Patient satisfaction with antiretroviral therapy service provided by pharmacists in Dembia district health institutions, Northwest Ethiopia.
The patients' perception of the health service is a vital tool for measuring health service quality. Besides, Patient satisfaction is an essential feature in assessing the quality of health services. Health institution leaders are considering quantifiable patient satisfaction data as a means to evaluate the health care service. An institution-based cross-sectional study was employed from 21/8/2022 to 21/9/2022 among 308 patients attending ART pharmacy services in three health institutions of Dembia distinct. Data were collected by using a questionnaire and reviewing medical charts. Results were calculated and presented in the form of texts, tables, and graphs. Variables with a p-value of 0.05 were considered significant determinants of patient satisfaction. A total of 308 HIV patients were recruited with a response rate of 100%. The overall prevalence of satisfaction among respondents was 231(75%). Being unable to read and write [1.21(AOR = 1.07-4.31)] and patient age greater than 48 years 1.9(0.73-2.59) were significantly associated with the level of patient satisfaction. Among the participants 66.9% were satisfied with clear and organized service, and 76% were satisfied with the convenience of a private counseling room. The general patient satisfaction at the antiretroviral therapy clinic did not achieve the national target of 85% satisfaction with significant differences among health centers. Being educated to a higher level, absence of signs and directions to ART clinics, and not having the opportunity to ask questions were the factors influencing patient satisfaction with ART service.


The role of radiation therapy in treatment of adults with newly diagnosed glioblastoma multiforme: a systematic review and evidence-based clinical practice guideline update.
These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. QUESTION 1 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is the addition of radiation therapy (RT) more beneficial than management without RT in improving survival? Level I: Radiation therapy (RT) is recommended for the treatment of newly diagnosed malignant glioblastoma in adults. QUESTION 2 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is the RT regimen of 60 Gy given in 2 Gy daily fractions more beneficial than alternative regimens in providing survival benefit while minimizing toxicity? Level I: Treatment schemes should include dosage of up to 60 Gy given in 2 Gy daily fractions that includes the enhancing area. QUESTION 3 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is a tailored target volume superior to regional RT for reduction of radiation-induced toxicity while maintaining efficacy? Level II: It is recommended that radiation therapy planning include 1-2 cm margin around the radiographically T1 weighted contrast-enhancing tumor volume or the T2 weighted abnormality on MRI. Level III: Recalculation of the radiation volume during RT treatment may be necessary to reduce the radiated volume of normal brain since the volume of surgical defect will change during the long period of RT. QUESTION 4 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, does the addition of RT of the subventricular zone to standard tumor volume treatment improve tumor control and overall survival? No recommendation can be formulated as there is contradictory evidence in favor of and against intentional radiation of the subventricular zone (SVZ) QUESTION 5 : In elderly (age > 65 years) and/or frail patients with newly diagnosed glioblastoma, does the addition of RT to surgical intervention improve disease control and overall survival? Level I: Radiation therapy is recommended for treatment of elderly and frail patients with newly diagnosed glioblastoma to improve overall survival. QUESTION 6 : In elderly (age > 65 years) and/or frail patients with newly diagnosed glioblastoma, does modification of RT dose and fractionation scheme from standard regimens decrease toxicity and improve disease control and survival? Level II: Short RT treatment schemes are recommended in frail and elderly patients as compared to conventional 60 Gy given in 2 daily fractions because overall survival is not different while RT risk profile is better for the short RT scheme. Level II: The 40.05 Gy dose given in 15 fractions or 25 Gy dose given in 5 fractions or 34 Gy dose given in 10 fractions should be considered as appropriate doses for Short RT treatments in elderly and/or frail patients. QUESTION 7 : In adult patients with newly diagnosed glioblastoma is there advantage to delaying the initiation of RT instead of starting it 2 weeks after surgical intervention in decreasing radiation-induced toxicity and improving disease control and survival? Level III: It is suggested that RT for patients with newly diagnosed GBM starts within 6 weeks of surgical intervention as compared to later times. There is insufficient evidence to recommend the optimal specific post-operative day within the 6 weeks interval to start RT for adult patients with newly diagnosed glioblastoma that have undergone surgical resection. QUESTION 8 : In adult patients with newly diagnosed supratentorial glioblastoma is Image-Modulated RT (IMRT) or similar techniques as effective as standard regional RT in providing tumor control and improve survival? Level III: There is no evidence that IMRT is a better RT delivering modality when compared to conventional RT in improving overall survival in adult patients with newly diagnosed glioblastoma. Hence, IMRT should not be preferred over the Conventional RT delivery modality. QUESTION 9 : In adult patients with newly diagnosed glioblastoma does the use of radiosensitizers with RT improve the efficacy of RT as determined by disease control and overall survival? Level III: Iododeoxyuridine is not recommended to be used as radiosensitizer during RT treatment for patients with newly diagnosed GBM QUESTION 10 : In adult patients with newly diagnosed glioblastoma is the use of Ultrafractionated RT superior to standard fractionation regimens in improving disease control and survival? There is insufficient evidence to formulate a recommendation regarding the use of ultrafractionated RT schemes and patient population that could benefit from it. QUESTION 11 : In patients with poor prognosis with newly diagnosed glioblastoma is hypofractionated RT indicated instead of a standard fractionation regimen as measured by extent of toxicity, disease control and survival? Level I: Hypofractionated RT schemes may be used for patients with poor prognosis and limited survival without compromising response. There is insufficient evidence in the literature for us to be able to recommend the optimal hypofractionated RT scheme that will confer longest overall survival and/or confer the same overall survival with less toxicities and shorter treatment time. QUESTION 12 : In adult patients with newly diagnosed glioblastoma is the addition of brachytherapy to standard fractionated RT indicated to improve disease control and survival? Level I: Brachytherapy as a boost to external beam RT has not been shown to be beneficial and is not recommended in the routine management of patients with newly diagnosed GBM. QUESTION 13 : In elderly patients (> 65 year old) with newly diagnosed glioblastoma under what circumstances is accelerated hyperfractionated RT indicated instead of a standard fractionation regimen as measured by extent of toxicity, disease control and survival? Level III: Accelerated Hyperfractionated RT with a total RT dose of 45 Gy or 48 Gy has been shown to shorten the treatment time without detriment in survival when compared to conventional external beam RT and should be considered as an option for treatment of elderly patients with newly diagnosed GBM. QUESTION 14 : In adult patients with newly diagnosed glioblastoma is the addition of Stereotactic Radiosurgery (SRS) boost to conventional standard fractionated RT indicated to improve disease control and survival? Level I: Stereotactic Radiosurgery boost to external beam RT has not been shown to be beneficial and is not recommended in patients undergoing routine management of newly diagnosed malignant glioma.


Evaluation of detail reproduction for three die materials by using scanning electron microscopy and two-dimensional profilometry.
This study evaluated the reproduction of detail by Fuji-rock artificial stone, Epoxydent epoxy resin, and Steady-plast polyurethane resin. A polyvinyl siloxane impression was made of a disk-shaped calibration model, with etched grooves ranging from 1 to 46 microns in depth. The die materials were poured in the silicone impression of the disk, then examined with a scanning electron microscope and two-dimensional profilometer. The results revealed that the artificial stone could not reproduce details smaller than 20 microns because of the size of the crystalline structure, whereas epoxy resin and polyurethane resin accurately reproduced details of 1 to 2 microns.


Plumbagin reduction by thioredoxin reductase 1 possesses synergy effects with GLUT1 inhibitor on KEAP1-mutant NSCLC cells.
Thioredoxin reductase 1 (TrxR1 or TXNRD1) is a major enzyme in cellular redox regulation and is considered as a drug target for cancer therapy. Previous studies have reported that plumbagin caused reactive oxygen species (ROS)-dependent apoptosis via inhibiting TrxR1 activity or being reduced by TrxR1, leading to selectively cancer cell death. However, the mechanism of TrxR1-mediated redox cycling of plumbagin is obscure and the evidence for plumbagin targeting TrxR1 is still lacking. Herein, we demonstrated that TrxR1 catalyzed plumbagin reduction in both selenocysteine (Sec)-dependent and independent manners, and its activity relied on the intact N-terminal motif of TrxR1, but a high-efficiency reduction was supported by the C-terminal thiols. During the redox cycling of plumbagin, excessive ROS production was observed coupled with oxygen. Using LC-MS and TrxR1 mutants, we found that the Sec residue of TrxR1 was modified by plumbagin, which converted the enzyme from antioxidant to pro-oxidant. Furthermore, we evaluated the therapeutic potential of plumbagin in non-small cell lung cancer (NSCLC), and found that Kelch-like ECH-associated protein 1 (KEAP1)-mutant NSCLC cells, which possess constitutive nuclear factor erythroid 2-related factor 2 (NRF2) activity, were insensitive to plumbagin; however, inhibition of glucose transporter 1 (GLUT1) by small-molecule BAY-876 or inhibiting glucose-6-phosphate dehydrogenase (G6PD) by 6-aminonicotinamide (6-AN) overcame the plumbagin-resistance of KEAP1-mutant NSCLC cells. Taken together, this study elucidated the pharmacological mechanism of plumbagin by targeting TrxR1 and revealed the synergy effect of plumbagin and BAY-876, which may be helpful for applying naphthoquinone compounds to chemotherapy, particularly for treating KEAP1-mutant NSCLC cells.


Membrane polypeptides co-induced with the bacterial bioluminescent system.
Electrophoretic analysis of membrane proteins and electron microscopy of freeze-fracture replicas reveal that certain polypeptides and intramembrane particles are absent in Beneckea harveyi harvested prior to luminescence induction but present after induction. The polypeptides and particles are also absent in mutants which fail to synthesize the luminescent system. These correlations implicate membrane polypeptides in the bacterial bioluminescent system.


