (MMR) system and strongly correlates with high tumor mutation burden (TMB). Herein, we developed a novel method that integrates MSI score, MMR mutation status and TMB level to identify MSI status from next-generation sequencing (NGS) data. The novel method displays a sensitivity of 96.80%, a specificity of 99.96% and an overall accuracy of 99.89%, compared to current standards. Using our novel method, we analyzed 11 395 Chinese patients across 30 cancer types. High microsatellite instability (MSI-H) was detected in 210 (1.84%) samples in 18 of 30 cancer types assessed. Mutations in ACVR2A (73%), KMT2D (68%), KMT2B (66%) and MMR-related genes (MLH1, MSH2, MSH6 and PMS2) were enriched in MSI-H samples. Furthermore, MSI-H samples were more likely to have high TMB (P < .01), high PD-L1 expression (P < .05) and more tumor-infiltrating immune cells than microsatellite-stable (MSS) samples. Compared to the TCGA patients, the prevalence of MSI-H in the Chinese cohort was significantly lower in colorectal, gastric and pancreatic cancer, while significantly higher in urinary and prostate cancer. Mutations in ACVR2A (73% vs 28%, P < .01) and MMR-related genes (51.4% vs 21.3%, P < .01) were significantly higher in the Chinese population. Thus, our study suggests the fraction of MSI-H attributable to MMR inactivation mutations were lower in European than in Chinese patients, while the proportion of MSI-H due to other events may be higher.


Methylation data of mouse Rb-deficient pineoblastoma.
Methylation profiling is widely used to study tumor biology and perform cluster analysis, particularly in brain cancer research where tissue biopsies are scarce. We have recently reported on the development of novel mouse models for germ line mutations in pineoblastoma (Nature Communications, 2020). Here, we present unpublished methylation profiling of 8 Rb-deleted/p53-deleted pineoblastoma from our mouse model as well as 3 normal cerebellum tissues as control. The primary dataset can be accessed via SRA (PRJNA638504). These methylation data can be used to perform inter- and intra-species comparisons with other brain cancers as well as with specific subtypes of pineoblastoma, and to investigate potential epigenetic mechanisms and pathways underlying Rb-deficient pineoblastoma-genesis..


Injury of the lateral vestibulospinal tract in a patient with the lateral medullary syndrome: Case report.
Lateral medullary syndrome is a central vestibular disorder characterized by vertigo and ataxia. We report on a patient with injury of the lateral vestibulospinal tract (VST) following lateral medullary syndrome, detected on diffusion tensor tractography (DTT). A 56-year-old male patient was diagnosed with lateral medullary syndrome due to an infarction in the posterior inferior cerebellar artery area. Two weeks following the infarction, he was transferred to the rehabilitation department of the same university hospital with severe vertigo, ataxia (Berg balance scale: 16 point), and dysphasia. In contrast, he maintained good motor power and cognitive function (Mini-mental state test: 26 points). N/A OUTCOMES:: Both the patient's medial VSTs and left lateral VST were well-reconstructed. In contrast, the right lateral VST was not reconstructed. On DTT parameters of the VST, the patient's medial VSTs and left lateral VST did not differ significantly from the control subjects. An injury of the right lateral VST was demonstrated in a patient with lateral medullary syndrome. We believe that the result will be helpful in clinical management and research for patients with lateral medullary syndrome.


Hydrolysis of small peptide substrates parallels binding of chymotrypsin inhibitor 2 for mutants of subtilisin BPN'.
Variants of subtilisin BPN' that possess improved specificity towards isoleucine compared with alanine at the P4 position of small peptide substrates, were analysed for their ability to bind chymotrypsin inhibitor 2. The binding of the inhibitor with isoleucine (wild-type) and with alanine as the P4 residue parallels the hydrolysis of tetrapeptide substrates. There is a linear relationship between the free energy of binding of the transition state of the substrate and the free energy of binding of the inhibitor with a slope of 2.0. The data suggest that the inhibitor uses predominantly ground state rather than transition state binding energy.


Bonding Energetics of Palladium Amido/Aryloxide Complexes in DMSO: Implications for Palladium-Mediated Aniline Activation.
Thermodynamic knowledge of the metal-ligand (M-L) σ-bond strength is crucial to understanding metal-mediated transformations. Here, we developed a method for determining the Pd-X (X=OR and NHAr) bond heterolysis energies (ΔGhet (Pd-X)) in DMSO taking [(tmeda)PdArX] (tmeda=N,N,N',N'-tetramethylethylenediamine) as the model complexes. The ΔGhet (Pd-X) scales span a range of 2.6-9.0 kcal mol-1 for ΔGhet (Pd-O) values and of 14.5-19.5 kcal mol-1 for ΔGhet (Pd-N) values, respectively, implying a facile heterolytic detachment of the Pd ligands. Structure-reactivity analyses of a modeling Pd-mediated X-H bond activation reveal that the M-X bond metathesis is dominated by differences of the X-H and Pd-X bond strengths, the former being more influential. The ΔGhet (Pd-X) and pKa (X-H) parameters enable regulation of reaction thermodynamics and chemoselectivity and diagnosing the probability of aniline activation with Pd-X complexes.


[Enhanced activity of the protective factors in patients with suppurative surgical infection using interferon preparations].
Administration of leukocytic interferon to patients with sepsis and purulent resorptive fever resulted in a reliable increase in the indices of the host protective factors with respect to the infections. Addition of interferon to the surgical and antibacterial treatment promoted a decrease in the periods providing the clinical effect to 19.8 days against 43.8 days in the treatment without interferon.


Development of a specific molecular marker for SLG7 on high-quality rice breeding.
In recent years, the long-grain shape has been found as a new desired quality trait in the breeding of rice in China. The SLG7 gene is a novel gene responsible for slender grain shape in rice. So far, not much information is known regarding the functional molecular markers of SLG7. In this study, a functional marker M-SLG7 for the 11-bp deletion of promoter region of SLG7 was developed. Specificity and applicability of the marker were verified by 60 core breeding accessions and two breeding populations. The accessions, which possessed the SLG7 allele with 11-bp deletion in the promoter region, had longer grain length and better quality. Here, we recommend the use of the simple, inexpensive assay for routine genotyping of slender grain and lower chalkiness in the breeding population for discrimination of SLG7 genotype in rice germplasm.


