Perceived feasibility and usefulness of mHealth interventions for psychoeducational support among Nigerian women receiving chemotherapy for breast cancer: a focus group study.
Women diagnosed with breast cancer (BC) receiving chemotherapy have reported various side effects, which adversely affect their psychological state. Evidence suggests that psychoeducational interventions (PEIs) delivered through mobile phones might effectively provide psychoeducational support for this population. However, there is a lack of evidence on Nigerian women's perception of mobile health (mHealth) PEI, which prompted this study. A qualitative study was conducted among women with BC who had completed chemotherapy at two tertiary hospitals in Nigeria. Face-to-face focus group discussions were conducted at the oncology clinics. Data were collected using focus groups until data saturation was reached. Data were analyzed using thematic analysis. In total, 32 women were recruited, with seven focus group discussions conducted. The participants were between 22 and 75 years old and mostly diagnosed with Stage III BC. Four main themes emerged from the data analysis, including experiences of BC diagnosis and treatment phase, patients' needs during chemotherapy, coping with chemotherapy, and perception of mHealth intervention for psychoeducational support. BC diagnosis was devastating, and psychological disturbances were experienced while receiving chemotherapy, but the participants indicated that mHealth intervention was acceptable as it could provide psychological and informational support. The suggested contents include information on chemotherapy, how to deal with the fear of chemotherapy, nutritious diet locally available, and information on exercise. This study has shown that the participants perceived a mHealth PEI is feasible and acceptable in providing psychoeducational support for Nigerian women diagnosed with BC receiving chemotherapy. It is hoped that the unmet needs of this population will be addressed while receiving chemotherapy.


The role of phosphodiesterase-5 inhibitors in prostatic inflammation: a review.
Clinical and basic experimental evidence indicates that chronic inflammation is the greatest factor in benign prostatic hyperplasia (BPH) progression, which is the most common cause of Lower Urinary Tract Symptoms (LUTS). The use of anti-inflammatory agents such as steroids, cyclooxygenase-2 (COX-2) and phytotherapics have been investigated as forms of treatment for various prostate diseases. Recent evidence has demonstrated that PDE5 inhibitors (PDE5Is) improve symptoms of BPH/LUTS, possibly as a result of the relaxing of the smooth muscle fibers of the bladder and prostate by NO/cGMPc signaling, or by improving RhoA/Rho-kinase (ROCK), and reduction of the hyperactivity of the autonomic nervous system. However, some results have suggested that besides vasodilatation and their anti-proliferative effect, PDE5Is exert a direct anti-inflammatory effect, by raising cGMP. Given that inflammation is major factor in benign prostatic hyperplasia (BPH) progression, PDE5Is could act also restore prostatic function as they act as potent anti-inflammatory drugs. This review aims to provide a comprehensive summary of the use of phosphodiesterase-5 inhibitors to treat prostatic inflammation.


Extracellular vesicles from the inflammatory microenvironment regulate the osteogenic and odontogenic differentiation of periodontal ligament stem cells by miR-758-5p/LMBR1/BMP2/4 axis.
Extracellular vesicles (EVs) play a key role in constructing a microenvironment that favors the differentiation of stem cells. The present work aimed to determine the molecular mechanisms by which EV derived from inflammatory dental pulp stem cell (iDPSC-EV) influence periodontal ligament stem cells (PDLSCs) and provide a potential strategy for bone and dental pulp regeneration. The osteogenic and odontogenic differentiation was assessed by quantitative real-time polymerase chain reaction (qRT-PCR), western blot, alkaline phosphatase (ALP) activity assay, ALP staining, alizarin red S (ARS) staining, and immunofluorescence staining. To detect proliferation, the Cell Counting Kit-8 (CCK-8) assay, and flow cytometry analysis were used. EVs were isolated by the Exoperfect kit and ultrafiltration and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blot. The expression profile of miRNAs in EVs was studied using miRNA sequence and bioinformatics, and one of the upregulated miRNAs was evaluated on PDLSCs. The inflammatory microenvironment stimulated osteogenic and odontogenic differentiation of DPSCs and iDPSC-EV behaved alike on PDLSCs. MiR-758-5p was upregulated in iDPSC-EV and was demonstrated to play a significant role in the osteogenic and odontogenic commitment of PDLSCs. A dual-luciferase reporter assay confirmed the binding site between miR-758-5p and limb development membrane protein 1 (LMBR1). The knockdown of LMBR1 also enhanced the above potential. Mechanically, bone morphogenetic protein (BMP) signaling was activated. EVs from the inflammatory microenvironment enhanced the osteogenic and odontogenic differentiation of PDLSCs partly by shuttering LMBR1-targeting miR-758-5p via BMP signaling.


The limbic lobe and its output channels: implications for emotional functions and adaptive behavior.
Current dissatisfaction with the limbic system concept reflects a desire to move beyond the limbic system in efforts to explain key facets of emotional functions and motivational behavior. This review promotes an anatomical viewpoint, which originated as a result of histotechnical advances. These improvements paved the way for anatomical discoveries, which in turn led to the concepts of the ventral striatopallidal system and extended amygdala. These two systems, together with the basal nucleus of Meynert and the septum-diagonal band system, serve as output channels for an expanded version of the classic limbic lobe of Broca, which contains all non-isocortical parts of the cortical mantle together with the large laterobasal-cortical amygdaloid complex. Thus defined, the limbic lobe contains all of the major cortical (e.g. orbitofrontal, cingulate and insular cortices in addition to the hippocampal formation) and cortical-like (laterobasal-cortical amygdala) structures known to be especially important for emotional and motivational functions. In their role as output channels for the limbic lobe, the basal forebrain functional-anatomical systems contribute to the establishment of a number of cortico-subcortical circuits, which provide an important part of the anatomical substrate for the elaboration of emotional functions and adaptive behavior.


Regulate the hydrophobic motif to enhance the non-classical secretory expression of Pullulanase PulA in Bacillus subtilis.
Bacillus subtilis has been widely used as a prokaryotic host for the secretory expression of heterologous proteins. In this study, a pullulanase (PulA) from Anoxybacillus sp. LM18-11 was firstly identified to be expressed in Bacillus subtilis 1A751 through non-classical secretion pathway. Results showed that both the N- and C-terminal regions of PulA were essential for its soluble expression. To explore its specific structural basis of secretion in B. subtilis, we revealed a hydrophobic motif A501-H507 which is vital for the secretion of the whole protein of PulA. Through a series of site-specific mutagenesis, the triple-sites mutants R503E/I506E/H507E and R503E/I506Y/H507E showed the highest extracellular activity (160.07 U/mL) and total activity (243.37 U/mL) which was 1.71 times and 1.55 times higher than those of PulA. The highest secretion rate of mutant I506E/H507E was more than 50% which was 34.72% higher comparing with that of PulA. The glutamic acid substitution on these three key surface sites which decreased the surface hydrophobicity of that region was confirmed to be beneficial to improve the secretory expression of PulA. This novel discovery for the secretory expression of PulA in B. subtilis would make a new perspective on regulating a kind of non-classical secretion in B. subtilis.


[Prioritization of risk situations in neuro-urology: Guidelines based on the Delphi method from Association française d'urologie (AFU), Association francophone internationale des groupes d'animation de la paraplégie (AFIGAP), Groupe de neuro-urologie de langue française (GENULF), Société française de médecine physique et de réadaptation (SOFMER) and Société interdisciplinaire francophone d'urodynamique et de pelvi-périnéologie (SIFUD-PP)].
During the COVID-19 pandemic, a care reorganization was mandatory, and affected patients in different areas, including management of neurogenic lower urinary tract dysfunction. This work aims to provide validated schedule concerning the assessment and management of patients in neuro-urology. Based on a literature review and their own expertise, a steering committee composed of urologists and physical medicine and rehabilitation practitioners generated a comprehensive risk-situation list and built a risk scale. A panel of French-speaking experts in neuro-urology was asked to define the timing for each clinical situation and validated these new recommendations through a Delphi process approach. The 49 experts included in the rating group validated 163 propositions among the 206 initial items. The propositions were divided into four domains - diagnosis and assessment, treatment, follow-up, and complications - and two sub-domains - general (applicable for all neurological conditions) and condition-specific (varying according to the neurological condition (spinal cord injury, multiple sclerosis, brain injury, Parkinsonism, spinal dysraphism, lower motor neuron lesions)). This multidisciplinary collaborative work generates recommendations based on expert opinion, providing a validated timing for assessment and management of patients in neuro-urology which may help clinicians to reorganize their patients' list with a personalized medicine approach, in a context of health crisis or not.


Intravitreal injection of adenosine A2A receptor antagonist reduces neuroinflammation, vascular leakage and cell death in the retina of diabetic mice.
Diabetic retinopathy is a major complication of diabetes mellitus and a leading cause of blindness. The pathogenesis of diabetic retinopathy is accompanied by chronic low-grade inflammation. Evidence shows that the blockade of adenosine A2A receptors (A2AR) affords protection to the retina through the control of microglia-mediated neuroinflammation. Herein, we investigated the therapeutic potential of an antagonist of A2AR in a model of diabetic retinopathy. Type 1 diabetes was induced in 4-5 months old C57BL/6 J mice with a single intraperitoneal injection streptozotocin. Animals were treated one month after the onset of diabetes. The A2AR antagonist was delivered by intravitreal injection once a week for 4 weeks. Microglia reactivity and inflammatory mediators were increased in the retinas of diabetic animals. The treatment with the A2AR antagonist was able to control microglial reactivity and halt neuroinflammation. Furthermore, the A2AR antagonist rescued retinal vascular leakage, attenuated alterations in retinal thickness, decreased retinal cell death and the loss of retinal ganglion cells induced by diabetes. These results demonstrate that intravitreal injection of the A2AR antagonist controls inflammation, affords protection against cell loss and reduces vascular leakage associated with diabetes, which could be envisaged as a therapeutic approach for the early complications of diabetes in the retina.


A novel aza-anthrapyrazole blocks the progression of experimental autoimmune encephalomyelitis after the priming of autoimmunity.
Mitoxantrone is one of the few FDA-approved drugs available to treat rapidly progressing forms of multiple sclerosis; however, its utilization is compromised by a cardiotoxic potential and the risk of mitoxantrone-induced leukemia. BBR3378, a novel aza-anthrapyrazole, is structurally similar to mitoxantrone, but lacks the ring hydroxyls that may contribute to cardiotoxicity. Here, we investigated the therapeutic activity of BBR3378 in a C57BL/6 mouse model of multiple sclerosis. Mice given BBR3378, before or after the priming and expansion of MOG-specific responses, were protected from ascending paralysis. Strikingly, two doses of BBR3378 given a week after EAE induction were sufficient to provide significant protection from clinical symptoms and reduce MOG-specific proinflammatory T cell cytokine production, and serum IgG responses. Furthermore, while mitoxantrone is associated with persistent lymphopenia and cardiotoxicity, no such outcomes were detected in BBR3378-treated mice. Our findings show that BBR3378 can ameliorate encephalitogenic mechanisms in EAE and antagonize underlying autoimmune mechanisms.