Cardiac Function, Perfusion, Metabolism, and Innervation following Autologous Stem Cell Therapy for Acute ST-Elevation Myocardial Infarction. A FINCELL-INSIGHT Sub-Study with PET and MRI.
Beneficial mechanisms of bone marrow cell (BMC) therapy for acute ST-segment elevation myocardial infarct (STEMI) are largely unknown in humans. Therefore, we evaluated the feasibility of serial positron emission tomography (PET) and MRI studies to provide insight into the effects of BMCs on the healing process of ischemic myocardial damage. Nineteen patients with successful primary reteplase thrombolysis (mean 2.4 h after symptoms) for STEMI were randomized for BMC therapy (2.9 × 10(6) CD34+ cells) or placebo after bone marrow aspiration in a double-blind, multi-center study. Three days post-MI, coronary angioplasty, and paclitaxel eluting stent implantation preceded either BMC or placebo therapy. Cardiac PET and MRI studies were performed 7-12 days after therapies and repeated after 6 months, and images were analyzed at a central core laboratory. In BMC-treated patients, there was a decrease in [(11)C]-HED defect size (-4.9 ± 4.0 vs. -1.6 ± 2.2%, p = 0.08) and an increase in [(18)F]-FDG uptake in the infarct area at risk (0.06 ± 0.09 vs. -0.05 ± 0.16, p = 0.07) compared to controls, as well as less left ventricular dilatation (-4.4 ± 13.3 vs. 8.0 ± 16.7 mL/m(2), p = 0.12) at 6 months follow-up. However, BMC treatment was inferior to placebo in terms of changes in rest perfusion in the area at risk (-0.09 ± 0.17 vs. 0.10 ± 0.17, p = 0.03) and infarct size (0.4 ± 4.2 vs. -5.1 ± 5.9 g, p = 0.047), and no effect was observed on ejection fraction (p = 0.37). After the acute phase of STEMI, BMC therapy showed only minor trends of long-term benefit in patients with rapid successful thrombolysis. There was a trend of more decrease in innervation defect size and enhanced glucose metabolism in the infarct-related myocardium and also a trend of less ventricular dilatation in the BMC-treated group compared to placebo. However, no consistently better outcome was observed in the BMC-treated group compared to placebo.


New class of exact solutions to Einstein-Maxwell-dilaton theory on four-dimensional Bianchi type IX geometry.
We construct new classes of cosmological solution to the five dimensional Einstein-Maxwell-dilaton theory, that are non-stationary and almost conformally regular everywhere. The base geometry for the solutions is the four-dimensional Bianchi type IX geometry. In the theory, the dilaton field is coupled to the electromagnetic field and the cosmological constant term, with two different coupling constants. We consider all possible solutions with different values of the coupling constants, where the cosmological constant takes any positive, negative or zero values. In the ansatzes for the metric, dilaton and electromagnetic fields, we consider dependence on time and two spatial directions. We also consider a special case of the Bianchi type IX geometry, in which the geometry reduces to that of Eguchi-Hanson type II geometry and find a more general solution to the theory.


Morbidity and mortality of complex spine surgery: a prospective cohort study in 679 patients validating the Spine AdVerse Event Severity (SAVES) system in a European population.
Most literature on complications in spine surgery has been retrospective or based on national databases with few variables. The Spine AdVerse Events Severity (SAVES) system has been found reliable and valid in two Canadian centers, providing precise information regarding all adverse events (AEs). This study aimed to determine the mortality and examine the incidence of morbidity in patients undergoing complex spinal surgery, including pediatric patients, and to validate the SAVES system in a European population. A prospective, consecutive cohort study was conducted using the SAVES version 2010 in the period from January 1, 2013 until December 31, 2013. A retrospective analysis was performed on all patients operated from November 1, 2011 until October 31, 2012 for comparison. Patients undergoing spinal surgery at a tertiary referral center comprised the patient sample. Morbidity and mortality were determined according to the newest version of the SAVES system and compared with the Canadian cohort. Other outcomes were length of stay, readmission, unplanned second surgery during index admission, as well as wound infections requiring revision. All patients undergoing spinal surgery at an academic tertiary referral center in the study period were prospectively included. The newest version of SAVES system was used, and a research coordinator collected all intraoperative and perioperative data prospectively. Once a week all patients were reviewed for additional events, validation of the data, and clarification of any questions. Patients were grouped according to the type of admission (elective of emergency) and age, and subgrouped according to a major diagnostic group. The survival status was registered on January 31, 2014 to obtain 30-day survival. A total of 679 consecutive cases were included with 100% data completion. The in-hospital mortality was 1.3% and the 30-day mortality was 2.7%; all occurring after emergency procedures. The number of intraoperative AEs was 162 (overall incidence 20%), and the number of postoperative AEs was 1,415 (overall incidence 77%). Of the patients, 2.2% had postoperative infections requiring surgical revision. A prospective registration improves AE recognition, and our data confirm the generalizability of the SAVES system to pediatric and non-Canadian populations.


4D digital subtraction angiography: implementation and demonstration of feasibility.
Conventional 3D-DSA volumes are reconstructed from a series of projections containing temporal information. It was our purpose to develop a technique which would generate fully time-resolved 3D-DSA vascular volumes having better spatial and temporal resolution than that which is available with CT or MR angiography. After a single contrast injection, projections from the mask and fill rotation are subtracted to create a series of vascular projections. With the use of these projections, a conventional conebeam CT reconstruction is generated (conventional 3D-DSA). This is used to constrain the reconstruction of individual 3D temporal volumes, which incorporate temporal information from the acquired projections (4D-DSA). Typically, 30 temporal volumes per second are generated with the use of currently available flat detector systems, a factor of ∼200 increase over that achievable with the use of multiple gantry rotations. Dynamic displays of the reconstructed volumes are viewable from any angle. Good results have been obtained by using both intra-arterial and intravenous injections. It is feasible to generate time-resolved 3D-DSA vascular volumes with the use of commercially available flat detector angiographic systems and clinically practical injection protocols. The spatial resolution and signal-to-noise ratio of the time frames are largely determined by that of the conventional 3D-DSA constraining image and not by that of the projections used to generate the 3D reconstruction. The spatial resolution and temporal resolution exceed that of CTA and MRA, and the small vessel contrast is increased relative to that of conventional 2D-DSA due to the use of maximum intensity projections.


Broad Outcome Measures May Underestimate Effectiveness: An Instrument Comparison Study.
Outcome measures are routinely used in child and adolescent mental health services to demonstrate the effectiveness or otherwise of interventions. We followed up a consecutive sample from a large teaching hospital's Obsessive Compulsive Disorder (OCD) service for young people, comparing improvements using instruments of differing broadness. The effect size of improvement decreased as the breadth of the questionnaire increased. Specialist clinics are recommended to use two questionnaires: a broad one to facilitate comparability with other clinics, and a narrow one to maximise power to detect significant changes.


Role of PKC-dependent pathways in HNE-induced cell protein transport and secretion.
The beta isoforms of protein Kinase C (PKC) are closely involved in the regulation of cell protein transport and secretion. We have shown in different cellular types that treatment with HNE in a concentration range detectable in many pathophysiological conditions is able to induce selective activation of betaPKCs through direct interaction between the aldehyde and these isoenzymes. In isolated rat hepatocytes this specific isoenzyme activation plays a key role in the transport of procathepsin D from the trans-Golgi network to the endosomal-lysosomal compartment and in the exocytosis of mature cathepsin D. In NT2 neurons, HNE-mediated betaPKC activation induces an increase in intracellular amyloid beta production, without affecting full-length amyloid precursor protein expression. In a mouse macrophage-like cell line, the same beta isoform activation increases the release of the MCP-1 chemokine. Thus, pathophysiological HNE concentrations (0.1-1 microM) derived from a slight imbalance of the redox state are able to alter protein trafficking through beta PKC activation. These results suggest that mild oxidative stress and the PKC signal transduction pathway are closely involved in the pathophysiology of many diseases caused by changes in protein trafficking and release.


Uncemented metal-back glenoid component in revision of aseptic glenoid loosening: a prospective study of 10 cases with a minimum follow-up of 2 years.
Glenoid component loosening comprises 25 % of all complications related to total shoulder arthroplasties (TSA). This prospective study was undertaken to assess the accuracy of an uncemented metal-back glenoid component in cases of revision of aseptic glenoid loosening. Between September 2007 and January 2010, a total of ten patients with symptomatic glenoid loosening after TSA (7 cemented and 3 non-cemented) underwent revision surgery with an uncemented metal-back glenoid component (MB). The rotator cuff was functional in all cases. The reconstruction of the glenoid was obtained using an iliac crest graft (8 patients) or synthetic bone substitute (2 patients). The non-cemented glenoid component was fixed into the glenoid native bone, thus stabilizing the graft reconstruction. A clinical and radiological checkup was performed at the long-term follow-up and compared with the preoperative values. The patients were also asked to quantify their pain and satisfaction. There were no intraoperative complications. In all cases, the radiological evaluation showed a good integration of the bone graft with no radiolucency or new glenoid loosening. In one patient, the revision surgery was indicated for the dissociation between MB and polyethylene. After more than 2 years of follow-up, all patients were satisfied or highly satisfied with the outcomes. The pain VAS score (0-10) decreased from 5.1 to 0.6 (p < 0.001). The simple shoulder test increased from 3.4 to 7.9 points (gain 4.5; p < 0.001). The Constant and Murley score increased from 39.4 to 71 points (gain 31.6; p < 0.001). The gain in anterior elevation was 31°, from 118° to 149° (p < 0.001). External rotation elbow to the body (ER1) increased from an average of 34° preoperatively to 47° after surgery (p < 0.001) and external rotation at 90° of abduction from 43° to 66° (p < 0.001). This study suggests that revision with a non-cemented glenoid component associated with a bone graft can solve the difficult challenge of glenoid loosening, provided that the rotator cuff is functional and the glenoid is reconstructable. Cohort studies (prospective) without controls, Level IV.


Neuronal structure and synaptic distribution of a uropod closer motor neuron in the crayfish terminal ganglion.
One of the uropod closer muscles in the crayfish, the adductor exopodite, is innervated by two large identified motor neurons. They were injected intracellularly with horseradish peroxidase or nickel chloride to reveal the structure and distribution of the input and output synapses using electron microscopy. The development of nickel with rubeanic acid greatly improved the tissue preservation at the ultrastructural level compared with ammonium sulphide. Cell bodies of the motor neurons lying in the ventro-lateral cortex of the ganglion are extensively invaginated by glial cells. Input synapses occur directly upon the primary neurite within the neuropil or upon the major anterior neurite. They are most abundant, however, upon the numerous smaller neurites of the motor neuron. The primary neurite in the dorsal region of the neuropil, upon which no synapses were made, is wrapped with glial cells. Occasionally, these two adductor exopodite motor neurons were found as adjacent postsynaptic profiles at the same synapse when both cells were stained simultaneously in the same preparation. In the present study we could not locate any sites of synaptic output which strictly fulfil the structural criteria of a synapse on the processes of the motor neuron. This result is inconsistent with physiological evidence which suggests that spikeless interactions occur between the two adductor exopodite motor neurons and their synergists. This might be the result of two possible features of the interaction: the sites of synaptic output may be limited to a few restricted branches, and the interaction between these motor neurons may depend largely upon electrical synapses.


High current gain transistor laser.
A transistor laser (TL), having the structure of a transistor with multi-quantum wells near its base region, bridges the functionality gap between lasers and transistors. However, light emission is produced at the expense of current gain for all the TLs reported up to now, leading to a very low current gain. We propose a novel design of TLs, which have an n-doped InP layer inserted in the emitter ridge. Numerical studies show that a current flow aperture for only holes can be formed in the center of the emitter ridge. As a result, the common emitter current gain can be as large as 143.3, which is over 15 times larger than that of a TL without the aperture. Besides, the effects of nonradiative recombination defects can be reduced greatly because the flow of holes is confined in the center region of the emitter ridge.