A new three-dimensional patient-specific cutting guide for opening wedge high tibial osteotomy based on ct scan: preliminary in vitro results.
The aim of this study was to evaluate the accuracy of a patient-specific cutting guide on both coronal and sagittal alignment compared to the pre-operative planning in OWHTO. Twelve OWHTO on 6 cadaveric specimens were performed by 3 experienced knee surgeons using patient-specific cutting guides based on 3D pre-operative planning. Since the specimens had no major deformities, a fixed correction of 6° on the left and 10° on the right legs were carried out to simulate different scenarios. A pre-operative and post-OWHTO 3D CT scans were performed, and images were superimposed using the dedicated 3D planning software to align their reference axes. A pre-operative planning was performed considering both Medial Proximal Tibial Angle (MPTA) and Posterior Tibial Slope (PTS), and a patient-specific cutting guide was produced. Planned and post-OWHTO MPTA and PTS were evaluated (mean and standard deviation), and Pearson's correlation coefficient was calculated to assess precision and accuracy of the whole treatment. A mean correction of 6,1° (SD 1,9°) and 1,2° (SD 1°) was obtained respectively in the coronal plane (MPTA) and in the sagittal plane (PTS). The average difference between planned and post-OWHTO MPTA and PTS was respectively 1,2° (SD 0,6°) and 1,2° (SD 1°) in the sagittal plane (PTS). Pearson's correlation coefficient demonstrated a good accuracy of the treatment in both coronal and sagittal plane (respectively r=0,95 and r=0,86). No lateral hinge fractures were detected at the post-operative CT scan. OWTHO performed with the help of 3D patient specific cutting guide on cadaveric specimens demonstrated good accuracy and reliability in obtaining the planned correction. In vivo studies are necessary to confirm these results and evaluate cost-effectiveness of this system. Level IV cadaveric study.


[Quality of life becomes measurable. What are the consequences for general practice?].
Research into quality of life in medicine has since developed from a stepchild viewed with skepticism to a major aspect of patient-oriented medicine. Measuring instruments are now available, are increasingly being applied, and can make a contribution towards improving the care afforded the patient.


Age and the balance of emotions.
With age, the quality of emotions may shift from negative in tone to positive, but also from active to passive. The shift from negative to positive is consistent with the age as maturity perspective. The shift from active to passive supports the age as decline perspective. If these generalities are correct, then they should apply to positive emotions as well as negative emotions. We should see a shift in positive emotions from active (excitement) to passive (serenity), as well as in the negative emotions (from the agitation of anxiety and anger to the lethargy of depression). In order to accurately portray the shifts in emotional tone, age may best be considered as simultaneously indicating maturity and decline. This paper examines results from the emotions module of the 1996 U.S. General Social Survey and finds support for the idea that age is associated with a shift from negative to positive and from active to passive emotions.


Cancer-related post-treatment pain and its impact on treatment satisfaction with medication in women with breast cancer: a cross-sectional study from Palestine.
Pain after therapy is an important clinical problem in patients with breast cancer. Unfortunately, cancer patients have a lower quality of life due to inadequate treatment of posttreatment pain; therefore, improving medication management plans and palliative care has become one of the most important targets of cancer therapy. Therefore, the current study aimed to examine the impact of posttreatment pain on medication satisfaction in patients with various stages of breast cancer in Palestine. A cross-sectional analytical study was conducted et al.-Watani Hospital and An-Najah National University Hospital in the Nablus area. Using the Brief Pain Inventory (BPI), the intensity and interference of pain were evaluated. In addition, patients' satisfaction with cancer management medications was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM). Two hundred fifty-four patients were included in this study. All were women, with a mean ± SD age of 53.1 ± 10.7 years. The median score for pain severity was 7.0. Pain in the lower extremities was the most reported location. There was a negative association between the global satisfaction domain and the presence of posttreatment pain (p < 0.001). Furthermore, significant differences and negative correlations were found between global satisfaction and posttreatment pain on the day of the interview (p = 0.001), pain medication (p < 0.001), paracetamol use (p < 0.001), and the presence of side effects (p = 0.003). There were significant negative correlations (p < 0.05) between pain severity and interference with effectiveness (r = -0.258, -0.319, respectively), side effects (r = -0.414, -0.514, respectively), convenience (r = -0.274, -0.307, respectively), and global satisfaction domain scores (r = -0.293, -0.287, respectively). Exposure to chemotherapy was the only significant positive correlation with global satisfaction (p = 0.007). The regression analysis results indicated an independent association between chemotherapy use and a higher global satisfaction score (p = 0.011). Patients with posttreatment pain, side effects, and greater interference of pain with their functioning had lower satisfaction scores. Therefore, better management of their treatment medications, side effects, and pain medications is recommended to enhance their satisfaction and quality of life. Several aspects of palliative care should be organized to improve the patient's satisfaction and quality of life in addition to conducting longitudinal studies to evaluate the pain and satisfaction of different types of cancers.


Integration of metal-free ATRP and Diels-Alder reaction toward sustainable and recyclable cellulose-based thermoset elastomers.
Well-defined sustainable and recyclable thermoset elastomers derived from cellulose, fatty acid and furfural were successfully prepared via photoinduced metal-free ATRP and Diels-Alder (DA) reaction. Firstly, metal free ATRP was applied to prepare a range of thermoplastic cellulose graft copolymers with furfural groups. Then, a modified epoxidized soybean oil bearing 6-maleimidohexanoic group (ESOM) as a crosslinker was employed to perform DA reaction with furfural groups in these cellulose graft copolymers, by which the copolymer formed the dynamic crosslinked network and achieved the thermoset elastomers. The dynamic crosslinked network formed by DA reaction not only could increase the chain entanglement that was associated with the improved flexibility and could contribute to enhancing the mechanical strength up to 166 %, but also endowed these thermoset elastomers with recyclability, excellent shape memory and self-healing property. These thermoset elastomers can be used as self-healing strain sensor and wearable sensing devices after compounding them with carbon nanotubes.