The Golgi apparatus and cell polarity: Roles of the cytoskeleton, the Golgi matrix, and Golgi membranes.
Membrane trafficking plays a crucial role in cell polarity by directing lipids and proteins to specific subcellular locations in the cell and sustaining a polarized state. The Golgi apparatus, the master organizer of membrane trafficking, can be subdivided into three layers that play different mechanical roles: a cytoskeletal layer, the so-called Golgi matrix, and the Golgi membranes. First, the outer regions of the Golgi apparatus interact with cytoskeletal elements, mainly actin and microtubules, which shape, position, and orient the organelle. Closer to the Golgi membranes, a matrix of long coiled-coiled proteins not only selectively captures transport intermediates but also participates in signaling events during polarization of membrane trafficking. Finally, the Golgi membranes themselves serve as active signaling platforms during cell polarity events. We review here the recent findings that link the Golgi apparatus to cell polarity, focusing on the roles of the cytoskeleton, the Golgi matrix, and the Golgi membranes.


Diagnostic utility of autonomic measures for major depressive disorders.
The diagnostic utility (sensitivity, specificity, and overall efficiency) of autonomic nervous system measures in distinguishing hospitalized patients with unipolar depression from age-matched normal controls is reported. Tonic resting skin conductance level (SCL), tonic resting heart rate level (HRL), and the phasic skin conductance and heart rate responses (SCRs and HRRs) to task-related stimuli were used. The overall efficiency of SCL of 70% was generally consistent with previous research. The other measures yielded greater efficiency: 80% for SCR, 90% for HRL, and 83% for HRR. The possible role of autonomic measures in the diagnosis of major depressive episodes is discussed.


2020 NAEPP Guidelines Update and GINA 2021-Asthma Care Differences, Overlap, and Challenges.
The 2020 National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group (NAEPP [2020 Focused Asthma Update]) guidelines and the Global Initiative for Asthma (GINA) 2021 strategy report are compared in this Rostrum article. The methodologies of each publication are described. Subsequently, 4 different selected pharmacological recommendations are compared in the 2 documents: step 1 for children 0 to 4 years of age with viral-induced wheezing, step 2 in ages 12 years and older with the intermittent use of inhaled corticosteroid, steps 3 and 4 with single-inhaler maintenance and reliever therapy with inhaled corticosteroids-formoterol (SMART), and steps 3, 4, and 5 with add-on long-acting muscarinic antagonist therapy. Nonpharmacological recommendations are also considered and contrasted, including for exhaled nitric oxide, environmental control, immunotherapy, and bronchial thermoplasty. Similarities and differences in these 2 documents are highlighted, and recommendations are made about harmonizing the approaches where possible.


A pharmacogenetics study of TPMT and ITPA genes detects a relationship with side effects and clinical response in patients with inflammatory bowel disease receiving Azathioprine.
Pharmacogenetic studies in inflammatory bowel diseases (IBD) are mainly focused on genes involved in the metabolism of Azathioprine (AZA). Use of AZA is limited by its toxicity, which occurs in 20-30% of patients. Variants in the Thiopurine S-methyltransferase (TPMT) and Inosine triphosphate pyrophosphatase (ITPA) genes have been associated with AZA toxicity, but also can contribute to the lack of response. The aims of this study were to determine the contribution of TPMT and ITPA variants in the development of AZA-related toxicity and response. Variants associated with the decrease of enzyme activity in TPMT and ITPA genes were genotyped with the Snapshot system in 232 IBD patients treated with AZA, and correlated with the clinical response and development of adverse drug reactions in a retrospective case-control study. Genotypic analysis showed that there is a statistical significance between c.94C > A variant on ITPA gene with non response to AZA treatment (p=0.005) and arthralgia (OR 8.2353; 95%CI 1.752-38.87, p=0.0041), as well as between mutant TPMT alleles and myelosuppression (OR 7.5; 95%CI 1.4456-38.91, p=0.0304). There is a positive correlation between c.94C > A variant on ITPA with clinical response. Mutant alleles on TPMT and the variant c.94C > A on ITPA gene predict side effects induced by AZA in our population (myelosuppression and arthralgia).


Verification of cell viability at progressively higher scanning forces using a hybrid atomic force and fluorescence microscope.
The prudent use of the atomic force microscope as a supra-vital live cell imaging tool requires that cell viability must be determined before and after scanning. Complementary optical techniques in conjunction with the fluorescent dyes rhodamine-123 and ethidium homodimer have been used within this study to determine cell viability after increasing loads are applied in contact mode. Guideline force ranges for five commonly cultured cell lines, human squamous carcinoma (A431), fibroblast, HeLa, Potorous tridactylis (PtK2) and rat intestinal epithelial (RIE) cells are given.


The potential for stem cells in cerebral palsy--piecing together the puzzle.
The substantial socioeconomic burden of a diagnosis of cerebral palsy, coupled with a positive anecdotal and media spin on stem cell treatments, drives many affected families to seek information and treatment outside of the current clinical and scientific realm. Preclinical studies using several types of stem and adult cells--including mesenchymal stem cells, neural precursor cells, olfactory ensheathing glia and Schwann cells--have demonstrated some regenerative and functional efficacy in neurologic paradigms. This paper describes the most common cell types investigated for transplant in vivo and summarizes the current state of early-phase clinical trials. It investigates the most relevant and promising coadministered therapies, including rehabilitation, drug targeting, magnetic stimulation, and bioengineering approaches. We highlight the need for adjunctive combinatorial strategies to successfully transfer stem cell treatments from bench to bedside.


Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids.
Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.


Electrocardiogram characteristics of methadone and buprenorphine maintained subjects.
There has been recent concern about the association between high dose methadone and prolongation of QTc in the electrocardiogram. QTc is the time from the beginning of the QRS complex to the end of the T have as measured on an electrocardiogram and corrected for heart rate. To date, no association has been made between methadone and buprenorphine in commonly used doses and prolonged QTc. Electrocardiograms were performed on groups of methadone (n = 35, mean daily dose +/- standard deviation, 69 +/- 29 mg) and buprenorphine (n = 19, mean daily dose 11 +/- 5 mg) subjects and a group of non-opioid dependent controls (n = 17). Mean QTc did not differ (p = 0.45) between methadone, buprenorphine, or controls. Methadone subjects were significantly (odds ratio of 7.8) more likely to have U waves than buprenorphine and controls combined. Methadone subjects with U waves were maintained on higher (p = 0.004) doses (89 +/- 29 mg/day) than methadone subjects without U waves (60 +/- 24 mg/day). Methadone subjects taking 60 mg and above had higher (p = 0.02) QTc (405 +/- 29 milliseconds) than methadone subjects taking less than 60 mg per day (381 +/- 27 milliseconds). Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.


Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke.
Stroke is a leading cause of long-term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathophysiological process of stroke-induced functional loss may provide a novel strategy for stroke recovery. Focal stroke was induced by photothrombosis. LV-HDAC2-shRNA-GFP, LV-GFP, Ad-HDAC2-Flag, or Ad-inactive-HDAC2-Flag was microinjected into the peri-infarct area immediately after stroke. HDAC inhibitors were microinjected into the peri-infarct area 4 to 10 days after stroke. Grid-walking task and cylinder task were conducted to assess motor function. Golgi-Cox staining, chromatin immunoprecipitation, and electrophysiology were used to reveal the mechanisms underlying stroke recovery. Knockdown or knockout of HDAC2 promoted stroke recovery, whereas overexpression of HDAC2 worsened stroke-induced functional impairment. More importantly, trichostatin A, a pan-HDAC inhibitor, promoted functional recovery from stroke in WT mice when used in the delayed phase, but it was ineffective in Hdac2 conditional knockout (Hdac2 CKO) mice. Treatment with suberoylanilide hydroxamic acid, a selective HDAC1 and HDAC2 inhibitor, in the delayed phase of stroke produced sustained functional recovery in mice via epigenetically enhancing neuroplasticity of surviving neurons in the peri-infarct zone. Our novel findings provide evidence that HDAC2 is a crucial target for functional recovery from stroke. As there are clinically available HDAC inhibitors, our findings could be directly translated into clinical research of stroke.


Successful Return to Sport and Daily Activities After Suture Augmentation of Both the Anterior Talofibular Ligament and Calcaneofibular Ligament.
To evaluate the return to sport and daily activities in addition to clinical outcomes after modification of the Brostöm repair, specifically using suture augmentation for concomitant fixation of both the anterior talofibular ligament and calcaneofibular ligament. Patients who had grade III ankle sprains and lateral ankle instability, all of whom failed supervised conservative management, were included. Patients underwent a modified Broström procedure consisting of suture augmentation for both the anterior talofibular ligament and calcaneofibular ligament. For clinical outcome evaluation, Foot and Ankle Ability Measure (FAAM) and Karlsson-Peterson Scoring System for Ankle Function questionnaires coupled with questions regarding time of return to sport and level of sports activity were used. Thirty-one patients were included. The differences in preoperative and postoperative FAAM scores for both the Activities of Daily Living subscale and Sports subscale were significant (P < .001). The FAAM Activities of Daily Living score improved from an average of 46.06 preoperatively to 77.49 postoperatively (P < .001, 99% confidence interval, 26.4-36.4). The FAAM Sports score improved from an average of 4 preoperatively to 19.31 postoperatively (P < .001, 99% confidence interval, 11.6-19.0). For the Karlsson-Peterson Scoring System for Ankle Function, the surveyed population reported a mean of 82.74 points out of 100 post-op (standard deviation 20.14). The mean time to return to sport activity was 5.72 months. Mean follow-up time was 24.12 months. This variant Broström procedure with suture anchors and augmentation of both the anterior talofibular ligament and calcaneofibular ligament was effective in helping patients return to their preinjury functionality level in both daily life and sports activity. Level IV, therapeutic case series.