Patient teaching for X-ray and other diagnostics.
Many patients scheduled for diagnostic tests want to know in detail what they will experience. Here are the first in a new series of patient guides to X-ray exams.


The effect of vitamin D supplementation on the progression of benign prostatic hyperplasia: A randomized controlled trial.
Inflammation and proliferation are the cause of benign prostatic hyperplasia (BPH) and are the key components of its mechanism of action. In this study we sought to determine the role of 25-hydroxyvitamin D in BPH, because of its anti-inflammatory activities, and its effect on prostate volume and BPH symptoms. This randomized clinical trial (RCT) was conducted on 108 participants >50 years of age who had either asymptomatic or mild BPH symptoms according to the International Prostate Symptom Score (IPSS) questionnaire. Patients were randomly divided into two groups, intervention and control. The intervention group received 50 000 units of vitamin D3 and the control group received a placebo every two weeks for six months. Prostate ultrasound, routine clinical examinations, toucher rectal (TR), and laboratory tests were performed for all patients. After six months, the patients underwent another ultrasound evaluation, measurement of prostate-specific antigen (PSA) levels and completed the IPSS. Results of the evaluations before and after the intervention were compared between the groups using the chi-square, t-test, and logistic regression analysis. Repeated measure analysis was used to evaluate the effect of vitamin D intervention on the changes in the IPSS score. The mean age of the participants was 56 ± 9 years. In the control group, the mean prostate volume was higher compared to the intervention group (p < 0.001). The control group had a higher mean PSA level than the intervention group (p < 0.001). Although the IPSS score decreased over time in both groups, analysis of variance showed that the amount of change or decrease in IPSS score in the intervention group was significantly more than the control group (p < 0.001). The results of our study support the effect of vitamin D in reducing prostate volume and PSA levels, and in improving BPH symptoms. Further studies are needed to confirm these findings to verify the use of vitamin D as a treatment for BPH.


Natural killer cell-target interactions: the role of 4F2 antigen in the human system.
The manner by which natural killer cells discriminate between target and nontarget cells is a subject of intense investigation. Recently, the antigen recognized by the 4F2 monoclonal antibody has been implicated as the target recognition molecule of cloned human natural killer cells. Here we report the results of our studies on the possible role of 4F2 antigen in target recognition by natural killer cells present in the peripheral blood. In our hands, the 4F2 antibody only weakly blocked the killing of K562 leukemia cells by human natural killer cells. Furthermore, no correlation was observed between the level of cell surface 4F2 antigen and the natural killer susceptibility of several tumor cell lines, the ability of these cells to bind to natural killer cells, or the ability of these cell lines to compete with K562 cells in a natural killer assay. Therefore, the 4F2 antigen does not appear to be the target recognition molecule of most peripheral blood natural killer cells.


Metastasis of renal cell carcinoma to central nervous system hemangioblastoma in two patients with von Hippel-Lindau disease.
Here we report tumor-to-tumor metastases identified in two patients with von Hippel-Lindau (VHL) disease. The first patient had bilateral renal carcinomas and multiple cerebellar hemangioblastomas, and the second patient had a renal carcinoma and multiple hemangioblastomas in the retina, cerebellum and spinal cord. A cerebellar lesion from the first patient and a spinal lesion from the second patient contained two distinct components. The inner part of these tumors consisted of a nested mass of polygonal clear cells that expressed cytokeratin and epithelial membrane antigen, while the outer part of the tumors showed proliferation of capillaries and intervening foamy stromal cells that were negative for cytokeratin and epithelial membrane antigen. The tumors were thus considered to be hemangioblastomas complicated by metastatic lesions of renal cell carcinoma of clear cell type. These cases indicate that tumor-to-tumor metastasis should be considered when hemangioblastoma contains a clear cell carcinoma component in the setting of VHL disease, and that immunohistochemical staining for cytokeratin and epithelial membrane antigen is useful for the diagnosis.


Pregnancy- and lactation-associated osteoporosis with vertebral fractures: a systematic review.
To review, analyze and characterize the pregnancy and lactation-related osteoporosis (PLO) with vertebral fractures based on the extraction data in the previous studies. A comprehensive literature search of electronic databases including the PubMed, Embase and Web of Science was conducted from January 1st,1990 to December 1st, 2020. The enrolled data were pooled to analyze the baseline characteristics, clinical features, risk factors and treatment options. A total of 65 articles with 338 cases were enrolled for data extraction. The enrolled cases aged from 19 to 47 years, with a mean value of 35.7 years old. The average body mass index (BMI) was 22.2 kg/m2 ranged from 16.0 to 39.0 kg/m2. Of the 173 cases, 149 cases with vertebral fractures occurred in the first pregnancy, 19 cases in the second pregnancy, four cases in the third pregnancy and one case in the fourth pregnancy. Up to 91.5% of the back pain occurred within the last 3 months of pregnancy and the first 3 months after delivery. The most involved vertebral levels were L2, L1 and T12 accounting for 32.6% of all the fractures. The average fracture numbers were 4.4 levels per patient. The lumbar Z-scores were mostly recorded with a mean value of - 3.2 ranged from - 7.8 to 0. PLO with vertebral fractures is a rare clinical entity, which is more likely to occur in older and thinner pregnant women. Back pain is the clinical complaint and mostly occurs in the late pregnancy and early lactation periods. Most vertebral fractures appear in the first pregnancy but it can occur in any time of pregnancy. Thoracolumbar region is the mostly involved region. As compared with postmenopausal osteoporotic fractures, PLO usually has multiple levels fractures. Bisphosphonates are the most widely used treatment so far, however, many factors need to be taken into account to decide which drug to choose in PLO and further studies are necessary for clear recommendation in the future.


Circ-XPR1 promotes osteosarcoma proliferation through regulating the miR-214-5p/DDX5 axis.
Circular RNAs (circRNAs) are a new class of RNAs that play an important role in the development of various tumors. However, the expression profile and biological function of circRNAs in osteosarcoma (OS) progression remain unclear. OS-related circRNA expression profiles from the GEO database (GSE96964) were downloaded to identify differentially expressed circRNAs between OS and normal tissues. We identified one upregulated circRNA (Circ-XPR1), and RT-PCR was performed to further confirm the expression abundance in OS tissue. Circ-XPR1 was closely related to overall survival and disease-free survival of OS patients. Knockdown of Circ-XPR1 significantly reduced the proliferation of OS cells. Gain- and loss-of-function studies showed that Circ-XPR1 promoted OS cell proliferation by sponging miR-214-5p to regulate DDX5 expression. Our findings suggested that Circ-XPR1 regulates OS cell proliferation by sponging miR-214-5p to regulate DDX5 expression. Therefore, the Circ-XPR1/miR-214-5p/DDX5 axis may serve as a potential therapeutically relevant target for OS.


Regulation of the kiss2 promoter in yellowtail clownfish (Amphiprion clarkii) by cortisol via GRE-dependent GR pathway.
Kisspeptin plays a vital role in mediating the stress-induced reproductive regulation. Cortisol, known as a stress-related hormone, is involved in gonadal development and sexual differentiation by binding with glucocorticoid receptor (GR) to regulate the expression of kiss gene. In the present study, cortisol treatment in yellowtail clownfish (Amphiprion clarkii) showed that the expression of kiss (kiss1 and kiss2) and gr (gr1 and gr2) genes were increased significantly. We demonstrated that the yellowtail clownfish Kiss neurons co-express the glucocorticoid receptors in the telencephalon, mesencephalon, cerebellum, and hypothalamus. We further cloned the promoter of kiss2 gene in yellowtail clownfish and identified the presence of putative binding sites for glucocorticoid receptors, estrogen receptors, androgen receptors, progesterone receptors, AP1, and C/EBP. Applying transient transfection in HEK293T cells of the yellowtail clownfish kiss2 promoter, cortisol (dexamethasone) treatment was shown to enhance the promoter activities of the yellowtail clownfish kiss2 gene in the presence of GRs. Deletion analysis of kiss2 promoter indicated that cortisol-induced promoter activities were located between position -660 and -433 with GR1, and -912 and -775 with GR2, respectively. Finally, point mutation studies on the kiss2 promoter showed that cortisol-stimulated promoter activity was mediated by one GRE site located at position -573 in the presence of GR1 and by each GRE site located at position -883, -860, -851, and -843 in the presence of GR2. Results of the present study provide novel evidence that cortisol could regulate the transcription of kiss2 gene in the yellowtail clownfish via GRE-dependent GR pathway.


The MAPK (ERK) Pathway: Investigational Combinations for the Treatment Of BRAF-Mutated Metastatic Melanoma.
The arrival of ipilimumab and vemurafenib has provided oncologists with new choices in a field in which options were slim and the prognosis was grim. Combination therapy may lead to an improved survival benefit.


A high body mass index has a protective effect on the amount of joint destruction in small joints in early rheumatoid arthritis.
Obesity is a state of chronic low-grade inflammation that predisposes people to several diseases and that is increasingly prevalent. Rheumatoid arthritis (RA) is marked by the presence of proinflammatory cytokines and, in general, the presence of high levels of inflammatory markers is associated with a severe disease course and joint damage. To evaluate prospectively (a) whether obesity is a risk factor for the development of RA and (b) whether the body mass index (BMI) is associated with the amount of joint destruction in early RA after 3 years' follow-up. In a cohort of 570 patients with undifferentiated arthritis, the relation between the BMI and the development of RA during 1 year of follow-up was assessed. In a cohort of 488 patients with early RA the correlation between the BMI and degree of radiological joint destruction (Sharp-van der Heijde score) after 3 years of follow-up was determined. The findings were replicated in an independent cohort of 247 patients with early RA. Obesity did not influence the likelihood of developing RA. In both RA cohorts, the BMI was inversely correlated with the Sharp-van der Heijde score after 3 years' follow-up (r = -0.15, p = 0.025 for the Leiden EAC and r = -0.27, p<0.001 for the replication cohort). Linear regression analyses in both cohorts showed that the BMI was independently and inversely associated with the level of joint destruction in anti-CCP-positive patients with RA, but not in anti-CCP-negative patients. A high BMI is associated with a less severe disease outcome in anti-CCP-positive patients with RA.