Effect of Vitamin D3 on Depressive Behaviors of Rats Exposed to Chronic Unpredictable Mild Stress.
Depression is a psychiatric disorder that negatively affects how a person feels, thinks, and acts. Several studies have reported a positive association between vitamin D (VD) deficiency and depression. Therefore, we aimed to examine the effects of intraperitoneal injection of VD3, fluoxetine (antidepressant), and a combination of VD3 + fluoxetine on a rat model of chronic unpredictable mild stress (CUMS). A total of 40 male Wistar rats (224-296 g) were divided into five groups (n = 8 each) as follows: (1) the control group, (2) the CUMS group, (3) the CUMS group that received vitamin D (10 μg/kg), (4) the CUMS group that received fluoxetine (5 mg/kg), and (5) the CUMS group that received both vitamin D (10 μg/kg) and fluoxetine (5 mg/kg). The CUMS model was produced by exposing rats to frequent social and physical stressors for 21 days. In addition, blood samples were collected to determine corticosterone and serum VD levels. Also, behavioral tests were conducted, including the sucrose preference test (SPT), the forced swimming test (FST), the tail suspension test (TST), the open field test (OFT), and the elevated plus maze test (EPM). Our results show that VD3 had effects similar to fluoxetine on the depressive behavior of the rats when measured by three behavioral tests, namely SPT, FST, and OFT (p < 0.001). Additionally, VD3 had a protective effect against depression similar to that of fluoxetine. Corticosterone levels were lower in the CUMS group that received vitamin D and the CUMS group that received both vitamin D and fluoxetine than in the CUMS group (p < 0.000). In conclusion, VD3 has a protective effect against anxiety and depressive behaviors produced by CUMS in rats.


Temperature-dependent skin disorders.
The skin is important in preserving homeostasis between man and his environment. One main role of the skin is in thermoregulation, where cutaneous blood flow, and hence skin temperature, vary widely in order to help preserve core body temperature. Under extreme conditions, frostbite or burns may occur. Prolonged exposure to moderate degrees of heat or cold can result in erythema ab igne and chilblains. Temperature plays a direct role in some of the physical urticarias and is one of several important pathogenic factors in conditions such as Raynaud's syndrome, cold panniculitis, and cryoglobulinemia. These and other temperature-dependent skin disorders are reviewed.


Analysis on ecological characteristics of Mississippian coral reefs in Langping, Guangxi.
Several Late Viséan-Serpukhovian coral reefs were identified in Langping, Tianlin. They provided an opportunity to investigate paleo-environments suitable for the development of reef-building communities and the construction of coral reefs in Langping. In this paper, part of the reef-building environmental and the ecological characteristics of coral reefs then were elaborated by analyzing the development settings, palaeogeography, sedimentation of reefs, the response to hydrodynamic conditions of reef-building corals, effects of disturbance and non-reef-building organism on reef communities, and the influence of coral morphology on reef development. It is considered that the sedimentary environment of Langping in Late Viséan-Serpukhovian is suitable for the development of benthic communities. The current appearance of reefs is determined by both coral populations ecological characteristics and reef-building environment.


Amelioration of tacrolimus-induced nephrotoxicity in rats using juniper oil.
Calcineurin-inhibitor nephrotoxicity plays a role in the pathogenesis of chronic allograft nephropathy by causing renal ischemia mediated by vasoconstrictive metabolites of the prostanoid pathway. The purpose of our study was to evaluate whether altering the prostanoid profile using juniper oil (JO) would afford renoprotection in rats treated with tacrolimus. Diets supplemented with biologic oils (no supplementation, JO, fish oil [FO], safflower oil [SO], and arachidonic acid [AA]) were fed to five groups of rats for 5 weeks; during the last 2 weeks, tacrolimus was administered to all groups except for a control group of animals. At week 5, urinary prostaglandin (PG)F(2-alpha) and inulin clearances were measured. The rat kidneys were harvested to determine the renal cell membrane composition for arachidonic, eicosatrienoic, and eicosapentaenoic acids. Both JO and FO completely reversed the decrease in inulin clearance seen with tacrolimus, the greatest effect being with JO (inulin clearance 15.1+/-3 vs. 6.0+/-1.1 ml/min in the nonsupplemented group; P<0.001); urinary PGF(2-alpha) excretion was also highest in the JO group (328+/-23 pg/mL, P<0.001 vs. the nonsupplemented group). Fatty acid membrane analysis showed greatest incorporation of eicosapentaenoic and eicosatrienoic acids in the JO- (5.7+/-0.6% and 3.1+/-0.4%, respectively) and FO- (8.1+/-0.7% and 2.8+/-0.6%, respectively) treated animals. JO supplementation in tacrolimus-treated rats was associated with incorporation of vasodilatory prostanoids in the renal-cell membrane and elevated urinary PGF(2-alpha) excretion, and the precipitous fall in inulin clearance induced by tacrolimus was completely prevented. Whether this benefit will translate into a reduction in chronic allograft nephropathy remains to be determined. However, our preliminary data point towards the need for human trials.


Setting the stage subliminally: unconscious context effects.
An important approach to understand how the brain gives rise to consciousness is to probe the depth of unconscious processing, thus to define the key features that cause conscious awareness. Here, we investigate the possibility for subliminal stimuli to shape the context for unconscious processing. Context effects have generally been assumed to require consciousness. In the present experiment, unconscious context processing was investigated by looking at the impact of the context on the response activation elicited by a subliminal prime. We compared the effects of the same subliminal prime on target processing when the prime was embedded in different unconscious contexts. Results showed that the same prime can evoke opposite responses depending on the unconscious context in which it is presented. Taken together, the results of this study show that context effects can be unconscious.