[Experimental investigations on the effect of various doses of streptokinase on blood viscosity (author's transl)].
The decrease in blood viscosity induced by streptokinase (SK) in the present investigation in proportional to the streptokinase concentration up to a concentration of 2000 IE/ml blood. A maximum decrease in viscosity is attained with a dosage of between 200 and 300 IE/ml blood. The decrease in viscosity is already clearly detectable at 10 minutes at all investigated doses and is completed after 20 to 30 minutes. An increase in SK resistance delays the decrease in viscosity. Prevention of the decrease, however, only seems to occur with a very high SK resistance and a very low SK dosage (50 IE/ml blood). The optimum dosage of SK to achieve a maximum decrease in viscosity is 200 IE/ml blood.


[Expression of nm23 in gastrointestinal smooth muscle tumors and its relation to cell proliferative activity].
To determine the relationship between nm23 expression and benign or malignant degree, metastasis, prognosis and cell proliferative activity of gastrointestinal smooth muscle tumors (GISMT). 86 cases of GISMT were studied, and nm23 was detected by the immunohistochemical staining S-P method. The cell proliferative activity was evaluated by the silver colloid method for argyrophilic nucleolar organizer regions proteins (AgNORs) and by the immunohistochemical staining S-P method for proliferating cell nuclear antigen (PCNA). The expression of nm23 declined significantly according to the following order: leiomyomas, low malignant leiomyosarcomas, high malignant leiomyosarcomas (P < 0.01). The expression of nm23 was associated with the tumors with or without contiguous organ invasion or distant metastasis, the size of tumors, the tumors with or without center necrosis (P < 0.01 or P < 0.05). The five-year survival rate was significantly higher in patients with nm23 positive expression than that with nm23 negative expression (P < 0.05). The expression of AgNORs and PCNA with nm23 negative cases was obviously higher than that with nm23 positive cases (P < 0.01). nm23 is a valuable indicator for the biological characteristics of GISMT. nm23 expression and cell proliferative activity can supply a deficiency each other in distinguishing malignant from benign tumors, judging the malignant degree, and predicting the prognosis of the patients with GISMT.


HVEM signaling promotes protective antibody-dependent cellular cytotoxicity (ADCC) vaccine responses to herpes simplex viruses.
Herpes simplex virus (HSV) glycoprotein D (gD) not only is required for virus entry and cell-to-cell spread but also binds the host immunomodulatory molecule, HVEM, blocking interactions with its ligands. Natural infection primarily elicits neutralizing antibodies targeting gD, but subunit protein vaccines designed to induce this response have failed clinically. In contrast, preclinical studies demonstrate that an HSV-2 single-cycle strain deleted in gD, ΔgD-2, induces primarily non-neutralizing antibodies that activate Fcγ receptors (FcγRs) to mediate antibody-dependent cellular cytotoxicity (ADCC). These studies were designed to test the hypothesis that gD interferes with ADCC through engagement of HVEM. Immunization of Hvem-/- mice with ΔgD-2 resulted in significant reduction in HSV-specific IgG2 antibodies, the subclass associated with FcγR activation and ADCC, compared with wild-type controls. This translated into a parallel reduction in active and passive vaccine protection. A similar decrease in ADCC titers was observed in Hvem-/- mice vaccinated with an alternative HSV vaccine candidate (dl5-29) or an unrelated vesicular stomatitis virus-vectored vaccine. Unexpectedly, not only did passive transfer of immune serum from ΔgD-2-vaccinated Hvem-/- mice fail to protect wild-type mice but transfer of immune serum from ΔgD-2-vaccinated wild-type mice failed to protect Hvem-/- mice. Immune cells isolated from Hvem-/- mice were impaired in FcγR activation, and, conversely, addition of gD protein or anti-HVEM antibodies to in vitro murine or human FcγR activation assays inhibited the response. These findings uncover a previously unrecognized role for HVEM signaling in generating and mediating ADCC and an additional HSV immune evasion strategy.


Quality of care during rural care transitions: a qualitative study on structural conditions.
Registered nurses are critical for the delivery of high-quality healthcare during care transitions from hospital to home. Older co-morbid patients are most vulnerable during these transitions. A growing population of older adults with a higher prevalence of diseases implies increased demands on healthcare and its quality, which is affected by the environment where healthcare is provided. One can draw inferences on the quality of care when classified into structure, process, and outcome. This study explored registered nurses' perspectives on structural conditions that promote or hinder good quality care during transitions from hospital to home healthcare in rural areas. We conducted a reflexive thematic analysis of interviews with 21 registered nurses experienced in care transitions from hospital to home healthcare in a rural area of Sweden. We based the theoretically driven analysis on Donabedian's definition of structures regarding the quality of care. The structural conditions were represented by three themes; (I) "Distances and inaccessibility" explains physical matters such as geographical (in)accessibility, bed (un)availability and electronic aids. (II) "Competence of the actors" explains continuity, knowledge and collaboration among the individuals involved. (III) "Levels of organizational governance" explains laws, expectations, values, and agreements regarding care transitions. All themes involved promoting and hindering factors, mutually influencing aspects of the others. Care actors, educators, managers, and decision-makers need to understand how structures in the physical, social and symbolic environment interactively affect the quality of care during care transitions since understanding this is a prerequisite for improvements. These aspects must be considered to optimize conditions for high-quality care transitions from hospital to rural home healthcare and implemented continuously to improve transitions within the respective organization and inter-organizationally. According to this study, these aspects are critical in a rural context due to structural care quality influencers such as geographical challenges, difficulties in finding competent staff members, development of technical devices, and access to the Internet.


Regional blood flow distribution in endotoxin-treated dogs: modification by ibuprofen.
The aim of this study was to determine whether the improved hemodynamic profiles reported with cyclooxygenase inhibition during sepsis include improvements in tissue perfusion is unknown. Our hypothesis was that cyclooxygenase inhibition with ibuprofen will prevent the endotoxin-induced alterations in regional blood flow distribution from developing and/or restore the endotoxin-induced loss of responsiveness to intravascular volume expansion. We measured cardiac output, regional blood flow, and total systemic shunt flow in dogs using radiolabeled 15-microns microspheres. These parameters were assessed in control (N = 10) and endotoxin-treated animals (N = 7). Additional endotoxin-treated animals (N = 7) were also pretreated with ibuprofen. Compared with controls, endotoxin-treated animals exhibited marked reductions in blood flow to most systemic organs that were not reversed with large, intravenous saline infusions (ie, isotonic saline; 40 mL/kg; N = 4). By contrast, although ibuprofen pretreatment (12.5 mg/kg; N = 7) completely prevented the reductions in mean arterial pressure caused by endotoxin from occurring, it did little to prevent the development of endotoxin-induced alterations in regional blood flow distribution. Nonetheless, in contrast to the endotoxin-treated animals, there were significant increases in cardiac output and blood flow to several organs after saline infusion in the ibuprofen-pretreated animals. Cyclooxygenase inhibition with ibuprofen has few direct effects on regional blood flow distribution after endotoxin. However, cyclooxygenase inhibition with ibuprofen does attenuate the endotoxin-induced decrease in vascular responsiveness to intravenous saline infusion.


Endocrine therapy in post-menopausal women with metastatic breast cancer: From literature and guidelines to clinical practice.
Current international guidelines recommend endocrine therapy as the initial treatment of choice in hormone receptor positive advanced breast cancer. Endocrine therapy has been a mainstay of hormone responsive breast cancer treatment for more than a century. To date it is based on different approaches,such as blocking the estrogen receptor through selective receptor estrogen modulators, depleting extragonadal peripheral estrogen synthesis by aromatase inhibitors or inducing estrogen receptor degradation using selective down-regulators. Despite estrogen and/or progesterone receptor positive status, up to a quarter of patients could be either primarily resistant to hormone therapies or will develop hormone resistance during the course of their disease. Different mechanisms, either intrinsic or acquired, could be implicated in endocrine resistance. In the present work available endocrine therapies and their appropriate sequences have been reviewed, and the most promising strategies to overcome endocrine resistance have been highlighted.


Reversion of liver cirrhosis after endovascular treatment in Chinese patients with Budd-Chiari syndrome.
To investigate the impact of endovascular (EV) treatment on liver cirrhosis in Chinese patients with Budd-Chiari syndrome (BCS). From September 2011 to March 2022, 97 patients from four hospitals in China who were diagnosed with primary BCS complicated with liver cirrhosis and received EV treatment were retrospectively enrolled in this study for clinical analysis. In addition, liver tissues for basic research were acquired from 25 patients between June 2022 and March 2023, including six with benign liver tumors, 11 with BCS before EV treatment, and eight with EV-treated BCS. Liver cirrhosis was assessed by clinical outcomes, histological studies, and the expression of related genes at the mRNA and protein levels. The patients with BCS had better liver function after EV treatment, evidenced by an increased albumin level and reduced total bilirubin, ALT, and AST. The imaging findings suggested an amelioration of liver cirrhosis and portal hypertension, including increased portal vein velocity (13.52 ± 8.89 cm/s vs. 17.51 ± 6.67 cm/s, p < 0.001) and decreased liver stiffness (30.37 ± 6.39 kPa vs. 23.70 ± 7.99 kPa, p < 0.001), portal vein diameter (14.97 ± 3.42 mm vs. 13.36 ± 2.89 mm, p < 0.001), and spleen volume (870.00 ± 355.61 cm3 vs. 771.36 ± 277.45 cm3 , p < 0.001). Furthermore, histological studies revealed that EV treatment resulted in a restoration of liver architecture with reduced extracellular matrix deposition. Meanwhile, hepatic angiogenesis and inflammation, which have a close relationship with cirrhosis, were also inhibited. In addition, the state of hepatocytes switches from apoptosis to proliferation after EV treatment. BCS-induced liver cirrhosis could be reversed by EV treatment from macroscopic to microscopic dimensions. Our study may provide further insights into understanding BCS and treating cirrhosis.