Contribution of the mandible position to the facial profile perception of a female facial profile: An eye-tracking study.
Studies concerning the visual attention of laypersons viewing the soft tissue facial profile of men and women with malocclusion are lacking. This study aimed to determine the visual attention to the facial profile of patients with different levels of mandibular protrusion and facial background attractiveness using an eye-tracking device. The scanning paths of 54 Chinese laypersons (50% female, 50% male, aged 18-23 years) were recorded by an eye-tracking device when they observed composite female facial profile images (n = 24), which were combinations of different degrees of mandibular protrusion (normal, slight, moderate, and severe) and different levels of facial background attractiveness (attractive, average, and unattractive). Dependent variables (fixation duration and first fixation time) were analyzed using repeated-measures factorial analysis of variance. For normal mandibular profiles, the fixation duration of the eyes was significantly higher than that of other facial features (P <0.001). The lower face and nose received the least attention. As the degree of protrusion increased from slight to moderate, more attention was drawn to the lower face accompanied by less attention to eyes in the unattractive group (P <0.05). When protrusion degree increased from moderate to severe, attention shifted from nose to lower face significantly in the attractive group (P <0.05). Attention shift from eyes to lower face was also found in the average group when protrusion degree rose to moderate protrusion from normal profile (P <0.05). A significant interaction between facial attractiveness and mandibular protrusion was found in the lower face duration (P = 0.020). The threshold point (the point of mandibular protrusion degree that evoked attention to the lower face) of the attractive facial background was higher than that of the unattractive background. Once evoked, the effect of mandibular protrusion of the attractive group tended to be stronger than that of the unattractive group, though without statistical difference. Eyes are the most salient area. The increasing degree of mandibular protrusion tends to draw attention to the lower face from other facial features. Background attractiveness can modify this behavior.


Internal dosimetry of [99m Tc]NTP15-5 radiotracer for cartilage imaging in preclinical and clinical models using the GATE Monte Carlo platform.
This study aims to perform dosimetry for [99m Tc]NTP15-5 radiotracer used in imaging of articular cartilage in rabbits and humans. The radiotracer (covered by a world patent WO 01/00621 A1) has been proposed in the previous years for the study of cartilage in osteoarthritis diseases. A sensitive imaging approach is essential to quantify osteoarthritis progression and monitor response to new therapies. [99m Tc]NTP15-5 binds to cartilage proteoglycans whose decreased content is associated to a loss of biomedical function of cartilage. We have implemented the whole dosimetry study concerning this new radiotracer for rabbits and humans using the GATE Monte Carlo platform. Absorbed doses to critical organs are determined using the MIRD formalism. Biodistribution data are obtained by organ sampling, measuring the activity in organs for three rabbits sacrificed at various times postadministration, and by SPECT/CT imaging at different times after injection. Most important sources are cartilages (in knees and intervertebral discs), due to localization together with the liver and kidneys due to excretion of the agent. S-values are calculated from rabbit's CT scan and human CT scan using the GATE v8.0 Monte Carlo platform. Cumulated activity in humans is extrapolated from animals using the %kg-dose/g method. Particular attention is given to dose calculation in bones, bone marrow and organs at risk. The dosimetry performed in rabbits shows highest absorbed doses for liver and kidneys with respectively 22.5 and 43.8 µGy per MBq of injected activity. In humans, we found absorbed doses for a maximum injected activity of 15 MBq/kg, that is, 1050 MBq for an adult of 70 kgs of 9.03 mGy for kidneys and 4.16 mGy for knee cartilages. Effective dose is 2.69 µSv/MBq. The dosimetry profile of [99m Tc]NTP15-5 in the context of preclinical trials is of major importance in order to make sure that organs at risk are not overexposed. GATE provides all the capability needed to calculate dose profiles for internal dosimetry. The extrapolation of the dose for a human model is a first step towards clinical trials.


[Mandibular joint pain--a soft tissue rheumatic disease?].
Results from female patients suffering from temporomandibular joint (TMJ) pain syndrome show that the majority of them also suffer from pain in other regions of the body. Temporomandibular joint disease represents a part of a "general myalgia syndrome" or of rheumatism of the soft tissues. The severity of the disease depends upon individual personality and conditions of life.


The Haemo-QoL Index: developing a short measure for health-related quality of life assessment in children and adolescents with haemophilia.
As quality of life (QoL) research is increasingly focusing on children and adolescents with haemophilia, the need for both age-appropriate and disease-specific assessment tools becomes apparent. Therefore, a set of questionnaires measuring QoL in children and adolescents with haemophilia was simultaneously developed in six languages within the European Haemo-QoL project (Haemophilia, 8, 2002, 47; Haemophilia, 10, 2004, 17). For implementation in larger studies and for use in daily clinical routine, a both short and psychometrically robust version of the questionnaire is needed. Using from the Haemo-QoL field study complete data sets of 306 children and adolescents (4-16 years) and their parents, a multivariate approach of item selection was applied to construct an eight-item instrument, the Haemo-QoL Index. The instrument is applicable to different age groups and represents the core content as well as the multidimensional structure of the original long versions. According to preliminary analyses, the index's psychometric performance concerning reliability and convergent validity is good. Further validation of the instrument's performance on a new and independent sample is needed.


Quality assessment of red blood cell suspensions derived from pathogen-reduced whole blood.
We used laboratory indicators to evaluate the quality of pathogen-reduced red blood cell suspension (RBCS) compared with gamma-irradiated RBCS. To determine biochemical and metabolic parameters of RBCS, we obtained 50 whole blood units from healthy volunteers and randomized them into 2 groups: 25 were pathogen-reduced, and then, RBCS prepared from them. RBCS from the other 25 was gamma-irradiated. Sampling was carried out on day zero before and after treatment and at 7, 14, 21 and 28 days. To determine lymphocyte inactivation, we collected another 35 whole blood units. Each was sampled to form 3 study groups: untreated, gamma-irradiated and pathogen-reduced. Daily sampling was carried out during 3 days of storage. The quality of RBCS from both groups was largely the same, except for haemolysis and red blood cell fragility, which were more pronounced in the pathogen-reduced group. This finding limited the shelf life of pathogen-reduced RBCS to 14 days. Lymphocyte viability was significantly reduced after both treatments. Proliferation of lymphocytes after pathogen reduction was reduced to the detection limit, while low-level proliferation was observed in gamma-irradiated samples. Pathogen-reduced red blood cells have acceptable quality and can be used for transfusion within 14 days. Results of inactivation of lymphocytes demonstrate that pathogen reduction technology, applied on WB, can serve as an alternative to irradiation.


Chemical characterization of phosphoribosylamine, a substrate for newly discovered trifunctional protein containing glycineamide ribonucleotide synthetase activity.
PRA has been characterized for the first time using 13C-NMR spectroscopy. Incubation of [1-13C]ribose-5-phosphate with NH3 results in the production of 38:62 alpha:beta anomeric mixture of PRA, alpha,beta ribose-5-phosphate and variable amounts of dimeric materials. NMR studies at various pHs allowed determination of the pH independent Kequi = 0.95 +/- 0.14 M-1 for this reaction. In addition, using magnetization transfer NMR methodology the rate of conversion of alpha to beta PRA was determined to be 44 sec-1 at 37 degrees C (pH 8.0). The rates of formation (from ribose-5-phosphate and NH3) and degradation of PRA were also measured using E. coli GAR synthetase (recently cloned, overproduced and purified to homogeneity) as a trap. Determination of these rates allowed an independent and accurate measurement of Kequi = 2.7 M-1. In addition, in close agreement with early studies of Nierlich and Magasanik, the half life of PRA at 37 degrees C and pH 7.5 was determined to be 35 sec. Characterization of the chemical stability of PRA and Kequi for ribose-5-phosphate, NH3 with PRA will now allow detailed kinetic analysis of the newly discovered trifunctional protein containing GAR synthetase activity in addition to AIR synthetase and GAR transformylase activities. Comparison of the properties of the 110 kd GAR synthetase and an independently isolated 54 kd GAR synthetase are reported. Experiments are underway to investigate the possibility that unstable intermediates such as PRA are not released into solution, but that the transfer is mediated by specific protein-protein interactions between GAR synthetase and PRPP amidotransferase.


Percentage grade 4 tumour predicts outcome for prostate adenocarcinoma in needle biopsies from patients with advanced disease: 10-year data from the TROG 03.04 RADAR trial.
Previous reports have shown that quantification of high tumour grade is of prognostic significance for patients with prostate cancer. In particular, percent Gleason pattern 4 (GP4) has been shown to predict outcome in several studies, although conflicting results have also been reported. A major issue with these studies is that they rely on surrogate markers of outcome rather than patient survival. We have investigated the prognostic predictive value of quantifying GP4 in a series of prostatic biopsies containing Gleason score 3+4=7 and 4+3=7 tumours. It was found that the length of GP4 tumour determined from the measurement of all biopsy cores from a single patient, percent GP4 present and absolute GP4 were all significantly associated with distant progression of tumour, all-cause mortality and cancer-specific mortality over a 10-year follow-up period. Assessment of the relative prognostic significance showed that these parameters outperformed division of cases according to Gleason score (3+4=7 versus 4+3=7). International Society of Urological Pathology (ISUP) Grade Groups currently divide these tumours, according to Gleason grading guidelines, into grade 2 (3+4=7) and grade 3 (4+3=7). Our results indicate that this simple classification results in the loss of important prognostic information. In view of this we would recommend that ISUP Grade Groups 2 and 3 be amalgamated as grade 2 tumour with the percentage of GP4 carcinoma being appended to the final grade, e.g., 3+4=7 carcinoma with 40% pattern 4 tumour would be classified as ISUP Grade Group 2 (40%).


Management of the central compartment in differentiated thyroid carcinoma.
Management of differentiated thyroid carcinoma (DTC) is gradually evolving with considerations of de-escalation of treatment and/or active surveillance in a significant proportion of patients on the basis of an improved understanding of the long-term disease and functional outcomes from both surgical and non-surgical approaches. This is fueled by improved risk stratification using clinicopathologic prognostic factors as determined through high resolution ultrasound and fine needle aspiration cytology. This paper discusses general recommendations for preoperative decision-making in the management of the central compartment in DTC with particular reference to micropapillary thyroid carcinoma and encapsulated follicular variant papillary thyroid carcinoma. Given the multitude of specific factors that must be considered for each patient, therapeutic decisions should occur in a multidisciplinary setting weighing the risks of treatment morbidity against the risks of disease progression or recurrence. Recurrent/persistent disease merits special attention with regard to pre-operative planning and surgical risk, and should be managed by high-volume thyroid surgeons.


Syndactyly and split hand. Supplement.
In a series of studies of clinical and radiological features of hand anomalies, the author has recently encountered cases which may be explained by reference to the relationship between syndactyly and split hand. These cases suggested how the typical split hand is formed prenatally, and it is concluded that the typical split hand should not be classed as "Arrest of Development of Parts" due to embryonal failures.


