Clinical Significance of Low 2-Methoxyestradiol Levels in Serum and Tissue of Recurrent Juvenile-Onset Laryngeal Papillomatosis.
Objective We aim to explore the correlation between serum and tissue 2-methoxyestradiol (2-ME-2) levels and recurrence of juvenile-onset respiratory papillomatosis (JORRP). Study Design Retrospective cohort studies. Settings Laboratory of Otolaryngology, Department of Head and Neck Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University. Subjects and Methods Sixty-four patients diagnosed with JORRP in our department from January 2007 to December 2012 were enrolled. Patients were divided into recurrence and nonrecurrence groups, with 32 patients in each group. ELISA detected the concentration of 2-ME-2 in serum and tissue samples collected during the first surgical procedure. Mann-Whitney analysis, receiver operating characteristic curves, logistic regression model, and Kaplan-Meier method were used for data processing. Results There was no difference in the serum 2-ME-2 concentration between the groups ( P = .237), while the tissue 2-ME-2 concentration of the recurrent group was significantly lower than that of the nonrecurrence group ( P = .0001). When the area under the curve was 0.752, the cutoff value of tissue 2-ME-2 at 670.02 pg/mL yielded the highest predictive sensitivity (71.9%) and specificity (71.9%). Regrouped by this cutoff point, patients with a lower tissue 2-ME-2 level (n = 26) had shorter disease-free survival and a higher recurrence odds ratio than patients with a higher tissue 2-ME-2 level (n = 38; P = .0408, odds ratio = 7.667). Conclusion A low tissue 2-ME-2 level is associated with a higher recurrence rate of JORRP. Tissue 2-ME-2 may be an effective target for JORRP treatment and a convenient measure for recurrence monitoring.


Database on veterinary clinical research in homeopathy.
The aim of the present report is to provide an overview of the first database on clinical research in veterinary homeopathy. Detailed searches in the database 'Veterinary Clinical Research-Database in Homeopathy' (http://www.carstens-stiftung.de/clinresvet/index.php). The database contains about 200 entries of randomised clinical trials, non-randomised clinical trials, observational studies, drug provings, case reports and case series. Twenty-two clinical fields are covered and eight different groups of species are included. The database is free of charge and open to all interested veterinarians and researchers. The database enables researchers and veterinarians, sceptics and supporters to get a quick overview of the status of veterinary clinical research in homeopathy and alleviates the preparation of systematical reviews or may stimulate reproductions or even new studies.


Assessment of skin permeability to topically applied drugs by skin impedance and admittance.
Pharmacokinetic and pharmacodynamic studies of topically applied drugs are commonly performed by sampling of interstitial fluid with dermal open flow microperfusion and subsequent analysis of the samples. However, the reliability of results from the measured concentration-time profile of the penetrating drug suffers from highly variable skin permeability to topically applied drugs that is mainly caused by inter- and intra-subject variations of the stratum corneum. Thus, statistically significant results can only be achieved by performing high numbers of experiments. To reduce the expenditures needed for such high experiment numbers we aimed to assess the correlation between skin permeability and skin impedance/skin admittance. We performed an ex vivo drug penetration study with human skin, based on the hypothesis that inter-subject variations of the respective concentration-time profiles can be correlated with variations of the passive electrical properties of the skin. Therefore, skin impedance and skin admittance were related to the skin permeability to the model drug Clobetasol-17-proprionate. The measured low frequency skin impedance and the skin admittance correlated linearly with the drug concentration-time profiles from dermal sampling. Skin permeability can be assessed by measuring the passive electrical properties of the skin, which enables correction of skin permeability variations. This allows reduction of experiment numbers in future pharmacokinetic and pharmacodynamic studies with human skin ex vivo and in vivo and leads to diminished study costs.