Host-parasite associations of Eimeria spp. (Apicomplexa:Eimeriidae) in kangaroos and wallabies of the genus Macropus (Marsupialia:Macropodidae).
Faecal samples from 514 kangaroos and wallabies representing 12 species of the genus Macropus were examined for oocysts of Eimeria spp. Six species of Eimeria were redescribed from their type hosts, and on the basis of finding homologous oocysts in the faeces of other Macropus spp., host ranges for these coccidia were extended. Eimeria hestermani Mykytowycz, 1964 is redescribed from M. giganteus (eastern grey kangaroo) and is described from M. fuliginosus (western grey kangaroo), M. rufogriseus (red-necked wallaby), M. dorsalis (black-striped wallaby), and M. eugenii (tammar wallaby). E. toganmainensis Mykytowycz, 1964 is redescribed from M. rufus (red kangaroo) and the host range is extended to M. giganteus, M. fuliginosus, M. rufogriseus and M. eugenii. E. wilcanniensis Mykytowycz, 1964 is redescribed from M. rufus, and the host range is extended to M. giganteus, M. fuliginosus and M. robustus (euro or wallaroo). E. macropodis Wenyon & Scott, 1925 is redescribed from M. rufogriseus, and is described from M. giganteus, M. fuliginosus, M. rufus, M. irma (western brush wallaby), M. parryi (whip-tailed wallaby), M. dorsalis, M. eugenii, and M. parma (parma wallaby). E. fausti Yakimoff & Matschoulsky, 1936, E. cunnamullensis Mykytowycz, 1964 and E. purchasei Mykytowycz, 1964 are synonymized with E. macropodis. E. marsupialium Yakimoff & Matschoulsky, 1936 is redescribed from M. giganteus, and from M. fuliginosus. E. gungahlinensis Mykytowycz, 1964 is redescribed from M. fuliginosus, and from M. giganteus. Seven new species of Eimeria are described. E. flindersi, new species, is described from M. eugenii, M. rufogriseus, and M. antilopinus (antilopine wallaroo). E. prionotemni, new species, is described from M. eugenii, M. parryi, M. rufogriseus, M. agilis (agile wallaby) and M. dorsalis. E. mykytowyczi, new species, is described from M. agilis, M. antilopinus, and M. parryi. E. parryi, new species, is described from M. parryi. E. yathongensis, new species, is described from M. fuliginosus and M. giganteus. E. parma, new species, is described from M. parma, and E. desmaresti, new species, is described from M. rufogriseus. E. kogoni Mykytowycz, 1964, and E. rufusi Prasad, 1960 are considered species inquirendae. The host-parasite associations of these coccidia, and of similar species of Eimeria in other genera of Macropodoid marsupials, are discussed in relation to the postulated phylogeny of the hosts.


Platelet cytosolic free calcium concentration in hypertension associated with early stage kidney disease.
Chronic hypertension accompanying early stage kidney disease is characterized by increased vascular resistance, but the underlying processes responsible for the enhanced vascular tone are unclear. We studied free calcium levels in blood platelets with the fluorescent dye quin-2. Platelets have many features in common with vascular smooth muscle cells. The cytosolic calcium concentration in platelets was elevated in 27 renal hypertensive patients, who were compared with 12 normotensive subjects (P less than 0.001). There was a close correlation between the free calcium level and mean blood pressure (r = 0.88, P less than 0.001). Short-term antihypertensive treatment with a calcium entry blocker or a diuretic resulted in a significant reduction in cytosolic calcium (P less than 0.05), and this correlated with the fall in blood pressure (r = 0.95, P less than 0.001). These data suggest an integrative contributory role of calcium in the pathophysiology of hypertension accompanying early stage kidney disease.


Multiwall carbon nanotubes increase the microbial community in crude oil contaminated fresh water sediments.
Since crude oil contamination is one of the biggest environmental concerns, its removal from contaminated sites is of interest for both researchers and industries. In situ bioremediation is a promising technique for decreasing or even eliminating crude oil and hydrocarbon contamination. However, since these compounds are potentially toxic for many microorganisms, high loads of contamination can inhibit the microbial community and therefore reduce the removal rate. Therefore, any strategy with the ability to increase the microbial population in such circumstances can be of promise in improving the remediation process. In this study, multiwall carbon nanotubes were employed to support microbial growth in sediments contaminated with crude oil. Following spiking of fresh water sediments with different concentrations of crude oil alone and in a mixture with carbon nanotubes for 30days, the microbial profiles in these sediments were obtained using FLX-pyrosequencing. Next, the ratios of each member of the microbial population in these sediments were compared with those values in the untreated control sediment. This study showed that combination of crude oil and carbon nanotubes can increase the diversity of the total microbial population. Furthermore, these treatments could increase the ratios of several microorganisms that are known to be effective in the degradation of hydrocarbons.


Previous infliximab therapy and postoperative complications after proctocolectomy with ileum pouch anal anastomosis.
It is unclear whether infliximab treatment induces increased complication rates after surgery for ulcerative colitis. Aim was to compare complication rates after pouch surgery in refractory ulcerative colitis patients with versus without previous infliximab therapy. We performed a retrospective study evaluating all patients who underwent an ileoanal J-pouch for refractory ulcerative colitis over a four-year period. Postoperative complications, infliximab use and time between last infliximab administration and restorative surgery were assessed. 1-stage procedures (proctocolectomy with pouch, with or without temporary diversion) and 2-stage procedures (emergency colectomy and subsequent completion proctectomy with pouch, with or without temporary diversion) were analyzed separately. Seventy-two patients were included; 33 underwent 1-stage procedure and 39 had 2-stage surgery. In the 1-stage group, 21 patients (64%) had previous infliximab therapy (median time between last infusion and surgery: 7.1 months (IQR 2.6-8.3)). Infliximab-treated patients had higher incidence of pelvic sepsis (5/21 vs. 0/12; risk difference 24%; 95% CI: 6 to 42, p=0.067) and non-infectious complications (8/21 vs. 1/12; risk difference 30%; 95% CI: 4 to 56, p=0.065). In the 2-stage group, 17 (44%) had previous infliximab therapy (median time between last infusion and surgery: 11.8 months (IQR 7.3-15.5)). Total, infectious, non-infectious complication rates and pelvic sepsis rates were similar for infliximab and non-infliximab patients in the 2-stage group. This small study suggests that infliximab use prior to 1-stage restorative proctocolectomy in patients with UC is associated with increased incidence of pelvic sepsis. A 2-stage procedure in these patients should be considered.


Carbon storage in northeast China as estimated from vegetation and soil inventories.
We have estimated the stocks of carbon in vegetation and soil in northeast China based on data for 122 plots from the fourth national forest inventory, and for 388 soil profiles from the second national soil survey. The techniques of Geographic Information System (GIS) have been used to extrapolate site-specific estimates of vegetation and soil organic carbon to the entire area of northeast China. Our estimate indicates that the amount of carbon in vegetation and soil for the region are 2.81 PgC (10(15) g C) and 26.43 PgC, respectively, and that the area weighted average density of vegetation and soil organic carbon are 22.7 MgC/ha and 212.7 MgC/ha, respectively. The eastern and northern parts of the region show much higher carbon storage than the rest of the region. Substantial spatial variations in vegetation and soil organic carbon across northeast China suggest that regional estimates on carbon stocks and fluxes should take into account these spatial variations. We suggest that the methodology developed can be used for the entire nation of China as well as other regions of the world.


Radioactive microsphere validation of a volume localized continuous saturation perfusion measurement.
Detre et al. (Magn. Reson. Med. 23, 37-45 (1992)) and Zhang et al., (Magn. Reson. Med. 25, 362 (1992)) have recently demonstrated a technique for the measurement of regional cerebral blood flow (rCBF) based on the continuous saturation (or inversion) of the arterial blood supply to the brain in rats at 4.7 T. In the work reported here, we combined this technique with volume localized (PRESS) readouts to benefit from recording "perfusion" signals averaged over a larger volume, resulting in rapid acquisition of data with sufficient signal-to-noise ratio for application at 2.0 T. In 10 baseline flow measurements, the mean error between the NMR technique and the microsphere flow measurement was -1.5% with a standard deviation of 15.2%. For five measurements obtained with occlusion of the middle cerebral artery, the mean error was -32.4 +/- 20.2%. Perfusion measurements from a single animal under hypercapnic conditions indicated that the NMR technique could underestimate rCBF at high flow rates. An error analysis of the NMR perfusion model is also presented, along with results for typical parameters encountered at 2.0 T.


Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat.
Morphine was administered to rats by oral, intraportal, and intravenous routes in a dose of 7.6 mg . kg-1. From the serum concentration data after intraportal administration it was calculated that the first-pass elimination of morphine in the liver amounts to 72 +/- 2% (SD). The first-pass fraction eliminated after oral administration was 85 +/- 7% (SD), thus yielding a contribution by the gut mucosa of 46% to the overall first-pass elimination after an oral dose. The results were obtained with a general compartmental model which included the kinetics of enterohepatic recirculation. The oral availability was also estimated with the aid of pharmacological effect data. This availability was in good agreement with the corresponding value determined from the serum concentration data. The results suggest that morphine is subjected to enterohepatic recirculation and that the slowest phase of decline of morphine concentrations in serum might be due to this physiological process.


Vestibular Schwannoma Hypofractionated Stereotactic Radiation Therapy in Five Fractions.
To retrospectively analyse the long-term results of hypofractionated stereotactic radiation therapy (HSRT) applied in five fractions for vestibular schwannomas. One hundred and thirty-four patients with vestibular schwannomas underwent medical treatment of HSRT. The median follow-up time interval was 54 months (range 6-121 months). All patients had a prescribed dose of 22 Gy in five fractions to D90. Restaging was carried out by thin-slice contrast-enhanced T1 magnetic resonance imaging. Progression was defined as 2 mm post-treatment tumour enlargement. Progression or death for any reason was counted as an event in progression-free survival rates. Acute toxicity was defined as adverse events occurring within 3 months of HSRT; long-term toxicity was defined as such events occurring after 3 months. In 74/128 patients who had >6 months of follow-up (54%), the HSRT resulted in a partial or a complete response. The mean time interval for response in 50% of these was 4 years, whereas in 49 patients (38%) vestibular schwannomas failed to show any response, resulting in stable disease. Five of 128 patients (4%) showed marked progressive vestibular schwannomas after treatment in the first 3 years; two of them received conventionally fractionated radiation therapy. Local control at 3, 5 and 7 years was 96%, 95% and 94%, respectively. Seven were lost to follow-up. The median planning target volume was 2.1 ml (range 0.78-8.66). The 3- and 5-year progression-free survival rates were 95% and 94%, respectively. Seven patients reported a marked deterioration in hearing ability. Post-radiation therapy magnetic resonance imaging showed variability in oedema collection, but no patient suffered from radio-necrosis. Grade 2 temporary facial nerve disorders were observed in 10 patients (8%) 3-6 months after HSRT. Delivering HSRT in five fractions for vestibular schwannoma appears safe and efficient, combining both efficiency and short treatment time while optimising neurological function preservation.


Improved detection and annotation of transposable elements in sequenced genomes using multiple reference sequence sets.
Transposable elements (TEs) are ubiquitous components of eukaryotic genomes that impact many aspects of genome function. TE detection in genomic sequences is typically performed using similarity searches against a set of reference sequences built from previously identified TEs. Here, we demonstrate that this process can be improved by designing reference sets that incorporate key aspects of the structure and evolution of TEs and by combining these sets with Repbase Update (RU), which is composed mainly of consensus sequences. Using the Arabidopsis genome as a test case, our approach leads to the detection of an extra 12.4% of TE sequences. These correspond to novel TE fragments as well as to the extension of TE fragments already detected by RU. Significantly, we find that TE detection could be readily optimized using only two reference sets, one containing true consensus sequences and the other mosaic sequences that capture the structural diversity of TE copies within a family.