Dry condition affects desquamation of stratum corneum in vivo.
We examined whether a dry condition actually induces scaly skin in vivo. Hairless mice were kept in a high humidity condition or a low humidity condition and skin changes were examined. Scales appeared on the backs of mice kept for 3 days under the dry condition. The weight of stratum corneum (SC) was increased at this point, and these alterations were not accompanied with hyperproliferation of the nucleated cell layer of the epidermis. A decrease of desmosomal degradation was observed, though, desquamation-related enzyme activity was not altered. The regulation mechanism of desquamation is not yet clear, however, in vitro experiments suggest that the water content in SC is an important factor. The water content of SC was decreased in the dry condition. These results indicate that a dry environment perturbs desmosome degradation in intact SC by decreasing the water content of SC, and the consequent impairment of desquamation in normal skin in vivo may lead to the induction of a scaly skin surface.


Mid-infrared 333 MHz frequency comb continuously tunable from 1.95 to 4.0 μm.
We report a 333 MHz femtosecond optical parametric oscillator in which carrier-envelope offset stabilization was implemented by using a versatile locking technique that allowed the idler comb to be tuned continuously over the mid-infrared range from 1.95 to 4.0 μm. A specially designed multi-section, multi-grating, periodically poled KTP crystal provided simultaneously phase-matched parametric down-conversion and pump + idler sum-frequency generation, enabling strong heterodyne signals with the pump supercontinuum (employed for locking) to be obtained across the tuning range of the device. The idler comb offset was stabilized to a 10 MHz reference frequency with a cumulative phase noise from 1 Hz-64 kHz of <1.3 rad maintained across the entire operating range, and average idler output powers up to 50 mW.


Sonographic findings in visceral leishmaniasis - A narrative review.
Visceral leishmaniasis (VL) is predominantly a neglected tropical parasitic disease but may also be acquired by travellers. We aimed at summarizing knowledge on sonographic presentation of VL to better understand sonographic features of VL. PubMed was searched for studies and case reports presenting original data on sonographic findings of VL, published before August 13th, 2019. Demographic, clinical, and sonographic data were extracted and summarized in a qualitative approach. A total of 36 publications were included in this review; 27 of these were case reports and the remainder were prospective or retrospective studies. No study reported systematic cross-sectional comparative imaging. Overall, publications reported on 512 patients with VL of whom 12 were reported HIV-infected. Spleno- and hepatomegaly were the most frequently reported findings. Further relevant and repeatedly reported findings were splenic and hepatic lesions, abdominal lymphadenopathy, pleural and pericardial effusion and ascites. Reported focal splenic lesions were heterogeneous in size, shape, and echogenicity. Several publications reported gradual diminution and resolution of sonographic findings with VL treatment. Available literature on sonographic findings of VL is limited. Available reports indicate that spleno- and hepatomegaly, free fluid, abdominal lymphadenopathy, and focal splenic lesions may be common sonographic features in patients with VL. Because of the apparent overlap of sonographic features of VL, extrapulmonary tuberculosis and other conditions, interpretation of sonographic findings needs to be made with particular caution.


Mass spectrometry of biogenic catecholamine ion pairs by direct liquid introduction.
The mass spectrometry of ion pairs of dopamine, noradrenaline and 3,4-dihydroxyphenylacetic acid with n-octylsulphonate has been investigated by direct liquid introduction in an acidic buffer currently used for their high-performance liquid chromatographic separation. In order to follow the fate of the ion pairs, they were first studied by desorption/chemical ionization as dichloromethane extracts or in the buffer. The results show that characteristic spectra of the solutes can be obtained by direct liquid introduction provided that the interface between the chromatographic system and the mass spectrometer permits the desolvation of the ion pairs from the cluster of solvent molecules.


Phosphatidylcholine composition of emulsions influences triacylglycerol lipolysis and clearance from plasma.
Sonicated emulsions containing triolein, a specific phosphatidylcholine and cholesterol were prepared. Bolus doses were injected intravenously into rats and plasma clearance kinetics and organ uptakes were determined. Emulsion triacylglycerol lipolysis by rat heart lipoprotein lipase was measured in vitro. Phosphatidylcholine molecular species influenced emulsion metabolism in vivo and in vitro. Emulsions containing saturated phosphatidylcholines at temperatures below their melting points were poor substrates for lipoprotein lipase, compared with those stabilized by mixed chain phosphatidylcholines. Distearoylphosphatidylcholine stimulated hepatic uptake compared with emulsions made with egg yolk phosphatidylcholine, which modeled chylomicrons closely. Emulsion populations with the same surface compositions but with mean diameters of 700-800 A and 1100-1300 A were metabolized similarly, suggesting that, within the normal chylomicron size range, size alone does not determine the disposition of triacylglycerol-rich emulsions or lipoproteins.


Association between ambient temperatures and injuries: a time series analysis using emergency ambulance dispatches in Chongqing, China.
Global warming and increasing extreme weather have become a severe problem in recent years, posing a significant threat to human health worldwide. Research exploring the link between injury as one of the leading causes of death globally and ambient temperature was lacking. Based on the hourly injury emergency ambulance dispatch (IEAD) records from 2019-2021 in the main urban area of Chongqing, this study explored the role of temperature extremes on the pathogenesis of injury by different mechanisms and identified sensitive populations for different mechanisms of injury. In this study, we collected hourly injury emergency ambulance dispatch (IEAD) records from Chongqing Emergency Dispatch Center in the main urban area of Chongqing from 2019 to 2021, and used a distributed lagged nonlinear model (DLNM) with quasi-Poisson distribution to evaluate the association between ambient temperature and IEADs. And the stratified analysis was performed by gender, age and different injury mechanisms to identify susceptible groups. Finally, the attributable burden of ambient extreme temperatures was also investigated. The risk for total IEADs increased significantly at high temperature (32 °C) compared with optimal temperature (9 °C) (CRR: 1.210; 95%CI[1.127,1.300]). The risks of traffic accident injury (CRR: 1.346; 95%CI[1.167,1.552]), beating injury (CRR: 1.508; 95%CI[1.165,1.952]), fall-height injury (CRR: 1.871; 95%CI[1.196-2.926]) and injury of sharp penetration (CRR: 2.112; 95%CI[1.388-3.213]) were significantly increased. At low temperature (7 °C), the risk of fall injury (CRR: 1.220; 95% CI [1.063,1.400]) increased significantly. Lag for 24 hours at extreme low temperature (5 °C), the risk of 18-45 years (RR: 1.016; 95%CI[1.009,1.024]) and over 60 years of age (RR: 1.019; 95%CI[1.011,1.025]) increased significantly. The effect of 0 h delay in extreme high temperature (36 °C) on males aged 18-45 years (RR: 1.115; 95%CI[1.071,1.162]) and 46-59 years (RR: 1.069; 95%CI[1.023,1.115]) had significant impact on injury risk. This study showed that ambient temperature was significantly related to the risk of injury, and different mechanisms of injury were affected differently by extreme temperature. The increasing risk of traffic accident injury, beating injury, fall-height injury and sharp penetrating injury was associated with extreme heat, while fall injury was associated with extreme cold. The risk of injury in high temperature environment was mainly concentrated in males and young adults. The results of this study can help to identify the sensitive population with different injury mechanisms in extreme temperature environment, and provide reference for public health emergency departments to respond to relevant strategies in extreme temperature environment to minimize the potential risk to the public.


Termites and the turnover of dead wood in an arid tropical environment.
The standing crop of woody litter (317 g m-2) and its rate of production (30.8 g m-2 a-1) and disappearance (27.8 g m-2 a-1) were measured in Tsavo National Park, Kenya, at a site with a mean rainfall of 352 mm a-1. Dead wood took about 11 years to disappear completely. Almost all of this wood is removed by termites, 90% by the fungus-cultivating subfamily Macrotermitinae.


[Loss of the balance between Th17 and Th1 populations in HIV/AIDS patients].
To evaluate the Th17/Th1 response in HIV infected patients and the mutual relationship between the response of Th17 and Th1. 38 chronic HIV infected patients as well as 24 healthy volunteers were performed in this study. The patients were divided into two groups, one group before treatment, the other after therapy. The whole blood intracellular cytokine staining was used, samples detected by BD FACSCanto, after that, the expression of CD4+ IL-17+ T cell and CD4 IFN-gamma+ T cell were analyzed by FACSDiva software and lastly compared the differences among different groups. The expression of CD4+ IL-17+ T cell in naive-therapy patients were significantly lower than that of the healthy controls (1.14 +/- 0.7)9% vs (3.98 +/- 1.14)%, P = 0.000, but increased remarkably after HARRT(highly antiretroviral treatment) (2.22 +/- 1.00)%, P = 0.001; however there were no significant differences in the expression of CD4+ IFN-gamma+ T cell before and after therapy (34.35 +/- 24.38)% vs (42.10 +/- 15.57%), also with the healthy control (P = 0.383). The frequency of CD4 IL-17+ T cell was positively correlated with CD4+ T counts (R = 0.345, P = 0.034), but no significant correlations was observed between the expression of CD4+ IFN-gamma T cell and CD4+ T counts (R = -0.247, P = 0.136). The infection of HIV virus down-regulated Th17 immune response and disturbed the balances between Th17 and Th1 evidently in human. Th17 response may play an important role in the pathogenesis of HIV infection.


Nutrition now. Ripe for reform.
Levels of nutritional care for patients in the community are difficult to gauge, but community nurses can make a difference to those at risk.


[The prevalence of abnormal glucose regulation after myocardial infarction: Comparative study in two French ethnic groups].
The aim of this study was to compare the prevalence of abnormal glucose tolerance in patients stemming from two French ethnic groups and admitted for acute coronary syndrome (ACS) to intensive coronary care unit. During a period of six months, 53 and 60 consecutive patients were enrolled at Fort-de-France (Martinique, French West Indies, Afrocaribbeans, group F) and at Bordeaux (France, Europeans, group B), respectively. Glucometabolic state was classified according to medical history and fasting glycemia measured from the fourth day after ACS. At baseline, 36% of the patients of group F and 20% of the patients of group B had previously known diabetes (p=0.06). Prevalence of hypertension was higher in Afrocaribbeans than in Europeans (60 versus 40%, p<0.05). According to fasting glycemia, newly detected diabetes were found in six Afrocaribbeans and only one was found in Europeans; two patients in group F and three patients in group B displayed impaired fasting glycemia. As a whole, 51% of Afrocaribbeans and 27% of Europeans showed abnormal glucose tolerance (p<0.05). Furthermore, Afrocaribbeans displayed lower levels of triglycerides and higher levels of HDL cholesterol than Europeans (p<0.05). Our study suggested a higher prevalence of impaired glucose metabolism in French Afrocaribbeans than in European counterparts after ACS. Furthermore, French Afrocaribbeans displayed a more favorable lipoprotein profile. These characteristics look like that of the American and British Afrocaribbeans, maybe because of a common genetic origin.