A Bayesian network meta-analysis of ALK inhibitor treatments in patients with ALK-positive non-small cell lung cancer.
To date, no direct comparisons have compared the effectiveness of all ALK inhibitors (ALKis) against ALK-positive non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the efficacy and safety of ALKis in ALK-positive NSCLC. The effectiveness of ALKis was evaluated by assessing progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and PFS with baseline brain metastasis (BM). The serious adverse events (SAEs: Grade ≥ 3) and adverse events (AEs) leading to discontinuation were pooled to evaluate safety. We conducted an indirect treatment comparison between all ALKis by using a Bayesian model. Twelve eligible trials including seven treatments were identified. All of the ALKis improved PFS and ORR relative to chemotherapy. Consistent with alectinib, brigatinib, lorlatinib, and ensartinib showed significant differences versus crizotinib and ceritinib. Lorlatinib seemed to prolong PFS compared with alectinib (0.64, 0.37 to 1.07), brigatinib (0.56, 0.3 to 1.05), and ensartinib (0.53, 0.28 to 1.02). No significant difference was found among them in OS except for alectinib versus crizotinib. Moreover, alectinib was significantly more effective than crizotinib (1.54, 1.02 to 2.5) in achieving the best ORR. Subgroup analyses based on BM indicated that PFS was dramatically lengthened by lorlatinib. Compared with other ALKis, alectinib notably reduced the rate of SAEs. There was no striking difference between discontinuation for AEs, except for ceritinib versus crizotinib. The ranking of validity showed that lorlatinib had the longest PFS (98.32%) and PFS with BM (85.84%) and the highest ORR (77.01%). The rank of probabilities showed that alectinib had the potentially best safety in terms of SAEs (97.85%), and ceritinib had less discontinuation (95.45%). Alectinib was the first choice for patients with ALK-positive NSCLC and even for those with BM, whereas lorlatinib was the second choice. Long-term follow-up and prospective studies are warranted to compare ALKis and to verify our conclusions directly.


Homeobox gene expression in human oocytes and preembryos.
Homeobox gene expression in human preimplantation development has not been established. We used reverse transcriptase-polymerase chain reaction (RT-PCR) with intron spanning primer sets to investigate the presence of mRNA of homeobox genes in human oocytes and preembryos. RT-PCR products obtained from normal and unfertilized oocytes, from cleaving normal and triploid embryos, and from morulae and blastocysts were cloned, sequenced, and analyzed for the presence of homeobox sequences. The presence of mRNA of homeoboxes HoxA4 and HoxA7 was demonstrated; HoxA4 was present in normal and unfertilized oocytes and also in a 4-cell embryo. HoxA7 was present in normal oocytes and cleaving triploid embryos.


SOSSB1 and SOSSB2 mutually regulate protein stability through competitive binding of SOSSA.
Human single-stranded DNA-binding protein homologs hSSB1 (SOSSB1) and hSSB2 (SOSSB2) make a vital impact on maintaining genome stability as the B subunits of the sensor of single-stranded DNA complex (SOSS). However, whether and how SOSSB1 and SOSSB2 modulate mutual expression is unclear. This study, demonstrated that the depletion of SOSSB1 in cells enhances the stability of the SOSSB2 protein, and conversely, SOSSB2 depletion enhances the stability of the SOSSB1 protein. The levels of SOSSB1 and SOSSB2 proteins are mutually regulated through their competitive binding with SOSSA which associates with the highly conservative OB-fold domain in SOSSB1 and SOSSB2. The destabilized SOSSB1 and SOSSB2 proteins can be degraded via the proteasome pathway. Additionally, the simultaneous loss of SOSSB1 and SOSSB2 aggravates homologous recombination (HR)-mediated DNA repair defects, enhances cellular radiosensitivity and promotes cell apoptosis. In conclusion, in this study, we showed that SOSSB1 and SOSSB2 positively regulate HR repair and the interaction between SOSSA and SOSSB1 or SOSSB2 prevents the degradation of SOSSB1 and SOSSB2 proteins via the proteasome pathway.


Mitochondrial biogenesis in cultured mammalian cells. II. Mitochondrial protein and phospholipid synthesis in chloramphenicol-treated BHK-21 cells.
The effect of growth of BHK-21 cells in chloramphenicol on the synthesis of cellular proteins and phospholipids has been examined. The incorporation of leucine into total cellular proteins, or into the proteins of specific subcellular fractions are not significantly reduced by cell culture in the presence of chloramphenicol. In cells treated with cycloheximide, a small amount of chloramphenicol-sensitive labelling of protein was detected within the first hour of exposure to the drug. Chloramphenicol inhibits the incorporation of delta-amino-levulinic acid into hemoproteins, only if it is present during both the 48-h culturing and 4-h labelling period. De novo synthesis of cellular lipids as measured by pulse labelling with 32Pi or [3H]glycerol, is decreased in chloramphenicol-treated cells. This decrease is observed in all sub-cellular fractions, although the mitochondrial fraction is most affected. All phospholipids are affected, with diphosphatidylglycerol labelling reduced to the greatest extent. Although fatty acid synthesis is inhibited, the labelling of diphosphatidylglycerol with fatty acids is stimulated on chloramphenicol treatment.


Marked increase in tumor transfection with a truncated branched polymer.
We previously determined that polyplexes formed by linear H2K peptides were more effective in transfecting tumors in vivo than polyplexes formed by branched H2K4b-20 peptides. Based on trypsin digest and salt displacement studies, the linear H2K polyplexes were less stable than the branched H2K4b-20 polyplexes. Because binding and release of the polymer and DNA from the H2K4b-20 polyplex may account for the ineffectiveness, we investigated whether four-branched histidine-lysine (HK) peptides with varying numbers of amino acids in their branches would be more effective in their ability to increase gene expression in tumors in vivo. Linear and branched peptides with multiple -KHHK- motifs were synthesized by solid-phase synthesis. The branched H2K4b-20, -18, -14 and 12 peptides had 20, 18, 14 and 12 amino acids in their branches, respectively. These peptides were examined for their ability to carry luciferase-expressing plasmids to human breast cancer xenografts in a mouse model. With gel retardation and in vivo transfection, the incorporation of a targeting ligand and an endosomal lysis peptide into these polyplexes was also examined. A blocking antibody was pre-injected prior to the polyplexes to determine the role of neuropilin 1 in the uptake of these polyplexes by the tumor. The size of the polyplexes was measured by dynamic light scattering. Of the four negative surface-charge polyplexes formed by the branched carriers, the H2K4b-14 polyplex was determined to be the most effective plasmid delivery platform to tumors. The incorporation of a targeting ligand and an endosomal lysis peptide into H2K4b-14 polyplexes further enhanced their ability to transfect tumors in vivo. Furthermore, after pre-injecting tumor-bearing mice with a blocking antibody to the neuropilin-1 receptor (NRP-1), there was a marked reduction of tumor gene expression with the modified H2K4b-14 polyplexes, suggesting that NRP-1 mediated their transport into the tumor. The present study established that branched peptides intermediate in length were very efficient in delivering plasmids to tumors in vivo.