Rapid progress in our understanding of COVID-19 vaccine allergy: A cause for optimism, not hesitancy.
Anaphylaxis is a life-threatening condition and when associated with vaccination, leads to vaccine hesitancy. The concerns around vaccine-related anaphylaxis have become even more important during the coronavirus disease 2019 (COVID-19) pandemic where the COVID-19 vaccines remain one of our most important tools. Although rates of anaphylaxis to COVID-19 vaccines are not significantly different from those to other vaccines, Centers for Disease Control and Prevention guidance recommends avoidance of the same COVID-19 vaccine in individuals who had an allergic reaction or are allergic to a COVID-19 vaccine component. Fortunately, our understanding of COVID-19 vaccine allergic reactions has improved dramatically in the past year in large part due to important research efforts from individuals in the allergy community. Initially, researchers published algorithmic approaches using risk stratification and excipient skin testing. However, as our experience and knowledge improved with ongoing research, we have better data showing safety of repeat vaccination despite an initial reaction. We review our progress starting in December 2020 when the Food and Drug Administration approved the first COVID-19 vaccine in the United States through early 2022, highlighting our success in understanding COVID-19 vaccine reactions.


Mechanical difference of left ventricle between rabbits of myocardial infarction and hypertrophy.
The analysis of cardiac wall stress is of importance to understand the development of heart failure (HF). The aim of the study is to carry out the cardiac mechanics analysis to show the changes of left ventricular (LV) wall stresses after LV hypertrophy (LVH) and myocardial infarction (MI). Here, LVH and MI were generated in rabbit hearts through the transverse aortic constriction (TAC) and the distal left circumflex (LCx) artery ligation operations, respectively. Physiological and CT measurements were carried out at postoperative 2 and 4 weeks, based on which a finite element (FE) model was developed to perform the mechanics computation. We found a gradual increase of end-diastolic myofiber stress in free wall and interventricular septum of LVH and MI (higher stress in the free wall than the septum). In the interventricular septum, the 4-weeks LVH group has the highest ED myofiber stresses (11.378 ± 3.022 kPa), while the 4-weeks MI group has the highest ED myofiber stresses (13.494 ± 2.835 kPa) in the free wall. LVH increased myocardial volume (3.49 ± 0.07 and 4.52 ± 0.26 ml at postoperative 2 and 4 weeks) while MI increased LV volume (from 2.75 ± 0.29 to 4.19 ± 0.27 ml). LVH and MI had different distributions of local myofiber stress.


Epigenetic silencing of microRNA-335 contributes to nasopharyngeal carcinoma metastasis.
MircoRNA-335 (miR-335), a member of mircoRNAs (miRNAs) family, has been found to be correlated with tumor invasion and metastasis. In this study, we aimed to detect the effect of miR-335 methylation on metastasis of nasopharyngeal carcinoma. RT-PCR and methylation-specific PCR were applied to detect the expression levels of miR-335 and miR-335 methylation in nasopharyngeal carcinoma tissues. The levels of miR-335 expression were significantly lower in nasopharyngeal cancer tissues with promoter methylation, compared to those with promoter unmethylation. The levels of miR-335 gene promoter methylation were higher in 14 (46.7%) out of 30 nasopharyngeal cancer tissues. Furthermore, the patients with cervical lymph node metastasis had higher methylation rate in miR-335 promoter (66.7% versus 16.7%) than those without cervical lymph node metastasis. Gene methylation contributes the expression of miR-335 in nasopharyngeal carcinoma. The expression of miR-335 methylation is correlated with the metastasis of nasopharyngeal carcinoma.


Torque capacity of multidisc wet clutch with reference to friction occurrence on its spline connections.
In this article developed mathematical model that includes friction occurrence on spline connections is presented. The work also contains results of experimental research on torque capacity of multidisc wet clutch. These results are expressed as a function of contact pressure for different number of friction surfaces. Due to increased interest in research concerning multidisc wet clutches it is essential to determine impact of friction on fit connections on transmitted torque. Analytical calculations that include both known loss coefficient and assumed lack of friction on fit connections are compared to results of experiments. The paper contains detailed description of test stand and methodology of experiment. As a result of conducted tests it was found that correction coefficients known from literature are highly inaccurate. Measured values of torque indicate that transmitted torque reach significantly higher values. It was also revealed that after slippage appeared, the pressure plate usually moved in the direction of exerted clamping force, but movement in reversed direction also took place for some experiments. While movement corresponding to clamping force reached ca. 0.08 mm, in opposite direction amounted to 0.02 mm. Furthermore, studies presented that lapping of adjacent friction surfaces greatly affects differences between respective results obtained for a specific experiment.


Multipotent mesenchymal stromal cells decrease transforming growth factor β1 expression in microglia/macrophages and down-regulate plasminogen activator inhibitor 1 expression in astrocytes after stroke.
Multipotent mesenchymal stromal cells (MSCs) decrease the expression of transforming growth factor β1 (TGFβ1) in astrocytes and subsequently decrease astrocytic plasminogen activator inhibitor 1 (PAI-1) level in an autocrine manner. Since activated microglia/macrophages are also a source of TGFβ1 after stroke, we therefore tested whether MSCs regulate TGFβ1 expression in microglia/macrophages and subsequently alters PAI-1 expression after ischemia. TGFβ1 and its downstream effector phosphorylated SMAD 2/3 (p-SMAD 2/3) were measured in mice subjected to middle cerebral artery occlusion (MCAo). MSC treatment significantly decreased TGFβ1 protein expression in both astrocytes and microglia/macrophages in the ischemic boundary zone (IBZ) at day 14 after stroke. However, the p-SMAD 2/3 was only detected in astrocytes and decreased after MSC treatment. In vitro, RT-PCR results showed that the TGFβ1 mRNA level was increased in both astrocytes and microglia/macrophages in an astrocyte-microglia/macrophage co-culture system after oxygen-glucose deprived (OGD) treatment. MSCs treatment significantly decreased the above TGFβ1 mRNA level under OGD conditions, respectively. OGD increased the PAI-1 mRNA in astrocytes in the astrocyte-microglia/macrophage co-culture system, and MSC administration significantly decreased this level. PAI-1 mRNA was very low in microglia/macrophages compared with that in astrocytes under different conditions. Western blot results also verified that MSC administration significantly decreased p-SMAD 2/3 and PAI-1 level in astrocytes in astrocyte-microglia/macrophage co-culture system under OGD conditions. Our in vivo and in vitro data, in concert, suggest that MSCs decrease TGFβ1 expression in microglia/macrophages in the IBZ which contribute to the down-regulation of PAI-1 level in astrocytes.


[Hepatitis B vaccine and liver cancer].
Hepatitis B Virus (HBV) chronic infection contributes to a high risk of hepatocellular cancer (HCC) development. HBV is a strong cancer inducer, due to natural history of infection, virological characteristics and viral DNA integrations events in host genome. Prolonged infection and high viral loads, particularly frequent in patients infected in childhood, are risk factors of HCC development for patients with HBV chronic infection. A HBV vaccine, based on immunization against the surface protein HBs, showed a strong efficacy to prevent chronic HBV infection. The development of universal neonatal vaccination programmes contributed to the decrease of HBV chronic infection incidence in children of high endemic areas. Although HBs antibodies levels diminished years after vaccination, HBV neonatal vaccination programmes led to a lower incidence of chronic HBV infection among young adults. The decrease of HBV chronic infection incidence was associated to a reduction of HCC incidence in children and young adults from areas with a high prevalence of HBV infection.


KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders.
KRAS mutations account for the most frequent mutations in human cancers, and are generally correlated with disease aggressiveness, poor prognosis, and poor response to therapies. KRAS is required for adult hematopoiesis and plays a key role in B cell development and mature B cell proliferation and survival, proved to be critical for B cell receptor-induced ERK pathway activation. In mature B cell neoplasms, commonly seen in adults, KRAS and RAS-MAPK pathway aberrations occur in a relevant fraction of patients, reaching high recurrence in some specific subtypes like multiple myeloma and hairy cell leukemia. As inhibitors targeting the RAS-MAPK pathway are being developed and improved, it is of outmost importance to precisely identify all subgroups of patients that could potentially benefit from their use. Herein, we review the role of KRAS and RAS-MAPK signaling in malignant hematopoiesis, focusing on mature B cell lymphoproliferative disorders. We discuss KRAS and RAS-MAPK pathway aberrations describing type, incidence, mutual exclusion with other genetic abnormalities, and association with prognosis. We review the current therapeutic strategies applied in mature B cell neoplasms to counteract RAS-MAPK signaling in pre-clinical and clinical studies, including most promising combination therapies. We finally present an overview of genetically engineered mouse models bearing KRAS and RAS-MAPK pathway aberrations in the hematopoietic compartment, which are valuable tools in the understanding of cancer biology and etiology.


Cardiovascular effects of the nifedipine analog, CGP 28 392, in the conscious dog.
The cardiovascular profile of the nifedipine analog, CGP 28 392, was studied in instrumented conscious dogs. CGP 28 392 (25, 50, 100, and 150 micrograms/kg) was administered intravenously, and systemic and coronary hemodynamics monitored with and without prior treatment with nifedipine, phentolamine, propranolol, or atropine. CGP 28 392 increased arterial blood pressure and coronary vascular resistance in a dose-related manner and reduced heart rate. No positive inotropic actions were observed. All hemodynamic effects of CGP 28 392 were blocked by nifedipine but were unaltered by phentolamine. The decrease in heart rate was attenuated by atropine and propranolol. These data demonstrate that the actions of CGP 28 392 are diametrically opposed to those of the dihydropyridine slow channel calcium entry blockers and are specifically blocked by nifedipine. The cardiovascular actions of this compound (with the exception of bradycardia) are not mediated through the autonomic nervous system, and interactions with other pharmacological agents suggest that CGP 28 392 has calcium channel activating properties.