Study protocol for a parallel-group, double-blinded, randomized, controlled, noninferiority trial: the effect and safety of hybrid electroconvulsive therapy (Hybrid-ECT) compared with routine electroconvulsive therapy in patients with depression.
Electroconvulsive therapy (ECT) is the most rapid and effective treatment for patients with depression, ECT can achieve remarkable antidepressant effects in the initial 3-4 sessions, but significant side effects limit its use. However, recent low-charge electrotherapy (LCE) studies have demonstrated antidepressant or antipsychotic effects with significantly fewer side effects. The aim of this study is to propose a novel two-step charge set strategy for ECT treatment, referred to as Hybrid-ECT, to decrease side effects by using a low charge while preserving treatment efficacy. A randomized, double-blinded, standard-controlled, parallel-group design will be carried out. We plan to enroll 112 inpatients diagnosed with depression (unipolar or bipolar) and randomly assign them to conventional ECT (control group) or to Hybrid-ECT (treatment group, 3 ECT sessions followed by LCE sessions (approximately 2.8 joules per session)). We will evaluate participants across a wide variety of domains including clinical symptoms, cognitive, psychological and functional metrics. We will also perform magnetic resonance imaging (MRI) and event-related potential (ERPs) assessments during treatment to explore brain function differences between ECT and LCE. This research proposes a simple but completely novel ECT strategy that aims to rapidly relieve depressive symptoms and minimize side effects. The mechanism of ECT and LCE will be further discussed. Chinese Clinical Trial Registry, Number: ChiCTR1900022905 (Registration date: April 30, 2019).


Apigeninidin-enriched Sorghum bicolor (L. Moench) extracts alleviate Aflatoxin B1-induced dysregulation of male rat hypothalamic-reproductive axis.
We examined the protective effect of the apigeninidin (API)-enriched fraction from Sorghum bicolor sheaths extracts (SBE-05, SBE-06, and SBE-07) against aflatoxin B1 (AFB1)-induced dysregulation of male rat's reproductive system that may trigger infertility. Male rats (160 ± 12 g) were treated with AFB1 (50 µg/kg) along with 5 or 10 mg/kg of SBE-05, SBE-06, and SBE-07 for 28 days. Subsequently, we assessed the reproductive hormone-prolactin, FSH, LH, testosterone levels, and testicular function enzymes. Moreover, we examined rats' testes, epididymis, and hypothalamus for oxidative and inflammatory stress biomarkers, caspase-9 activity and tissues pathology. We observed that comparative to AFB1 alone treated rats, API co-treatment significantly (p < 0.05) abated the AFB1-mediated decrease in prolactin and antioxidant defenses and lessened lipid peroxidation (LPO) and reactive oxygen and nitrogen species levels in the examined organs-testes, epididymis, and hypothalamus. API abated AFB1-induced hormone decreases-testosterone, FSH, and LH; and caused improvement in sperm quantity and quality. API lessened AFB1-mediated increase in pro-inflammatory cytokine, increased interleukin-10 level, an anti-inflammatory cytokine and reduced caspase-9 activities. In addition, API reduced alterations in the examined tissue histology. Our findings suggest that S. bicolor API-enrich extracts have active antioxidative, antiapoptotic, and anti-inflammatory activities, which can protect against AFB1-induced dysfunction of the hypothalamic-pituitary-gonadal axis.


Strategies for ultrastructural visualization of biotinated probes hybridized to messenger RNA in situ.
A progressive development of the application of in situ methodology to ultrastructural procedures has resulted in the ability to detect individual molecules of mRNA with high probability. Beginning with whole-mount cells and then developing myotubes, both in culture and detergent extracted before fixation, we were able to progress to methods which allow detection of mRNA in tissue sections. Initial results confirm that the detection of mRNA in thin-sectioned tissue is very similar to observations on the extracted, cultured cells, and that the same methods of data analysis apply. Current work is devoted to the application of the methodology to other cellular structures, such as the nucleus, and to other tissue-probe systems, such as brain. Acknowledgements. The authors appreciate the skilled help from John McNeil and Shirwin Pockwinse in the laborious and time-consuming preparations of material and photography. FS was on sabbatical leave from the Department of Pathology at Southwestern Medical Center.


Rat hepatic glutaminase: purification and immunochemical characterization.
A method for the purification of phosphate-activated glutaminase from the liver of streptozotocin-diabetic rats is described. The procedure involves solubilization of glutaminase activity from isolated mitochondria by sonication, followed by ammonium sulfate precipitation, polyethylene glycol precipitation, and sequential chromatography on DEAE, hydroxylapatite, and zinc-chelated resins. The enzyme was purified 600-fold to a specific activity of 31-57 U/mg protein. The purified enzyme has an apparent subunit molecular mass of 58,000-Da and is greater than 80% pure by scanning densitometry of sodium dodecyl sulfate-polyacrylamide gels. The purified enzyme has an apparent Km for glutamine of 17 mM and a pH optimum between 7.8 and 8.2. The physical and kinetic properties of this enzyme are similar to those of the enzyme from normal rat liver. Polyclonal antibodies raised against the enzyme specifically inhibit hepatic glutaminase activity and react primarily with a 58,000-Da peptide in liver fractions on immunoblots. These antibodies were used in equivalence point titrations and immunoblots to provide evidence for increased concentration of glutaminase protein in the liver of diabetic rats with no change in specific activity of the enzyme. In addition, the antibodies cross-react, at low affinity, with kidney-type glutaminases. On immunoblots, the antibodies did not react with fetal liver, mammary gland, or lung. Antibodies to rat hepatic glutaminase should prove useful as tools to study the long-term regulation of the enzyme.


Ovarian steroid and growth factor regulation of female reproductive function involves modification of hypothalamic alpha 1-adrenoceptor signaling.
The ovarian steroids estradiol (E(2)) and progesterone (P) act on target neurons in the hypothalamus and preoptic area to coordinate the expression of female reproductive behaviors with the timing of the preovulatory luteinizing hormone (LH) surge. This chapter will summarize evidence that E(2) and P facilitation of the receptive component of female reproductive behavior, lordosis, involves changes in both the expression of and intracellular signal transduction pathways engaged by alpha(1)-adrenergic receptors in the hypothalamus and preoptic area. The alpha(1)-adrenoceptors are thought to mediate the facilitatory effects of the catecholamine neurotransmitter norepinephrine on both lordosis behavior and LH release. E(2) first induces the expression of the alpha(1B)-adrenergic receptor subtype in the hypothalamus and preoptic area. P then acts in an E(2)-dependent manner to promote linkage of hypothalamic alpha(1)-adrenoceptors to an intracellular signaling pathway involving nitric oxide and cyclic GMP. This chapter will also describe recent findings that implicate brain insulin-like growth factor-I (IGF-I) receptors as obligatory co-mediators of hormonal regulation of hypothalamic alpha(1)-adrenoceptors and female neuroendocrine function. Additional studies suggest that E(2) and IGF-I facilitate lordosis behavior by activating kinases traditionally associated with growth factor signal transduction (mitogen-activated protein kinases and phosphatidlyinositol-3-kinases). These molecular events are proposed to help coordinate the timing of ovulation with the expression of sexual receptivity, thereby maximizing reproductive success.


Induction of cyclooxygenase-2 expression in human pulp cells stimulated by dentin bonding agents.
Histological investigations have demonstrated that dentin bonding agents can induce pulpal inflammation. However, there is little information on the precise mechanisms about dentin bonding agent-induced pulpal inflammation. Cyclooxygenase-2 (COX-2) is an inducible enzyme believed to be responsible for prostaglandin synthesis at the site of inflammation. The aim of this study was to investigate the effects of dentin bonding agents on the expression of COX-2 in human pulp cells. Human pulp cells were cultured from extracted impacted third molars using an explant technique. Patients gave informed consent. The reverse-transcriptase polymerase chain reaction and Western blot assays were used to investigate the effects of cultured human pulp cells exposed to dentin bonding agents. In addition, NS-398 (a selective COX-2 inhibitor) was added to test how it modulated the cytotoxic effects of dentin bonding agents. The exposure of quiescent human pulp cells to dentin bonding agents resulted in the induction of COX-2 mRNA and protein expression. The expression of COX-2 signals depended on the materials tested. In addition, NS-398 at noncytotoxic dose was not able to prevent dentin bonding agent-induced cytotoxicity (P > .05). The activation of COX-2 expression may be one of the pathogenesis of dentin bonding agent-induced pulpal inflammation. In addition, dentin bonding agent-induced cytotoxicity is not directly via the induction of COX-2 expression.


Lack of association between TLR4 Asp299Gly and Thr399Ile polymorphisms and sepsis susceptibility: a meta-analysis.
Sepsis, a condition of systemic inappropriate inflammation response to the invasion of microorganisms, results in considerable morbidity and mortality in patients. Some, but not all, epidemiological studies have suggested that Toll-like receptor 4 (TLR4) polymorphisms, Asp299Gly and Thr399Ile, may influence the risk of at-risk patients for sepsis. Our work tried to further study the association of the two common polymorphisms with sepsis susceptibility by performing a meta-analysis of previous data. Electronic searches of MEDLINE, EMBASE and Web of Science databases were performed. Original observational studies dealing with the association between polymorphisms Asp299Gly and/or Thr399Ile and sepsis risk were selected. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with random-effects model or fixed-effects model based on the heterogeneity analysis. Seventeen studies including 2212 cases and 3880 controls were included with most subjects of Caucasian ethnicity. The odds ratio for the association of Asp299Gly polymorphism with sepsis risk was 1.22 (95% CI: 0.90-1.65, P=0.21), and the association of Thr399Ile polymorphism was 1.16 (95%CI: 0.70-1.91, P=0.57). Subgroup analysis and sensitivity analysis did not change the results. Our meta-analysis revealed that the two common TLR4 polymorphisms, Asp299Gly and Thr399Ile, have no strong association with the likelihood of sepsis in Caucasian populations. Further studies are needed to investigate the effect of genetic networks and their mutual interactions in TLR4 signaling pathway on sepsis susceptibility.


Malignancy in a 19-year experience of adult celiac disease.
Malignancy has developed in 10 of 93 patients with celiac disease who attended this hospital from 1959 to 1978. Four patients developed lymphoma, 5 a squamous carcinoma of the esophagus, and 1 an adenocarcinoma of the ileum. Because the majority of patients were ingesting varying amounts of gluten at the time of their follow-up no conclusion can be drawn about the possible role of a gluten-free diet in the prevention of malignancy.


[Characterization of lectin binding by psoriatic epidermis--dependence on pH].
The binding of five different lectins by normal as well as psoriatic lesional epidermis was investigated with regard to its dependence on the pH value. As we studied the reactions within the pH range of 3.0 to 9.66, we obtained the following results: lectin binding almost independent from pH (FITC-Con A, -PHA, HPA), fluorescence intensity dependent on pH (TRITC-Con A, FITC-LCA, -GCA), binding pattern dependent on pH (FITC-LCA, GCA). In contrast to normal epidermis, there was no pH dependence of the FITC-GCA binding pattern in psoriatic lesional epidermis.