A novel lncRNA ROPM-mediated lipid metabolism governs breast cancer stem cell properties.
Cancer stem cells (CSCs) are considered as the major cause to tumor initiation, recurrence, metastasis, and drug resistance, driving poor clinical outcomes in patients. Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in cancer development and progression. However, limited lncRNAs involved in CSCs have been reported. The novel lncROPM (a regulator of phospholipid metabolism) in breast CSCs (BCSCs) was identified by microarray and validated by qRT-PCR in BCSCs from breast cancer cells and tissues. The clinical significance of lncROPM was evaluated in two breast cancer cohorts and TANRIC database (TCGA-BRCA, RNAseq data). Gain- and loss-of-function assays were performed to examine the role of lncROPM on BCSCs both in vitro and in vivo. The regulatory mechanism of lncROPM was investigated by bioinformatics, RNA FISH, RNA pull-down, luciferase reporter assay, and actinomycin D treatment. PLA2G16-mediated phospholipid metabolism was determined by UHPLC-QTOFMS system. Cells' chemosensitivity was assessed by CCK8 assay. LncROPM is highly expressed in BCSCs. The enhanced lncROPM exists in clinic breast tumors and other solid tumors and positively correlates with malignant grade/stage and poor prognosis in breast cancer patients. Gain- and loss-of-function studies show that lncROPM is required for the maintenance of BCSCs properties both in vitro and in vivo. Mechanistically, lncROPM regulates PLA2G16 expression by directly binding to 3'-UTR of PLA2G16 to increase the mRNA stability. The increased PLA2G16 significantly promotes phospholipid metabolism and the production of free fatty acid, especially arachidonic acid in BCSCs, thereby activating PI3K/AKT, Wnt/β-catenin, and Hippo/YAP signaling, thus eventually involving in the maintenance of BCSCs stemness. Importantly, lncROPM and PLA2G16 notably contribute to BCSCs chemo-resistance. Administration of BCSCs using clinic therapeutic drugs such as doxorubicin, cisplatin, or tamoxifen combined with Giripladib (an inhibitor of cytoplasmic phospholipase A2) can efficiently eliminate BCSCs and tumorigenesis. Our study highlights that lncROPM and its target PLA2G16 play crucial roles in sustaining BCSC properties and may serve as a biomarker for BCSCs or other cancer stem cells. Targeting lncROPM-PLA2G16 signaling axis may be a novel therapeutic strategy for patients with breast cancer.


Sestrin regulation of TORC1: Is Sestrin a leucine sensor?
Sestrins are highly conserved, stress-inducible proteins that inhibit target of rapamycin complex 1 (TORC1) signaling. After their transcriptional induction, both vertebrate and invertebrate Sestrins turn on the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which activates the tuberous sclerosis complex (TSC), a key inhibitor of TORC1 activation. However, Sestrin overexpression, on occasion, can result in TORC1 inhibition even in AMPK-deficient cells. This effect has been attributed to Sestrin's ability to bind the TORC1-regulating GATOR2 protein complex, which was postulated to control trafficking of TORC1 to lysosomes. How the binding of Sestrins to GATOR2 is regulated and how it contributes to TORC1 inhibition are unknown. New findings suggest that the amino acid leucine specifically disrupts the association of Sestrin2 with GATOR2, thus explaining how leucine and related amino acids stimulate TORC1 activity. We discuss whether and how these findings fit what has already been learned about Sestrin-mediated TORC1 inhibition from genetic studies conducted in fruit flies and mammals.


Adsorption of Cd(II), Cu(II) and Ni(II) ions by Lemna minor L.: effect of physicochemical environment.
The free floating macrophyte Lemna minor L. was harvested locally. Untreated, acid pretreated (H2SO4), alkali pretreated (NaOH) biomass were used for adsorption of copper, cadmium and nickel ions from aqueous solutions. The effect of initial pH, initial metal concentration and multi metal interaction were carried out in a batch system. The equilibrium adsorption was reached within 40-60 min. The Langmuir and Freundlich models were used for describing of adsorption isotherm data. The maximum adsorption capacities of alkali pretreated biomass were determined as 83, 69 and 59 mg g(-1) for the Cd(II), Cu(II) and Ni(II) ions, respectively. The pseudo first- and second-order intraparticle diffusion models were used to describe the adsorption kinetics. The experimental data fitted to pseudo second-order kinetic. Adsorption capacity decreased with acid pretreatment; however alkali pretreatment was not affected significantly adsorption capacity and adsorption capacity a little increased according to native biomass. The FT-IR results of Lemna biomass showed that biomass has different functional groups and these functional groups are able to react with metal ions in aqueous solution.


The effects on glucose metabolism of feeding a high-urea diet to sheep.
1. Sheep were given either a basal diet of 107 g crude protein (nitrogen X 6.25)/kg or the same diet to which urea was added to increase the crude protein content to 221 g/kg. Isotope-dilution techniques with [U-14C]glucose and [2-3H]glucose were used to measure various criteria of glucose metabolism. The plasma concentrations of urea and potassium were determined. The sheep were then given the alternative diet and the experiment was repeated. 2. Plasma K concentrations were decreased on feeding urea (P less than 0.05). 3. Plasma glucose concentrations were reduced on the urea treatment (P less than 0.05), while glucose space and metabolic clearance rate were not significantly reduced (P greater than 0.05). 4. Some implications for the feeding of non-protein-N to ruminants are discussed.


'Effective inefficiency': cellular control of protein trafficking as a mechanism of post-translational regulation.
The great writer and polyglot, W Somerset Maugham said, 'I'll give you my opinion of the human race in a nutshell...their heart's in the right place, but their head is a thoroughly inefficient organ.' If his words are applied to trafficking of the human pituitary gonadotropin-releasing hormone receptor, it turns out that he was more right than he knew. Paradoxically, the inefficiency of receptor trafficking to the plasma membrane can bring regulatory advantages to cells. Understanding the mechanism by which cells recognize correctly folded proteins in health and disease opens doors to new therapeutic approaches and provides a more accurate view of mechanisms of normal cell function than is presently available.