Aging with Pride: Innovations in Dementia Empowerment and Action (IDEA).
Sexual and gender minority (SGM) older adults and their care partners, compared to the general population, face unique vulnerabilities that exacerbate living with dementia, including elevated disparities in comorbidities, social isolation, and structural inequities, such as discrimination and lack of access to supports. This paper describes the virtual adaptation process of the first-ever randomized controlled clinical trial intervention, Aging with Pride: Innovations in Dementia Empowerment and Action (IDEA), that was designed for SGM older adults living with dementia and their care partners and built upon the foundation of RDAD and NHAS. The virtual adaptation of IDEA was guided by the goals of accessibility, quality, ease of delivery, sustainability, and cultural relevance. The implementation required the development of a HIPPA-compliant online virtual platform, coach and participant virtual training, and modification of necessary intervention elements and materials, as needed. Based on the preliminary findings, the participants and intervention coaches responded well to the virtual adaptation of IDEA. When comparing to in-person delivery, the virtual delivery decreased attrition among both intervention participants and coaches. The virtual adaptation of the IDEA intervention resulted in preliminary, unexpected, yet potentially important benefits, including the ability to expand the reach of the intervention and decreased attrition. Virtual interventions are an emerging field for people living with dementia and their care partners and additional systematic research is needed to fully assess the benefits and limitations as well as to evaluate if specific subgroups are better served by differing delivery modalities.


Statistical correlates of perceived gloss in natural images.
It is currently debated whether the perception of gloss is linked to the statistical parameters of the retinal image. In particular, it has been suggested that gloss is highly correlated with the skewness of the luminance histogram. However, other psychophysical work with artificial stimuli has shown that skewness alone is not enough to induce the perception of gloss. Here, we analyzed many images of natural surfaces to search for potential statistical correlates of perceived gloss. We found that skewness indeed correlates with gloss when using rendered stimuli, but that the standard deviation, a measure of contrast, correlates better with perceived gloss when using photographs of natural surfaces. We verified the important role of contrast by manipulating skewness and contrast within images. Changing the contrast in images significantly modulates perceived gloss, but manipulating the skewness of the luminance histogram had only a small effect.


Association between cardiorespiratory fitness level and insulin resistance in adolescents with various obesity categories.
An association between cardiorespiratory fitness (CRF) and insulin resistance in obese adolescents, especially in those with various obesity categories, has not been systematically studied. There is a lack of knowledge about the effects of CRF on insulin resistance in severely obese adolescents, despite their continuous rise. To investigate the association between CRF and insulin resistance in obese adolescents, with special emphasis on severely obese adolescents. We performed a prospective, cross-sectional study that included 200 pubertal adolescents, 10 years to 18 years of age, who were referred to a tertiary care center due to obesity. According to body mass index (BMI), adolescents were classified as mildly obese (BMI 100% to 120% of the 95th percentile for age and sex) or severely obese (BMI ≥ 120% of the 95th percentile for age and sex or ≥ 35 kg/m2, whichever was lower). Participant body composition was assessed by bioelectrical impedance analysis. A homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. Maximal oxygen uptake (VO2max) was determined from submaximal treadmill exercise test. CRF was expressed as VO2max scaled by total body weight (TBW) (mL/min/kg TBW) or by fat free mass (FFM) (mL/min/kg FFM), and then categorized as poor, intermediate, or good, according to VO2max terciles. Data were analyzed by statistical software package SPSS (IBM SPSS Statistics for Windows, Version 24.0). P < 0.05 was considered statistically significant. A weak negative correlation between CRF and HOMA-IR was found [Spearman's rank correlation coefficient (rs) = -0.28, P < 0.01 for CRFTBW; (rs) = -0.21, P < 0.01 for CRFFFM]. One-way analysis of variance (ANOVA) revealed a significant main effect of CRF on HOMA-IR [F(2200) = 6.840, P = 0.001 for CRFTBW; F(2200) = 3.883, P = 0.022 for CRFFFM]. Subsequent analyses showed that obese adolescents with poor CRF had higher HOMA-IR than obese adolescents with good CRF (P = 0.001 for CRFTBW; P = 0.018 for CRFFFM). Two-way ANOVA with Bonferroni correction confirmed significant effect of interaction of CRF level and obesity category on HOMA-IR [F(2200) = 3.292, P = 0.039 for CRFTBW]. Severely obese adolescents had higher HOMA-IR than those who were mildly obese, with either good or poor CRF. However, HOMA-IR did not differ between severely obese adolescents with good and mildly obese adolescents with poor CRF. CRF is an important determinant of insulin resistance in obese adolescents, regardless of obesity category. Therefore, CRF assessment should be a part of diagnostic procedure, and its improvement should be a therapeutic goal.


Involvement of stress in the sleep rebound mechanism induced by sleep deprivation in the rat: use of alpha-helical CRH (9-41).
A previous study demonstrated the efficacy of the corticotropin-releasing hormone (CRH) receptor antagonist, alpha-helical CRH (9-41), in blocking the paradoxical sleep increase induced by stress. In the present study, this peptide was used to evaluate the involvement of the stress component of the sleep deprivation, in the paradoxical sleep rebound. Rats were subjected for 10 h to the classical water-tank sleep-deprivation technique and were given, every 2 h throughout the sleep deprivation period, intracerebroventricular injections of either 100 microg/5 microl of alpha-helical CRH (9-41) or vehicle alone. Continuous recordings showed that antagonist treatment decreased the PS rebound, but not the SWS rebound, following sleep deprivation. These findings suggest that, in the water-tank sleep deprivation method, stress, acting via CRH activation, is the main factor inducing the paradoxical sleep rebound.


Newbouldiosides A-C, phenylethanoid glycosides from the stem bark of Newbouldia laevis.
From the stem bark of Newbouldia laevis three phenylethanoid glycosides, designated as newbouldioside A-C, were isolated together with a sodium salt of analogue B and the known compounds, verbascoside, 5-hydroxydehydro-iso-alpha-lapachone, 3,8-dihydroxydehydro-iso-alpha-lapachone, apigenin and luteolin. The structures of the phenylethanoid glycosides were elucidated by spectroscopic methods as beta-(3,4-dihydroxyphenyl)ethyl 5-O-syringoyl-beta-D-apiofuranosyloxy-(1-->2)-O-[alpha-L-rhamnopyranosyl-(1-->3)]-beta-D-glucopyranoside, ss-(3,4-dihydroxyphenyl)ethyl 5-O-syringoyl-beta-D-apiofuranosyloxy-(1-->2)-O-[alpha-L-rhamnopyranosyl-(1-->3)]-6-O-E-feruloyl-beta-D-glucopyranoside, and beta-(3,4-dihydroxyphenyl)ethyl 3-O-E-feruloyl-beta-D-apiofuranosyloxy-(1-->2)-O-alpha-L-rhamnopyranosyl-(1-->2)-6-O-E-sinapoyl-beta-D-glucopyranoside, respectively.


Alzheimer's disease: NMR studies of asialo (GM1) and trisialo (GT1b) ganglioside interactions with Abeta(1-40) peptide in a membrane mimic environment.
Amyloid peptide (Abeta) is the major protein constituent of neuritic plaques in Alzheimer's disease (AD). This peptide is an amphipathic molecule that perturbs membranes and binds to raft-like membranes composed of gangliosides. Ganglioside GM1 binds tightly with Abeta and it is speculated that GM1 inhibits Abeta from undergoing alpha-helix to beta-sheet conformational changes. Although the role of gangliosides in conformational changes of Abeta have been studied, the specific nature of these interactions have not been reported. In the present report multidimensional NMR studies of ganglioside-Abeta interactions were conducted in sodium dodecyl sulphate (SDS) micelles, a membrane-mimicking environment. These studies reveal that asialoGM1 binds specifically with Abeta in a manner which could prevent beta-sheet formation. but that ganglioside GT1b does not bind Abeta. Plausible pathways for the involvement of gangliosides in amyloidogenesis are discussed.


Clinical and epidemiological features of the 2014 large-scale dengue outbreak in Guangzhou city, China.
Dengue virus is transmitted by mosquito around the tropical and sub-tropical regions. There was a large-scale dengue epidemic in Guangdong province, China during 2014 and around fifty thousands dengue fever cases, including six deaths, have been reported. In this study, we aimed to understand the clinical characteristics of hospitalized patients with laboratory-confirmed dengue virus (DENV) infection and determined the origin of the virus from the outbreak. We have summarized the data from 138 hospitalized patients who were laboratory confirmed for dengue infection in Guangzhou city. Patients were classified as either non-severe dengue fever or severe dengue fever according to the guidelines from the WHO. Viral serotypes were determined by real time RT-PCR. Genetic sequences of the envelope and non-structural genes were amplified and analyzed from the serum samples of eleven patients. Co-circulation of dengue serotype 1 and 2 were identified from the outbreak. Patients infected by serotype 1 or 2 showed similar clinical features. Patients with severe dengue fever showed prolonged hospitalization and significant impairment of organ functions. Four samples from serotype 1 and five samples from serotype 2 were closely related respectively and clustered with Guangzhou isolates from previous years. The remaining isolates of serotype 1 were related to viruses found in Malaysia, India, Bangladesh and Singapore. The phylogenetic grouping of Guangdong isolates suggests that dengue is no longer an imported disease in China. Analysis of the isolates obtained in this study together with the size of the outbreak are suggestive of endemic circulation in Guangdong province.


Depression in mild dementia: associations with diagnosis, APOE genotype and clinical features.
Depression is common in dementia, with important clinical implications. Few studies of depression in dementia with Lewy bodies are available, and the results are inconsistent. To examine the frequency of depression and its characteristics and correlates, in people with mild dementia. All referrals for patients with a first time diagnosis of dementia to geriatric and older psychiatry outpatient clinics in the counties of Rogaland and Hordaland in Western Norway from March 2005 to March 2007 were screened for the study. Participants and their caregivers underwent a comprehensive and standardised diagnostic and assessment procedure. The depression subitem of the neuropsychiatric inventory (NPId) and Montgomery and Åsberg depression rating scale (MADRS) were used to estimate depression. Cut-off scores for any depression were 0/1 (NPId) and 6/7 (MADRS), and for clinically significant depression 3/4 and 14/15, respectively. Two hundered and twenty-three subjects with dementia participated, of whom 59 and 50% showed symptoms of depression assessed by NPI or MADRS, respectively, and 25 and 16% had clinically significant depression as measured by NPI and MADRS, respectively. Depression was more frequent in dementia with Lewy bodies (DLB) than in Alzheimer's disease (AD; p < 0.05). APOE genotype was available in 153 patients, and in AD, but not in DLB, a general linear model showed that the presence of APOEε4 allele was significantly associated with depression (F = 4.14; p = 0.045). Depression is common even in mild dementia, and more common and severe in DLB compared to AD. Future studies should explore the longitudinal course of depression in DLB, and the neural underpinnings of depression in DLB.