Tumor-regulated macrophage type 2 differentiation promotes immunosuppression in laryngeal squamous cell carcinoma.
Tumor-associated macrophage (TAM) residing in tumor microenvironment as the major niche cell made remarkable contribution to tumor growth. However, the functional role of macrophage and its different differentiating state as well as the regulating mechanism in laryngeal squamous cell carcinoma (LSCC) remains not fully clear. LSCC samples were collected from patients. Human peripheral blood mononuclear cells (PBMC) were collected from volunteers' blood, and used for macrophage induction. Enzyme-Linked Immunosorbent Assay (ELISA) was performed to detect proinflammatory cytokines. Immunostaining was prepared to observe tumor tissues. Here, we found the number of type 2 macrophage (MΦ2) and PDL-1 expression was increased in LSCC that was correlated with poor prognosis in patients with LSCC. Tumor cells induced macrophage into type 2 differentiation by TGF-β/Smad3 signaling. The primed MΦ2 produced IL-10 by activating JAK/STAT signaling that promoted PDL-1 expression in tumor cells leading to its immunosuppression. Inhibition of JAK/STAT signaling promoted tumor cells death from immune cells killing by regulating PDL-1 expression. Targeting cytokines TGF-β or IL-10 synergistically enhances the sensitivity of tumors to chemotherapy in vivo. In conclusion, our findings showed tumor cells and MΦ2 were bilaterally regulated through cytokines production that integrally advanced tumor progression through boosting anti-tumor immunity. It provides insight to develop immune strategies synergy with chemotherapy in treating laryngeal squamous cell carcinoma.


Structural modification of berberine alkaloids in relation to cytotoxic activity in vitro.
The cytotoxicity of two protoberberine alkaloids: berberine and lincangenine, their 8-hydroxy-7,8-dihydro-derivatives and tetrahydroprotoberberine:thaicanine, was evaluated. The cellular responses through the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] (MTT) method were measured in Hela (uterus carcinoma), SVKO3 (ovary carcinoma), Hep-2 (larynx carcinoma), primary culture from mouse embryon, and human fibroblast cells at the concentration: 10-1000 ppm (microg/ml) for 24 h. Berberine showed the highest cytotoxicity among the compounds tested, giving LC50 values for all cell lines at the concentration of 10 ppm. The results indicated that the cytotoxicity was notably decreased by structural changes, i.e. by modulation of the planarity caused by the introduction of hydroxyl group at C-8 and concomitant saturation of double bond between N-C8 in protoberberine molecules. In the case of berberine, the cytotoxic effect changed from 98.8 (berberine) to 39% for 8-hydroxydihydroberberine at the concentration of 100 ppm in Hela cells line. The same effect was observed with lincangenine and 8-OH-lincangenine (cytotoxicities 70 and 25%, respectively, at 1000 ppm in SVKO3 cells). On the other hand, these compounds showed a low selectivity for the different human cancer cell lines tested.


Mitophagy antagonism by ZIKV reveals Ajuba as a regulator of PINK1 signaling, PKR-dependent inflammation, and viral invasion of tissues.
Dysregulated inflammation dominated by chemokine expression is a key feature of disease following infection with the globally important human pathogens Zika virus (ZIKV) and dengue virus, but a mechanistic understanding of how pro-inflammatory responses are initiated is lacking. Mitophagy is a quality-control mechanism that regulates innate immune signaling and cytokine production through selective degradation of damaged mitochondria. Here, we demonstrate that ZIKV nonstructural protein 5 (NS5) antagonizes mitophagy by binding to the host protein Ajuba and preventing its translocation to depolarized mitochondria where it is required for PINK1 activation and downstream signaling. Consequent mitophagy suppression amplifies the production of pro-inflammatory chemokines through protein kinase R (PKR) sensing of mitochondrial RNA. In Ajuba-/- mice, ZIKV induces early expression of pro-inflammatory chemokines associated with significantly enhanced dissemination to tissues. This work identifies Ajuba as a critical regulator of mitophagy and demonstrates a role for mitophagy in limiting systemic inflammation following infection by globally important human viruses.


Laparoscopic Adrenalectomy is Feasible for Suspected Adrenal Tumors in Children Younger than 24 Months of Age - But is it Always Justified?
Tumors of the adrenal gland are rare in children younger than 24 months of age. While neuroblastomas are most important in this age group, adrenal hemorrhage and other tumors are sometimes difficult to distinguish. Harvesting biopsies is mandatory in these young patients to obtain information on molecular markers, namely, MYCN and 1p deletion. Between 03/2012 and 10/2013, 11 patients younger than 24 months of age with suspicious adrenal tumors were operated on laparoscopically. The diagnostic workup was coordinated by our pediatric oncologists according to the terms of the NB2004 trial protocol. 9 out of 11 had a diagnosis of neuroblastoma, the others were adenoma respective complete necrosis of the adrenal gland. All of the neuroblastomas were negative for both MYCN amplification and 1p deletion. A complete resection was successful in 9 out of 11 cases. 3 complications occurred, 1 major and 2 minor. Behind the recognition that laparoscopic adrenalectomy is technically feasible, the fact that all neuroblastomas were negative for MYCN amplification and 1p deletion raises the issue of whether biopsy is mandatory for risk stratification in this age group.


Influence of phytosphingosine-type ceramides on the structure of DMPC membrane.
The present paper describes the influence of the ceramides with phytosphingosine base, N-stearoylphytosphingosine (Cer[NP]) and alpha-hydroxy-N-stearoylphytosphingosine (Cer[AP]), on the structure and properties of multilamellar (MLVs) and unilamellar vesicles (ULVs) of dimyristoylphosphatidylcholine (DMPC). The lamellar repeat distance, D, has been measured at various temperatures using small angle X-ray diffraction. The incorporation of ceramides into the DMPC membrane causes larger D compared to pure DMPC membrane. For both ceramide types, at 32 degrees C, there is a linear relationship between the D value and the ceramide concentration. However, there is no such dependence at 13 or 60 degrees C. Unlike Cer[AP], Cer[NP] induces a new phase with a repeat distance of 38.5A. The membrane thickness and the vesicle radius of ULVs in water and in sucrose solution were calculated from small angle neutron scattering curves. Phytosphingosine ceramides increase both the membrane thickness and the radius in comparison to pure DMPC ULVs. The stability of ULVs in time was studied by dynamic light scattering. Both ceramides induce an aggregation of the ULVs into micrometer sized non-multilamellar structures in pure water. Presence of sucrose in the environment averts the vesicle aggregation.


Color stability of hybrid ceramics exposed to beverages in different combinations.
The aim of this study is to evaluate the color stability of hybrid ceramics stored in different combinations of beverages that are routinely consumed. The specimens were prepared with resin nano-ceramic (Lava Ultimate, 3M Espe, USA) and hybrid ceramic (Vita Enamic, Vita Zahnfabrik, Germany). The specimens were aged in a thermocycler machine for 10,000 cycles. They were stored in different combinations of beverages (water, tea, coke, coffee, red wine, pomegranate juice, and turnip juice) for 12 + 12 h. Surface roughness measurements were performed using a profilometer. The specimen colors were measured using a spectrophotometer. The color values (L-a-b) of the specimens and mean surface roughness values (Ra) were recorded at the end of the 1st (D1), 7th (D7), 14th (D14) and 28th (D28) d. When the solution groups were examined, significant color changes were observed in the Lava coffee-tea, Enamic coffee-tea, Lava coffee-wine, and Enamic coffee-wine groups compared with the other groups (p < 0.01). Except for the samples in the Lava coffee-wine 28th day (D28) and Enamic coffee-wine 28th day (D28) groups, more color changes were observed in the Lava samples than in the Enamic samples across all groups and periods. Greater color changes (except for the samples stored in coffee-wine) were observed in the Lava samples than in the Enamic samples across all groups and periods. It was observed that the coffee-tea and coffee-wine beverage combinations produced the greatest color change in hybrid ceramics within the limitations of this study.


A systematic review of randomized controlled trials of prenatal and postnatal vitamin A supplementation of HIV-infected women.
We searched the Cochrane Library, MEDLINE, EMBASE, AIDSearch, and Gateway to assess the effect of prenatal and/or postnatal vitamin A supplementation on the risk of mother-to-child transmission (MTCT) of HIV and other pregnancy outcomes. We included 5 trials totaling 7528 women (4 trials of prenatal and 1 trial of postnatal supplementation). Overall, there was no evidence of an effect of prenatal and/or postnatal vitamin A supplementation on the risk of MTCT of HIV (Relative Risk [RR] 1.06, 95% Confidence Interval [CI] 0.89-1.26). However, prenatal vitamin A supplementation significantly improved birth weight (weighted mean difference 89.78; 95% CI, 84.73-94.83), but there was no evidence of an effect on stillbirths (RR 0.99; 95% CI, 0.68-1.43), preterm births (RR 0.88; 95% CI, 0.65-1.19), death before 24 months among live births (RR 1.08; 95% CI, 0.91-1.29), and maternal death (RR 0.83; 95% CI, 0.59-1.17). The available evidence does not support vitamin A supplementation of HIV-infected pregnant and lactating women, despite improvement in birth weight.


Alkali treatment stabilizes fluctuations of urine AQP2 values measured by ELISA.
Aquaporin-2 (AQP2) in urine is now measured in many water-balance disorders and regarded as a useful biomarker for diagnosis and prognosis. An enzyme-linked immunosorbent assay (ELISA) method has been developed for measurement of large numbers of clinical samples. However, fluctuations in the measured values were sometimes observed depending on storage conditions. Urine AQP2 is present in exosome membranes and we speculated that this structural organization causes the fluctuations. Human urine samples from healthy subjects were measured by ELISA. Effects of maneuvers to disrupt the exosome membrane mechanically (freezing and thawing at different temperatures) and chemically (treating with alkali and detergents) prior to ELISA were examined. Urine samples stored at 4 or -80 °C did not show significant AQP2 values, whereas those stored at -25 °C for more that 2 weeks provided the values. Urine samples treated with 0.4 N NaOH and 0.5 % Triton X-305 showed the consistent and comparable values to those stored at -25 °C. Pretreatment with alkali (0.4 N NaOH) to disrupt exosome membranes allowed consistent ELISA measurements of urinary AQP2. This simple method is applicable to ELISA of other membrane proteins included in exosomes.