Development of an in-house bone marrow collection kit: The Catalan bone marrow transplantation group experience.
Bone marrow (BM) harvesting is one of the essential sources of stem cells for haematopoietic stem cell transplantation. In 2019, commercial BM collection kits became unavailable in Europe. Consequently, we created an in-house BM collection kit as an alternative. We compared two groups of BM collections. The first collections were taken using an in-house kit from June 2022 through February 2023 and the second with a commercial kit from February 2021 through May 2022. These all took place at seven collection centres (CC). We analysed the harvest quality (cell blood count, CD34+ cells, viability, potency and sterility), the incidents occurring with each kit and the time to neutrophil and platelet engraftment in recipients. A total of 23 donors underwent BM harvesting with the in-house kit and 23 with the commercial one. Both cohorts were comparable regarding donor characteristics, CC and time to procedure. No statistical differences were found in harvest quality between the in-house and commercial kits. A new transfusion set was required in three BM harvests (13%) with the in-house kit because of filter clogging. The median time to neutrophil and platelet engraftment was 21 days for both cohorts and 29 days (in-house) and 33 days (commercial), p = 0.284, respectively. The in-house BM collection kit offers a real approach to solve the diminished supply of commercial kits. A higher risk of filter clogging was observed compared with commercial kits due to the lack of 850 and 500 μm filters.


Isolation of 3-O-(4'-hydroxybenzyl)-beta-sitosterol and 4-[4'-(4"-hydroxybenzyloxy)benzyloxy]benzyl methyl ether from fresh tubers of Gastrodia elata.
Two new 4-hydroxybenzyl alcohol derivatives (1 and 2) were isolated from the methanol extract obtained from fresh tubers of Gastrodia elata together with 4-hydroxybenzyl methyl ether, 4-hydroxybenzyl alcohol, bis(4-hydroxyphenyl)methane, 4-hydroxybenzaldehyde, beta-sitosterol and palmitic acid. 1 and 2 were identified as 3-O-(4'-hydroxybenzyl)-beta-sitosterol and 4-[4'-(4"-hydroxybenzyloxy)benzyloxy]benzyl methyl ether, respectively, according to the spectroscopic data.


Public opinion and experiences of crime two and five years following the implementation of a targeted regulation of licensed premises in Newcastle, Australia.
In 2008 additional licensing restrictions were imposed on 'high-risk' licensed premises in the entertainment precinct of Newcastle (Australia) including earlier closing, a 'lock-out' and additional responsible service of alcohol restrictions. A study was conducted to assess community perceptions, experiences of crime and support for the restrictions, 2 and 5 years following implementation. Telephone surveys were conducted with random samples of Newcastle community members (≥18 years) in 2010 and 2013. Change over time in perceptions and experiences of crime, and awareness and support of the conditions was analysed using logistic regression analyses for all participants, and separately for night-time visitors. Among all participants (2010: n = 376; 2013: n = 314) the perception that alcohol misuse was a problem declined between 2010 and 2013 for all participants (90% to 85%; P = 0.02), and specifically among night-time visitors (87% to 75%; P = 0.06). Awareness of the restrictions was high among all participants and sub-groups, and remained constant over time. Support for the restrictions was also high, with drink restrictions being the most popular. More night-time visitors reported that conditions made the streets safer in 2013 (62%) than 2010 (47%; P = 0.05). Support for applying restrictions to all licensed premises in the Newcastle entertainment precinct (83%) and across New South Wales was high in 2013 (86%). At 2 years and 5 years following implementation of additional licensing restrictions, significant improvements in public perceptions of the occurrence of alcohol-related harm and crime were evident, as were high levels of support for the restrictions.


IL-19 Halts Progression of Atherosclerotic Plaque, Polarizes, and Increases Cholesterol Uptake and Efflux in Macrophages.
Atherosclerosis regression is an important clinical goal, and treatments that can reverse atherosclerotic plaque formation are actively being sought. Our aim was to determine whether administration of exogenous IL-19, a Th2 cytokine, could attenuate progression of preformed atherosclerotic plaque and to identify molecular mechanisms. LDLR(-/-) mice were fed a Western diet for 12 weeks, then administered rIL-19 or phosphate-buffered saline concomitant with Western diet for an additional 8 weeks. Analysis of atherosclerosis burden showed that IL-19-treated mice were similar to baseline, in contrast to control mice which showed a 54% increase in plaque, suggesting that IL-19 halted the progression of atherosclerosis. Plaque characterization showed that IL-19-treated mice had key features of atherosclerosis regression, including a reduction in macrophage content and an enrichment in markers of M2 macrophages. Mechanistic studies revealed that IL-19 promotes the activation of key pathways leading to M2 macrophage polarization, including STAT3, STAT6, Kruppel-like factor 4, and peroxisome proliferator-activated receptor γ, and can reduce cytokine-induced inflammation in vivo. We identified a novel role for IL-19 in regulating macrophage lipid metabolism through peroxisome proliferator-activated receptor γ-dependent regulation of scavenger receptor-mediated cholesterol uptake and ABCA1-mediated cholesterol efflux. These data show that IL-19 can halt progression of preformed atherosclerotic plaques by regulating both macrophage inflammation and cholesterol homeostasis and implicate IL-19 as a link between inflammation and macrophage cholesterol metabolism.


Intracellular signal cascade in CD4+ T-lymphocyte migration stimulated by interferon-gamma-inducible protein-10.
The intracellular signal cascades involved in chemokine-stimulated migration of in vitro activated human peripheral blood CD4+ T-lymphocytes were investigated. IP-10-mediated chemotactic response of lymphocytes was decreased in the presence of selective inhibitors of Src-kinases (by 40-45%), PI3-kinases (35-40%), and MAP-kinases ERK1/2 (35-40%) and p38 (20%). Combined addition of specific inhibitors of Src-kinases and PI3-kinases and inhibitors of Src-kinases and ERK1/2 MAP-kinases did not result in the further increase of the inhibitory effect, while the combined addition of specific inhibitors of PI3-kinases and ERK1/2 MAP-kinases decreased migration of CD4+ T-lymphocytes more effectively (by 55-60%) than any individual inhibitor. Immunoblotting analysis of activation of MAP-kinases ERK1/2 and p38 revealed increased level of phosphorylation of ERK1/2 and p38 MAP-kinases in the presence IP-10. Selective inhibitors of Src-kinases and PI3-kinases significantly inhibited phosphorylation of p38 but did not influence phosphorylation of ERK1/2 MAP-kinases. Our results suggest that Src-kinases, PI3-kinases, and ERK1/2 MAP-kinases are involved in intracellular signal cascade activated during IP-10-stimulated migration of T-lymphocytes, whereas p38 MAP-kinases do not participate in the migration process, although its activation induced by IP-10 depends on Src-kinases and PI3-kinases.