Binding of glyceraldehyde 3-phosphate dehydrogenase to microtubules.
The interaction of glyceraldehyde 3-phosphate dehydrogenase with microtubules has been studied by measurement of the amount of enzyme which co-assembles with in vitro reconstituted microtubules. The binding of glyceraldehyde 3-phosphate dehydrogenase to microtubules is a saturable process; the maximum binding capacity is about 0.1 mole of enzyme bound per mole of assembled tubulin. Half saturation of microtubule binding sites is obtained at a concentration of glyceraldehyde 3-phosphate dehydrogenase of about 0.5 microM. Glyceraldehyde 3-phosphate dehydrogenase (between 0.1 and 2 microM) induces a concentration-dependent increase a) in the turbidity of the microtubule suspension without alteration of the net amount of polymer formed and b) in the amount of microtubule protein polymers after cold microtubule disassembly. There is a linear relationship between the intensity of the glyceraldehyde 3-phosphate dehydrogenase-induced effects and the amount of microtubule-bound enzyme. The specificity of the association of glyceraldehyde 3-phosphate dehydrogenase to microtubules has been documented by copolymerization experiments. Assembly-disassembly cycles of purified microtubules in the presence of a crude liver soluble fraction results in the selective extraction of a protein with an apparent molecular weight of 35,000 identified as the monomer of glyceraldehyde 3-phosphate dehydrogenase by peptide mapping and immunoblotting. In conclusion, microtubules possess a limited number of binding sites for glyceraldehyde 3-phosphate dehydrogenase. The binding of the glycolytic enzyme to microtubules shows a considerable specificity and is associated with alterations of assembly and disassembly characteristics of microtubules.


Lipopolysaccharide-induced dopaminergic cell death in rat midbrain slice cultures: role of inducible nitric oxide synthase and protection by indomethacin.
Glial cell activation associated with inflammatory reaction may contribute to pathogenic processes of neurodegenerative disorders, through production of several cytotoxic molecules. We investigated the consequences of glial activation by interferon-gamma (IFN-gamma)/lipopolysaccharide (LPS) in rat midbrain slice cultures. Application of IFN-gamma followed by LPS caused dopaminergic cell death and accompanying increases in nitrite production and lactate dehydrogenase release. Aminoguanidine, an inhibitor of inducible nitric oxide synthase (iNOS), or SB203580, an inhibitor of p38 mitogen-activated protein kinase, prevented dopaminergic cell loss as well as nitrite production. SB203580 also suppressed expression of iNOS and cyclooxygenase-2 (COX-2) induced by IFN-gamma/LPS. A COX inhibitor indomethacin protected dopaminergic neurons from IFN-gamma/LPS-induced injury, whereas selective COX-2 inhibitors such as NS-398 and nimesulide did not. Notably, indomethacin was able to attenuate neurotoxicity of a nitric oxide (NO) donor. Neutralizing antibodies against tumour necrosis factor-alpha and interleukin-1beta did not inhibit dopaminergic cell death caused by IFN-gamma/LPS, although combined application of these antibodies blocked lactate dehydrogenase release and decrease in the number of non-dopaminergic neurons. These results indicate that iNOS-derived NO plays a crucial role in IFN-gamma/LPS-induced dopaminergic cell death, and that indomethacin exerts protective effect by mechanisms probably related to NO neurotoxicity rather than through COX inhibition.


Effects of two alpha-adrenoceptor antagonists, nicergoline and phentolamine, on myocardial oxygen consumption in the dog.
We compared the effects of two alpha-adrenoceptor antagonists, nicergoline and phentolamine, on myocardial oxygen consumption (MVO2) in open-chest dogs. Intravenous nicergoline, 2 micrograms/kg/min for 30 min, reduced blood pressure from 130 +/- 6 to 100 +/- 2 mm Hg, did not change heart rate, and reduced MVO2/beat from 63.1 +/- 6.6 to 43.6 +/- 4.0 microliters (p less than 0.05, compared with control saline-infused and phentolamine-treated dogs). Intravenous phentolamine, 8 micrograms/kg/min, reduced blood pressure from 123 +/- 6 to 95 +/- 8 mm Hg and increased heart rate from 199 +/- 4 to 235 +/- 9 beats/min ( p less than 0.05, compared with control and nicergoline-treated dogs). MVO2/beat did not change, but MVO2 increased from 11.1 +/- 1.5 to 13.1 +/- 2.0 ml/min (p less than 0.05, compared with nicergoline-treated dogs). These results suggest that nicergoline may be preferable to phentolamine in patients in whom it is important to avoid any increase in MVO2.


Elongation factor 1A family regulates the recycling of the M4 muscarinic acetylcholine receptor.
In this study, we tested the hypothesis that the elongation 1A (eEF1A) family regulates the cell surface density of the M4 subtype of the muscarinic acetylcholine receptors (mAChR) following agonist-induced internalization. Here, we show that mouse brains lacking eEF1A2 have no detectable changes in M4 expression or localization. We, however, did discover that eEF1A1, the other eEF1A isoform, is expressed in adult neurons contrary to previous reports. This novel finding suggested that the lack of change in M4 expression and distribution in brains lacking eEF1A2 might be due to compensatory effects of eEF1A1. Supporting this theory, we demonstrate that the overexpression of either eEF1A1 or eEF1A2 inhibits M4 recovery to the cell surface after agonist-induced internalization in PC12 cells. Furthermore, eEF1A1 or eEF1A2 had no effect on the recovery of the M1 subtype in PC12 cells. These results demonstrate the novel ability of the eEF1A family to specifically regulate the M4 mAChR.


Evaluation of inner retinal function at different stages of primary open angle glaucoma using the photopic negative response (PhNR) measured by RETeval electroretinography.
To investigate the objective function of the inner retinal layer in each stage of primary open angle glaucoma (POAG) using the photopic negative response (PhNR) measured by RETeval full-field electroretinography (ERG), and to identify which PhNR parameter is the most useful. Ninety eyes of 90 patients with POAG (30 with mild POAG (mean deviation (MD) ≥ -6 dB) and 60 with moderate-to-advanced POAG (MD < -6 dB)) and 76 eyes of 76 control cases were examined. We investigated six PhNR parameters and their relationships with the results of the Humphrey 30-2 visual field test and the thickness of the circumpapillary retinal nerve fiber layer (cpRNFL) obtained from optical coherence tomography. The following PhNR parameters were assessed: base-to-trough (BT), peak-to-trough (PT), 72msPhNR, the W-ratio, P-ratio, implicit time (IT), and a-wave and b-wave amplitudes on ERG. All PhNR parameters other than IT significantly differed between the all POAG (all stages) and control groups and between the moderate-to-advanced POAG and control groups. BT and 72msPhNR in the mild POAG group, significantly differed from those in the control group. Regarding the relationships between PhNR parameters and the visual field and between these parameters and cpRNFL thickness, correlations were observed between all PhNR parameters, except PT and IT, and both the visual field and cpRNFL thickness in the all and moderate-to-advanced POAG groups. 72msPhNR correlated with cpRNFL thickness in the mild POAG group. The area under the receiver operating characteristic curve was greater for BT than for the other PhNR parameters in both the mild and moderate-to-advanced POAG groups. The discriminant linear function for examining the presence or absence of POAG and the threshold for diagnosis were quantitatively obtained as follows. Regarding BT: discriminant = 0.505 × BT + 2.017; threshold = positive for POAG, negative for no POAG; correct answer rate = 80.7%. Concerning 72msPhNR: discriminant = 0.533 × 72msPhNR + 1.553; threshold = positive for POAG and negative for no POAG; correct answer rate = 77.1%. RETeval-measured PhNR parameters were useful for an objective evaluation of visual function in moderate-to-advanced POAG. BT appeared to be the most diagnostically useful parameter.


Home oxygen for children with acute bronchiolitis.
A prospective randomised controlled pilot study was performed comparing home oxygen therapy with traditional inpatient hospitalisation for children with acute bronchiolitis. Children aged 3-24 months with acute bronchiolitis, still requiring oxygen supplementation 24 h after admission to hospital, were randomly assigned to receive oxygen supplementation at home with support from "hospital in the home" (HiTH) or to continue oxygen supplementation in hospital. 44 children (26 male, mean age 9.2 months) were recruited (HiTH n = 22) between 1 August and 30 November 2007. Only one child from each group was readmitted to hospital and there were no serious complications. Children in the HiTH group spent almost 2 days less in a hospital bed than those managed as traditional inpatients: HiTH 55.2 h (interquartile range (IQR) 40.3-88.9) versus in hospital 96.9 h (IQR 71.2-147.2) p = 0.001. Home oxygen therapy appears to be a feasible alternative to traditional hospital oxygen therapy in selected children with acute bronchiolitis.


Cervical-Vaginal Mucin in Fertility Assessment: CA125 as a Predictor of the Fertile Phase of the Normal Menstrual Cycle.
: To evaluate the cervical-vaginal mucin, CA125, as a measure of fertility and possible method for natural family planning (NFP). Cervical-vaginal fluid (CVF) swab samples have been previously used to measure CA125, 'Qvaginal CA125 levels', as a function of time of cycle relative to Day 0, the first day of positive urine LH (luteinizing hormone). Data from 15 women, 20 cycles were used with an algorithm to establish the Fertile Start Day (FSD) for the cycles. The FSD was determined as either the second consecutive day of ≥20% Qvaginal CA125 rise or the first day of ≥400% rise. The interval, (FSD to Day +3), was used as the theoretical window of fertility, and conception rates assuming abstinence during this predicted period of fertility were computed using published day-specific probabilities of conception (PoC). The mean FSD was Day -4.8 ± 0.5 (SE), 95% CI (-5.9, -3.7). The estimated pregnancy failure rate (PFR) with abstinence during [FSD, +3] was 10.7% ± 2.0% (SE), 95% CI (6.9%, 14.8%); with exclusion of one cycle with very low levels of Qvaginal CA125, the estimated PFR was 9.8% ± 1.9%, 95% CI (6.3%, 13.8%). Furthermore, the day-specific Qvaginal CA125 values were normalized to the respective peak Qvaginal CA125 for each cycle, and a mean normalized day-specific Qvaginal CA125 plot was generated. The first derivative of the mean normalized day-specific Qvaginal CA125 plot showed a significant increase between Day -4.5 and Day -3.5, which correlated with the mean FSD. A Qvaginal CA125-based method holds promise as a means to identify the start of the fertile window and may prove useful in NFP, especially when combined with available home hormonal fertility awareness kits.