Aquaporin-4 mediates astrocyte response to β-amyloid.
It has been demonstrated that the water channel protein aquaporin-4 (AQP4) plays an important role in astrocyte plasticity in response to a variety of injuries or stimuli. However, the potential role of AQP4 in astrocyte response to β-amyloid (Aβ) has not been studied. The purpose of this study was to investigate this issue. Compared to media control, the lower concentrations of Aβ(1-42) (0.1-1 μM) increased AQP4 expression in cultured mouse cortical astrocytes, while the higher concentrations of Aβ(1-42) (10 μM) decreased AQP4 expression. AQP4 gene knockout reduced Aβ(1-42)-induced astrocyte activation and apoptosis, which was associated with a reduction in the uptake of Aβ via decreased upregulation of low-density lipoprotein receptor related protein-1. Moreover, time-course and levels of Aβ(1-42)-induced mitogen-activated protein kinase phosphorylation were altered in AQP4 null astrocytes compared with wild-type controls. Our data reveal a novel role of AQP4 in the uptake of Aβ by astrocytes, indicating that AQP4 is a molecular target for Alzheimer's disease.


SMARCB1 (INI-1) and NUT immunoexpression in a large series of head and neck carcinomas in a Brazilian reference center.
SMARCB1 (INI-1)-deficient carcinomas and NUT carcinomas are aggressive neoplasms, often affecting the sinonasal region. Not uncommonly, their diagnoses are made retrospectively. Through SMARCB1 (INI-1) and NUT immunomarkers, 643 head and neck carcinomas were assessed retrospectively. Moreover, SMARCB1 (INI-1)-deficient and NUT carcinomas were additionally evaluated by immunohistochemistry, as well as in situ hybridization analysis for HPV and EBV. Four SMARCB1 (INI-1)-deficient carcinomas (located in lower lip, soft palate, hypopharynx and vocal cord, this latter high-risk HPV positive) and three NUT carcinomas (all located in oropharynx) were detected, previously diagnosed as nonkeratinizing or moderately differentiated squamous cell carcinoma. All cases showed squamous differentiation. NUT carcinomas than SMARCB1 (INI-1)-deficient carcinomas showed low overall survival rate. The current cases expand the clinicopathological spectrum of SMARCB1 (INI-1)-deficient carcinomas and NUT carcinomas. Notably, the diagnosis of these cases is easily reached through immunohistochemistry, with impact on their accurate classification, treatment, and prognosis.


Triphenyl Phosphate at Environmental Levels Retarded Ovary Development and Reduced Egg Production in Japanese Medaka (Oryzias latipes).
Since triphenyl phosphate (TPhP) elicits both antiestrogenic activities via blocking the estrogen receptor (ER) and estrogenic activity by elevating 17β-estradiol (17β-E2) synthesis, its adverse effect on female reproduction is uncertain. In this study, we exposed Japanese medaka to TPhP at 131, 363, and 1773 ng/L for 100 days following hatching. TPhP significantly induced ovary retardation in all exposure groups (incidence: from 11.9 to 37.8%) and reduced egg production by 38.9 and 50.9% in the 363 and 1773 ng/L exposure groups, respectively. Vitellogenin (vtg) transcription was significantly downregulated by 35.4-57.4% after TPhP exposure, explaining the ovary retardation. Considering that 17β-E2 was only significantly decreased in the 1773 ng/L exposure group, ER antagonism could be the dominant contributor to the inhibition of vtg transcription and female reproductive toxicity of TPhP. As 4-hydroxyphenyl diphenyl phosphate, a metabolite of TPhP, was detected in livers with similar concentration [68.4-1237 ng/g lipid weight (lw)] to that of TPhP (485-1594 ng/g lw) and elicited medaka ER antagonistic activity (50% inhibitory concentration = 78.1 μM), TPhP and its metabolite should both contribute to the reproductive inhibition. We demonstrate that TPhP at environmentally relevant concentrations is toxic to female reproduction, which poses an ecological risk to wild fish at the population level.


Role of imipenem/cilastatin in the treatment of soft tissue infections.
Imipenem/cilastatin was given to 243 evaluable patients with moderately severe to severe soft tissue infections. Cultures prior to therapy yielded Staphylococcus aureus (108 isolates), group D and non-group D enterococci (49), group A streptococci (42), other aerobic gram-positive cocci (72), Pseudomonas aeruginosa (54), Escherichia coli (32), Proteus mirabilis (31), Enterobacter (21), Klebsiella (20), other aerobic gram-negative rods (58), Bacteroides fragilis group (16), and other anaerobes (65). Overall, 95 percent (230 of 243) of the patients treated had clinical cure (137 of 243) or improvement (93 of 243). Of the 506 strains of etiologic bacterial pathogens isolated from these patients and tested against imipenem, 498 (98 percent) were susceptible to the antibiotic. Many were resistant to both older and newer penicillins and cephalosporins. Serial cultures of infection sites revealed that 426 of 498 (86 percent) of pre-therapy bacterial isolates were eradicated by imipenem/cilastatin therapy. Eight of 498 etiologic pathogens (1.6 percent) acquired resistance to imipenem (seven P. aeruginosa and one enterococcus). Such resistance acquisition was associated with clinical failure in two patients. Imipenem/cilastatin appears to be a highly effective, relatively safe therapy of soft tissue infections caused by a wide variety of gram-positive and gram-negative aerobes and anaerobes, both polymicrobial and monomicrobial in nature. Imipenem/cilastatin should be considered particularly when infection by the more antibiotic-resistant of these bacteria is suspected or proved.


Molecular basis of cross-species reactivities of human versus porcine CTLA-4.
The binding motif of human CTLA-4 is well known to be MYPPPY and for porcine CTLA-4 the binding motif is LYPPPY. Is this single amino acid difference of methionine (M) versus leucine (L) critical for the CTLA-4 binding? Recently, we have reported that the recombinant soluble porcine CTLA-4 was incapable of binding to human CD80. In this study we mutated L to M in the binding motif of the soluble porcine CTLA-4 and mutated M to L in the binding motif of the soluble human CTLA-4. We then analyzed how these mutations affected the binding affinity of the mutants to both porcine and human CD80(+) cells. The soluble porcine CTLA-4-L97M mutant partially lost its binding affinity to porcine CD80 compared to the wild-type and conferred very weak binding ability to human CD80. These results indicate that the L in the binding motif of porcine CTLA-4 is important for determining its binding ability to porcine CD80. Wild-type soluble human CTLA-4 binds to both human and porcine CD80 with comparable affinity, however, the soluble human CTLA-4-M97L mutant almost lost its binding ability to human CD80 and increased its binding ability to porcine CD80. These results indicate that M in the human CTLA-4 binding motif is extremely critical for its binding to human CD80. Those data suggest that the human CTLA-4 based recombinant protein drugs such as human CTLA-4-Ig can be used and/or tested in a porcine model. Conversely, the use of porcine CTLA-4 based recombinant protein drugs such as porcine CTLA-4-Ig is restricted to swine models. The difference in binding specificity of CTLA-4 observed in this study may be useful for studies such as pig to nonhuman primate xeno-transplantation. Porcine CTLA-4- and human CTLA-4-M97L mutant-based recombinant protein drugs can be used to specifically block the direct presentation by donor antigen presenting cells in pig to nonhuman primate xeno-transplantation. Human CTLA-4-M97L mutant-based recombinant protein drugs will be more ideal as it is without immunogenicity to human being.


Exploring the effect of Yinzhihuang granules on alcoholic liver disease based on pharmacodynamics, network pharmacology and molecular docking.
Yinzhihuang granules (YZHG) is a commonly used Chinese patent medicine for the treatment of liver disease. However, the mechanism of YZHG in alcoholic liver disease (ALD) is still unclear. This study combined liquid chromatography-mass spectrometry technology, pharmacodynamics, network pharmacology and molecular docking methods to evaluate the potential mechanism of YZHG in the treatment of ALD. A total of 25 compounds including 4-hydroxyacetophenone, scoparone, geniposide, quercetin, baicalin, baicalein, chlorogenic acid and caffeic acid in YZHG were identified by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The pharmacodynamic investigations indicated that YZHG could improve liver function and the degree of liver tissue lesions, and reduce liver inflammation and oxidative stress in ALD mice. Network pharmacology analysis showed that YZHG treated ALD mainly by regulating inflammation-related signaling pathways such as the PI3K-Akt signaling pathway. The results of the PPI network and molecular docking showed that the targets of SRC, HSP90AA1, STAT3, EGFR and AKT1 could be the key targets of YZHG in the treatment of ALD. This study explored the potential compounds, potential targets and signaling pathways of YZHG in the treatment of ALD, which is helpful to clarify the efficacy and mechanism of YZHG and provide new insights for the clinical application of YZHG.


Scanned ion beam therapy for prostate carcinoma: Comparison of single plan treatment and daily plan-adapted treatment.
Intensity-modulated particle therapy (IMPT) for tumors showing interfraction motion is a topic of current research. The purpose of this work is to compare three treatment strategies for IMPT to determine potential advantages and disadvantages of ion prostate cancer therapy. Simulations for three treatment strategies, conventional one-plan radiotherapy (ConvRT), image-guided radiotherapy (IGRT), and online adaptive radiotherapy (ART) were performed employing a dataset of 10 prostate cancer patients with six CT scans taken at one week intervals. The simulation results, using a geometric margin concept (7-2 mm) as well as patient-specific internal target volume definitions for IMPT were analyzed by target coverage and exposure of critical structures on single fraction dose distributions. All strategies led to clinically acceptable target coverage in patients exhibiting small prostate motion (mean displacement <4 mm), but IGRT and especially ART led to significant sparing of the rectum. In 20% of the patients, prostate motion exceeded 4 mm causing insufficient target coverage for ConvRT (V95mean = 0.86, range 0.63-0.99) and IGRT (V95mean = 0.91, range 0.68-1.00), while ART maintained acceptable target coverage. IMPT of prostate cancer demands consideration of rectal sparing and adaptive treatment replanning for patients exhibiting large prostate motion.


High-dose galantamine augmentation inferior to placebo on attention, inhibitory control and working memory performance in nonsmokers with schizophrenia.
Dysfunction in the neuronal nicotinic acetylcholine receptor (nAChR) system has been implicated in the pathophysiology of schizophrenia, and it has been postulated that treatments that increase nAChR activity may improve symptoms of the disorder. We investigated the effects of the acetylcholinesterase inhibitor and allosteric nAChR modulator, galantamine, on cognitive performance and clinical symptoms when added to a stable antipsychotic medication regimen in nonsmoking outpatients with schizophrenia in a double-blind, placebo-controlled, parallel-group design. Participants were randomized to receive either galantamine (n=10) up to 32 mg/day or identical placebo (n=10) for 8 weeks and completed a cognitive battery at baseline and week 8 and clinical scales at baseline, week 4 and week 8. The primary outcome measure was attentional performance as measured by the d' measure in the Continuous Performance Test - Identical Pairs (CPT-IP) Version. Contrary to our hypothesis, galantamine treatment was associated with inferior performance on the CPT-IP, on the three-card Stroop task, and on the Letter-Number Span task without reordering. Galantamine had no effect on clinical symptoms. In summary, galantamine treatment, at a dose of 32 mg/day, was well tolerated but was not effective as an adjunctive treatment for cognitive deficits in stable nonsmokers with schizophrenia.