Outpatient electrical cardioversion of atrial fibrillation: efficacy, safety and patients' quality of life.
Atrial fibrillation (AF) is the most common sustained arrhythmia. To lower costs and to reduce hospitalization electrical cardioversion (CV) is frequently performed in an outpatient setting although data on safety and patient-acceptance are sparse. Aims of this study were to fill this gap by evaluating efficacy, complication rate, quality of life after CV and patient-acceptance of outpatient CV. One-hundred and eleven consecutive patients with persistent AF were included. Patients were under continuous monitoring throughout the procedure and 3 h after. CV was done in deep sedation using rising energies (200->360 J). Quality of life (QoL), late adverse events and patient-acceptance were assessed 4 weeks after CV. AF could be terminated with a mean of 1.4 shocks in all patients. Acute adverse events could be observed in 3.6%. Late adverse events were noted in 8.2%. Seventy-four percent of the patients felt "good" or "very good" the day of CV. Eighty-nine percent of the patients would undergo a CV again and in case of a further CV 69% of the patients would prefer an outpatient setting. Patients with a lower QoL-classification had longer duration of atrial fibrillation (median 1 vs. 3 months, p<0.05). No other clinical predictor for adverse events or a low QoL-classification could be identified. Electrical CV of persistent AF in an outpatient setting is feasible, safe and has a high patient-acceptance.


Clinical parameters and intrathecal IgG synthesis as prognostic features in multiple sclerosis. Part I.
In a search for early prognostic features in multiple sclerosis, the progression rate was calculated in 200 consecutive multiple sclerosis patients who had had a lumbar puncture, and correlated with age at onset, type of disease course, the patient's sex, as well as with indices of blood-brain barrier breakdown and intrathecal IgG synthesis. The present study demonstrates that age at onset plays a role in determining whether the disease will be remitting-relapsing or chronic progressive. Age at onset is also a factor determining the rate of progression of the remitting-relapsing form, but is without influence on the progression of the chronic progressive form. A chronic progressive disease course per se (independent of age at onset) is also associated with a more rapid deterioration. The patient's sex does not appear to be a differentiating factor. Only inconsistent correlations were found between IgG index or number of oligoclonal bands in the CSF and disease progression.


Stress radiography in the diagnosis and assessment of the outcomes of surgical treatment of chronic anterolateral ankle instability.
In about 20-40% of patients, damage to the soft tissues surrounding the ankle leads to recurrent and chronic pain with signs of instability of the talus in the tibiofibular fork. The aim of the study was to assess the usefulness of stress X-ray images in the diagnosis of long-term outcomes of conservative versus surgical treatment of anterolateral ankle instability. Thirty patients with chronic ankle instability (CAI) were recruited for the study. The participants were divided into two groups. The first group consisted of 15 non-operatively treated individuals diagnosed with anterior talofibular ligament (ATFL) damage. The second group consisted of 15 patients who had undergone surgical reconstruction of the ATFL. In both groups of patients, the contralateral normal limb was used as a control. In all patients, anteroposterior and lateral view stress radiographs of both ankles were taken using the TELOS Stress Device (GA - III/E, Hungen, Germany). Statistical tests showed that the surgically treated patients had a significantly greater ankle stability compared to the non-surgically treated patients (P = 0.001 for talar tilt angle and P = 0.009 for anterior drawer distance). The results obtained in this study indicate that this method can also be used in postoperative assessment of the function of the reconstructed lateral ankle ligaments. Stress radiography is a reliable and safe tool for diagnosing CAI. This imaging method is an objective instrument that can be successfully used in postoperative assessment of the function of the reconstructed ATFL.


Both allelic forms of the rat T cell differentiation marker RT6 display nicotinamide adenine dinucleotide (NAD)-glycohydrolase activity, yet only RT6.2 is capable of automodification upon incubation with NAD.
The finding that recently cloned mono-ADP-ribosyltransferases show sequence similarity to the rat T cell differentiation marker RT6 has led us to investigate the enzymatic activity of this alloantigenic system. To search for ADP-ribosylation of cell surface proteins, T cell populations from RT6.1- and RT6.2-expressing rat strains, as well as RT6.1+ and RT6.2+ T-T hybridoma cell lines, were incubated with [32P]nicotinamide adenine dinucleotide (NAD). All RT6.2+, but no RT6.1+ or RT6- cells, show incorporation of radioactivity into a single protein which could be identified as RT6.2 by immunoprecipitation with monoclonal antibodies. This automodification of RT6.2 is covalent, requires intact NAD as substrate, and displays characteristics typical for linkage of ADP-ribose to arginine. The alloantigens RT6.1 and RT6.2 differ in ten amino acids, RT6.2 having two arginine residues not present in RT6.1. Both alloantigens were found to display potent NAD-glycohydrolase activity.


Characteristics and potency of an acellular pertussis vaccine composed of pertussis toxin, filamentous hemagglutinin, and pertactin.
In an attempt to develop a safer pertussis vaccine, we successfully purified 3 pertussis protective antigens-pertussis toxin, filamentous hemagglutinin, and a 69-kDa outer membrane protein (also named pertactin), from Bordetella pertussis strain ATCC 9340. The toxicity of pertussis toxin could be effectively reduced by the treatment with formaldehyde 0.07% while preserving of a high degree of immunogenicity. By mixing purified pertussis antigens with diphtheria and tetanus toxoids (DT), we have formulated a DT acellular pertussis (DTaP) vaccine. Toxicity studies on body-weight gain in mouse, histamine sensitization, lymphocyte promoting, and Chinese hamster ovary cell clustering tests suggested that this DTaP vaccine is safer than a whole cell vaccine produced in France (DTP[F]). The formulated vaccine elicited high levels of anti-pertussis toxin antibodies in both mice and monkeys. In mice, a 2-fold neutralization of anti-pertussis toxin antibodies was produced by DTaP compared with DTP(F) vaccine and an acellular vaccine manufactured in Japan (DTaP[J]). More importantly, in intracerebral challenge assay in mouse, this vaccine also provided a better protection than DTaP(J).