Platycodin D (PD) regulates LncRNA-XIST/miR-335 axis to slow down bladder cancer progression in vitro and in vivo.
Recently, increasing evidences indicated that Platycodin D (PD) served as an effective anti-tumor drug for cancer treatment in clinic. However, the molecular mechanisms are still unclear. In the present study, we proved that PD regulated LncRNA-XIST/miR-335 axis to hamper the development of bladder cancer in vitro and in vivo. Mechanistically, PD inhibited malignant phenotypes, including cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT), and promoted cell apoptosis in bladder cancer cells in a time- and dose-dependent manner. In addition, the following experiments validated that PD inhibited LncRNA-XIST expressions, while increased miR-335 expression levels in bladder cancer cells. Next, by conducting the dual-luciferase reporter gene system assay and RNA pull-down assay, we validated that LncRNA-XIST inhibited miR-335 expressions through acting as RNA sponges, and the promoting effects of PD stimulation on miR-335 levels were abrogated by upregulating LncRNA-XIST. Interestingly, both silencing LncRNA-XIST and miR-335 overexpression enhanced the inhibiting effects of PD on the malignant phenotypes in bladder cancer cells. Consistently, the xenograft tumor-bearing mice models were established, and the data indicated that PD slowed down tumor growth and inhibited tumorigenesis in vivo, which were also aggravated by downregulating LncRNA-XIST. In general, analysis of data proved that targeting LncRNA-XIST/miR-335 axis was novel to enhance the anti-tumor effects of PD in bladder cancer in vitro and in vivo, and this study provided alternative therapeutic strategies for bladder cancer treatment in clinic.


Lateral thoracic expansion for Jeune's asphyxiating dystrophy: a new approach.
A new procedure is described for thoracic expansion in Jeune's asphyxiating dystrophy. The chest wall is enlarged by division of ribs and underlying tissue in a staggered fashion so that either rib or periosteum covers the lung. New bone formation has been demonstrated so that a viable enlargement has been obtained. The clinical result is excellent to date.


IL-17 producing gammadelta T cells are required for a controlled inflammatory response after bleomycin-induced lung injury.
gammadelta T cells play a key role in the regulation of inflammatory responses in epithelial tissue, and in adaptive immunity, as gammadelta T cell deficient mice have a severely impaired capacity to clear lung pathogens. gammadelta T cells regulate the initial inflammatory response to microbial invasion and thereby protect against tissue injury. Here we examined the response of gammadelta T cells to lung injury induced by bleomycin, in an effort to study the inflammatory response in the absence of any adaptive immune response to a pathogen. After lung injury by bleomycin, we localized the gammadelta T cells to the lung lesions. gammadelta T cells were the predominant source of IL-17 (as detected by flow cytometry and real-time PCR). Moreover, gammadelta T cell knockout mice showed a significant reduction in cellular infiltration into the airways, reduced expression of IL-6 in the lung, and a significant delay in epithelial repair. Mouse gammadelta T cells produce IL-17 in response to lung injury and are required for an organized inflammatory response and epithelial repair. The lack of gammadelta T cells correlates with increased inflammation and fibrosis.


The psychological impact of adverse events on urology trainees.
Adverse events (AE) are an inevitable reality in healthcare, with an incidence of 7.5-14.1% worldwide. AEs are recognised to cause psychological and emotional distress in healthcare workers, with surgeons being particularly susceptible. We report the first data on the emotional impact in relation to adverse events in surgeons in the Republic of Ireland (ROI). We distributed a web-based survey to all urology trainees in the ROI. The questionnaire focused on trainees' personal account of AEs, their emotional response, perceived contributing factors and perceived benefit of support systems. The primary care PTSD screen (PC-PTSD-V) assessed for PTSD. A total of 16 responses were received from 12 (75%) registrars and 4 (25%) SHOs. Of the AEs reported, 12 (75%) were ≥ Clavien-Dindo 3b. Contributing factors identified included lapse of judgement (n = 6, 37.5%), risk of procedure (n = 7, 43%), lack of experience (n = 4, 25%). Anxiety (n = 8, 50%), guilt (n = 7, 44%) and sleep problems (n = 4, 25%) were the most reported emotional responses. Physical symptoms were reported in 2 (12%) trainees. A PC-PTSD-V score ≥ 3 was reported in 2 (12%) trainees. Most trainees (n = 13, 81%) reported talking to someone following the event with most (n = 12, 93%) talking to a consultant or NCHD colleague. Most respondents (n = 14, 87%) agreed that their training could better prepare them for the personal impact of AEs. Surgical trainees report negative psychological and emotional responses that are consistent with second victim symptoms. Those surveyed felt that their training could better prepare them for the personal impact of such events.


Fragment screening at AstraZeneca: developing the next generation biophysics fragment set.
Fragment based drug discovery is a critical part of the lead generation toolbox and relies heavily on a readily available, high quality fragment library. Over years of use, the AstraZeneca fragment set had become partially depleted and instances of compound deterioration had been found. It was recognised that a redevelopment was required. This provided an opportunity to evolve our screening sets strategy, whilst ensuring that the quality of the fragment set met the robust requirements of fragment screening campaigns. In this communication we share the strategy employed, in particular highlighting two aspects of our approach that we believe others in the community would benefit from, namely that; (i) fragments were selected with input from Medicinal Chemists at an early stage, and (ii) the library was arranged in a layered format to ensure maximum flexibility on a per target basis.


Computational studies of modified [Fe3S4] clusters: why iron is optimal.
This work reports density functional computations of metal-substituted models of biological [Fe3S4] clusters in oxidation states [MFe2S4](+/0/-1) (M=Mn, Fe, Co, Ni, Cu, Zn, and Mo). Geometry optimization with a dielectric screening model is shown to provide a substantial improvement in structure, compared to earlier used standard procedures. The error for average Fe-S bonds decreased from 0.038A to 0.016A with this procedure. Four density functionals were compared, B3LYP, BP86, TPSS, and TPSSh. B3LYP and to a lesser extent TPSSh energies were inconsistent with experiment for the oxidized [Fe3S4]+ cluster. BP86 (and to a slightly lesser extent TPSS) was within expected theoretical and experimental uncertainties for all oxidation states, the only qualitative error being 5kJ/mol in favor of the M(S)=3/2 configuration for the [Fe3S4]+ cluster, so BP86 was used for quantitative results. Computed reorganization energies and reduction potentials point directly towards the [Fe3S4] cluster as the superior choice of electron carrier, with the [ZnFe2S4] cluster a close second. In addition, partially and fully Mo-substituted clusters were investigated and found to have very low reorganization energies but too negative reduction potentials. The results provide a direct rationale why any substitution weakens the cluster as an electron carrier, and thus why the [Fe3S4] composition is optimal in the biological clusters.


Medium for the selective isolation of members of the genus Pseudomonas from natural habitats.
A new medium was developed that was superior to four others tested in selecting for members of the genus Pseudomonas.


Combined chemotherapy and surgery for pulmonary metastases from osteogenic sarcoma. Results of 10 years experience.
Twenty-three patients presented with isolated pulmonary metastases from osteogenic sarcoma following primary treatment by amputation or limb salvage, combined with chemotherapy. The metastases were treated by conservative surgical excision combined with chemotherapy; surgical excision was repeated for recurrent pulmonary metastases, provided there were none elsewhere. Six patients are alive and disease-free following their initial surgery. Of the remaining 17, 10 had recurrence confined to the lungs, and 7 developed extra-pulmonary metastases. The 10 with isolated pulmonary metastases all had further thoracotomies but eventually 7 died, as did all those with extra-pulmonary metastases. There were in all 45 operations, with 1 hospital death and 1 serious complication. Actuarial survival at 1, 3, 5 and 7 years was 87%, 45%, 39% and 31%, respectively. In the 10 patients who had recurrence of isolated pulmonary metastases, survival at 1 and 3 years was 70% and 34%.


Pregnancy loss in a small chorionic villus sampling series.
Two previous reports have suggested that the pregnancy loss rate with chorionic villus biopsy is high in the initial 100 to 300 cases. In the initial 211 cases of this study, the total pregnancy loss rate (7.1%) and losses not attributed to induced abortion or cytogenetic abnormality (2.8%) do not support this contention.


Which advance directive do patients prefer?
This study examined patient acceptance of two different advance directives. Outpatients completed the two directives and a 12-item acceptability questionnaire for each, and then stated their directive preferences. Of 128 patients enrolled, 97 (76%) responded. Overall, 47% of the respondents were satisfied with the Let Me Decide directive and 53% with the Medical Directive (NS). Thirty-nine percent preferred the Let Me Decide directive, 37% preferred the Medical Directive, and 25% had no preference or were uncertain which they preferred. Although there was no difference in patient acceptance between the directives, 76% of the patients preferred one or the other. Therefore, different people like different directives, and a variety of directives should be available for patients to review before they complete one.


A review on possible mechanistic insights of Nitazoxanide for repurposing in COVID-19.
The global pandemic of Coronavirus Disease 2019 (COVID-19) has brought the world to a grinding halt. A major cause of concern is the respiratory distress associated mortality attributed to the cytokine storm. Despite myriad rapidly approved clinical trials with repurposed drugs, and time needed to develop a vaccine, accelerated search for repurposed therapeutics is still ongoing. In this review, we present Nitazoxanide a US-FDA approved antiprotozoal drug, as one such promising candidate. Nitazoxanide which is reported to exert broad-spectrum antiviral activity against various viral infections, revealed good in vitro activity against SARS-CoV-2 in cell culture assays, suggesting potential for repurposing in COVID-19. Furthermore, nitazoxanide displays the potential to boost host innate immune responses and thereby tackle the life-threatening cytokine storm. Possibilities of improving lung, as well as multiple organ damage and providing value addition to COVID-19 patients with comorbidities, are other important facets of the drug. The review juxtaposes the role of nitazoxanide in fighting COVID-19 pathogenesis at multiple levels highlighting the great promise the drug exhibits. The in silico data and in vitro efficacy in cell lines confirms the promise of nitazoxanide. Several approved clinical trials world over further substantiate leveraging nitazoxanide for COVID-19 therapy.


The effect of preparation design on the marginal stress of resin-bonded metal-free crowns: a finite element study.
The aim of this study was to evaluate the stress distribution at the marginal edge of metal-free crowns using 2 different materials (ceramic and hybrid composite) and 4 different preparation designs (knife edge, chamfer, heavy chamfer, rounded shoulder). All marginal preparation designs for hybrid composite crowns showed lower compression and tensile stress than the ceramic crowns. The rounded shoulder preparation provided more even stress distribution than the knife-edge preparation. Heavy chamfer was an acceptable preparation design for ceramic crowns. The chamfer preparation was preferred for hybrid composite crown.


Is injectable PrEP superior to oral therapy for HIV protection?
An RCT of HIV preexposure prophylaxis compared long-acting injectable cabotegravir with traditional daily oral tenofovir-emtricitabine-with clear results.