Spermine and spermidine act as chemical chaperones and enhance chaperone-like and membranolytic activities of major bovine seminal plasma protein, PDC-109.
The major bovine seminal plasma protein, PDC-109, binds to choline phospholipids of the sperm plasma membrane and induces an efflux of cholesterol and choline phospholipids (cholesterol efflux), which is crucial for sperm capacitation. PDC-109 also exhibits chaperone-like activity and protects target proteins against various kinds of stress. Here we show that the polyamines spermine and spermidine, present in high concentration in the seminal plasma of various mammals, increase the ability of PDC-109 to perturb membrane structure as well as its chaperone-like activity. Interestingly, spermine/spermidine alone did not perturb membrane structure but exhibited chaperone-like activity by protecting target proteins against thermal and oxidative stress. When spermine/spermidine was used along with PDC-109, the observed chaperone-like activity was considerably higher than that expected for a simple additive effect, suggesting that PDC-109 and the polyamines act in a synergistic fashion. These results indicate that at the high concentrations present in the seminal plasma spermine/spermidine exhibit a positive modulatory effect on the chaperone-like activity of PDC-109 and may also function as chemical chaperones and protect other seminal plasma proteins from various kinds of stress.


Peripheral arterial disease and intermittent claudication in coronary heart disease patients.
Peripheral artery disease (PAD) is associated with an increased risk of fatal and non-fatal coronary heart disease (CHD). The aims of the this study were 1) to investigate the prevalence of PAD and suspected PAD in a large population of established CHD patients, and 2) to assess the prevalence and control of risk factors in these patients as well health-related quality of life. In the EUROASPIRE V survey, 8243 patients with documented CHD were recruited from 27 ESC member countries and were invited to attend a study visit. Patients were investigated using questionnaires, in-depth interviews and a clinical examination. Intermittent claudication (IC) was assessed using the Edinburgh Claudication Questionnaire. Patients without previously diagnosed PAD were suspected of having PAD if they were found to have IC. Overall, 6.4% of the patients had already a confirmed diagnosis of PAD and another 6.3% were suspected of having PAD. Independent of age and gender, patients with previously diagnosed PAD were significantly more frequently current smokers, had the lowest smoking cessation rates, were less physically active, reported more often previously diagnosed diabetes and had significantly higher blood pressure levels, compared to patients without PAD. They had also significantly higher levels of serum triglycerides, lower HDL-C levels, and had more often renal insufficiency. In comparison with patients without PAD, those with suspected PAD demonstrated significantly higher smoking cessation rates but their obesity rates were significantly higher. In CHD patients with a history of PAD, the use of calcium channel blockers and diuretics was significantly higher than in patients without PAD. Compared to the latter group, the use of diuretics, anti-arrhythmics and anti-depressants in patients with suspected PAD was significantly higher. Moreover, patients with previously diagnosed PAD had significantly higher levels of anxiety and depression and reported a significantly worse health-related quality of life (HRQoL), in comparison with those without PAD. HRQoL levels were significantly reduced in patients with suspected PAD as well. In CHD patients without a previous diagnosis of PAD, IC is not infrequent. Diagnosed PAD was significantly associated with a worse CHD risk factor profile. Patients with known PAD as well as those with suspected PAD had a considerable loss of health-related quality of life. Therefore, physicians should consider to screen for IC in all their CHD patients.


[New developments in the area of echocardiography and Doppler cardiography].
The noninvasive diagnostic in cardiology was substantially enriched in the past few years by the development and validation of echocardiography systems which enable a simultaneous presentation of cardiac structures and blood flow velocities. Thereby, informations with respect to congenital and valvular heart disease can be obtained that prerequisited cardiac catheterisation in the years before. The valuation of ventricular function and the diagnosis of myocardial ischemia was advanced by computerized echo image processing.


A review of the NG17 recommendations for the use of basal insulin in type 1 diabetes.
To revisit the data analysis used to inform National Institute of Health and Care Excellence (NICE) NG17 guidance for initiating basal insulin in adults with type 1 diabetes mellitus (diabetes). We replicated the data, methodology and analysis used by NICE diabetes in the NG17 network meta-analysis (NMA). We expanded this data cohort to a more contemporary data set (extended 2017 NMA) and restricted the studies included to improve the robustness of the data set (restricted 2017 NMA) and in a post hoc analysis, changed the index comparator from neutral protamine Hagedorn (NPH) insulin twice daily to insulin detemir twice daily. The absolute changes in HbA1c were similar to those reported in the NG17. However, all 95% credible intervals for change in HbA1c point estimates crossed the line of null effect, except for detemir twice daily (in the NICE and extended 2017 NMAs) and NPH four times daily. In the detemir twice-daily centred post hoc analysis, the 95% credible intervals for change in HbA1c crossed the line of null effect for all basal therapies, except NPH. In NG17, comparisons of basal insulins were based solely on efficacy of glycaemic control. Many of the trials used in this analysis were treat-to-target, which minimize differences in HbA1c . In the NMAs, statistical significance was severely undermined by the wide credible intervals. Despite these limitations, point estimates of HbA1c were used to rank the insulins and formed the basis of NG17 guidance. This study queries whether such analyses should be used to make specific clinical recommendations.


Toxicity of mycotoxins produced by four Alternaria species toArtemia salina larvae.
22 isolates ofAlternaria alternata, A raphani, A consortiale, andA chartarum were examined for the production of alternariol (AOH), alternariol methyl ether (AME), altenuene (ALT), altertoxin I (ATX I), and tenuazonic acid (TA) on wheat grain and for toxicity of culture extracts toArtemia salina larvae. The total amount of 5 toxins produced under laboratory conditions ranged from 5 mg/kg to 11.112mg/kg. The toxic extracts showed EC50 values in the range of 3.3 to 144.5 mg/mL. There was no correlation between toxicity of extracts toArtemia salina and the amount of mentioned mycotoxins in culture.


Investigation of creep mechanical characteristics of femoral prostheses by simulated hip replacement.
In order to provide creep mechanical parameters for the clinical application of both traditional and reserved anatomy femoral artificial joint replacements, simulated hip replacement femoral stress relaxation and creep experiments were performed. Twenty-four corpse femoral specimens were obtained, with 8 specimens being randomly assigned to the control group and 8 specimens being randomly assigned to the traditional prosthesis group. Our results showed that the retaining femoral neck prosthesis and traditional prosthesis groups have different stress relaxation and creep mechanical properties.