Murine Leukemia Virus Exploits Innate Sensing by Toll-Like Receptor 7 in B-1 Cells To Establish Infection and Locally Spread in Mice.
Lymph-borne Friend murine leukemia virus (FrMLV) exploits the sentinel macrophages in the draining popliteal lymph node (pLN) to infect highly permissive innate-like B-1 cells and establish infection in mice. The reason for FrMLV sensitivity of B-1 cells and their impact on viral spread is unknown. Here we demonstrate that Toll-like receptor 7 (TLR7) sensing and type I interferon (IFN-I) signaling in B-1 cells contribute to FrMLV susceptibility. FrMLV infection in B-1 cell-deficient mice (bumble; IκBNS dysfunctional) was significantly lower than that in the wild-type mice and was rescued by adoptive transfer of wild-type B-1 cells. This rescue of FrMLV infection in bumble mice was dependent on intact TLR7 sensing and IFN-I signaling within B-1 cells. Analyses of infected cell types revealed that the reduced infection in bumble mice was due predominantly to compromised virus spread to the B-2 cell population. Our data reveal how FrMLV exploits innate immune sensing and activation in the B-1 cell population for infection and subsequent spread to other lymphocytes.IMPORTANCE Viruses establish infection in hosts by targeting highly permissive cell types. The retrovirus Friend murine leukemia virus (FrMLV) infects a subtype of B cells called B-1 cells that permit robust virus replication. The reason for their susceptibility had remained unknown. We found that innate sensing of incoming virus and the ensuing type I interferon response within B-1 cells are responsible for their observed susceptibility. Our data provide insights into how retroviruses coevolved with the host to co-opt innate immune sensing pathways designed to fight virus infections for establishing infection. Understanding early events in viral spread can inform antiviral intervention strategies that prevent the colonization of a host.


Prognostic value of biochemical markers, 12-lead ECG and patient characteristics amongst patients calling for an ambulance due to a suspected acute coronary syndrome.
To evaluate whether a 12-lead ECG, together with a multi-marker strategy that used point-of-care measurements of myoglobin, creatine kinase (CK-MB) and troponin I, was able to predict patients at short- and long-term risk of death, when simultaneously considering age, gender, previous history, symptoms and clinical findings on arrival of the ambulance. Prospective observational study. Consecutive patients (n=511) in ambulances in Stockholm and Göteborg in Sweden who called for an ambulance due to chest pain or other symptoms raising a suspicion of acute coronary syndrome. In almost all patients, a diagnostic ECG, patient baseline characteristics and measurements of CK-MB, troponin I and myoglobin were recorded. In univariate analysis, the highest 30-day mortality (17%) was found amongst patients with the combination of ECG signs of myocardial ischaemia and the elevation of any biochemical marker. The highest 1-year mortality (20%) was found amongst patients with ECG signs of myocardial ischaemia and the elevation of any biochemical marker. Increasing age (RR 1.07; 95 CI 1.02-1.13) lack of symptoms of chest pain and a previous history of hypertension (3.02; 1.08-8.79) were independent predictors of 30-day mortality. Myoglobin was the only biochemical marker independently associated with 30-day mortality (6.66; 1.83-22.3). Increasing age (1.11; 1.06-1.16), previous history of diabetes (3.42; 1.41-8.25) heart failure (2.64; 1.26-5.52) and other symptoms than chest pain and dyspnoea (5.23; 2.14-12.76) were independent predictors of 1-year mortality. In many of the variables the confidence limits were wide. Amongst patients with a clinical suspicion of acute coronary syndrome, those with the combination of ECG signs of myocardial ischaemia and the elevation of any biochemical marker on arrival of the ambulance form a group with a particularly high risk of death. However, age as well as aspects of clinical history and type of symptoms independently contribute to prognostic information.


[Kidney function study by radioisotope renography in lymphogranulomatosis patients subjected to radiation treatment].
An analysis of the results of renography in 68 patients with lymphogranulomatosis is presented. In 57 patients, a radionuclide investigation of renal function was carried out after irradiation of the spleen, paraaortic and iliac lymph nodes. Renograms were evaluated both qualitatively and quantitatively. The investigation established an impaired renal function in 18% of patients examined prior to radiation therapy. According to radionuclide renography, the excretory function of the tubular renal apparatus remains quite satisfactory after partial irradiation of kidneys in a dose of 38-40 Gy.


[Construction and analysis of soybean genetic map].
Molecular linkage maps provide a powerful tool for the analysis of plant genome structure and function including the detection of quantitative trait loci (QTL). The molecular linkage map of soybean was constructed using an 88-individual RIL population derived from a cross between cultivated Changnong 4 and semi-wild Xinmin 6. The map contains 22 linkage groups and 240 markers, including 100 RFLP, 33 SSR, 62 RAPD, 42 AFLP, 1 SCAR and 2 morphological markers. It covers approximately 3,713.5 cM of soybean genome. Analysis of 72 RFLP markers showed that 16 of them revealed two or more independent loci and it suggested that there is an extensive homologous region in soybean genome. This map compared very well with the other published soybean maps.


Estrogen, through estrogen receptor 1, regulates histone modifications and chromatin remodeling during spermatogenesis in adult rats.
Estrogen receptors (ESR1 and ESR2) play crucial roles in various processes during spermatogenesis. To elucidate individual roles of ESRs in male fertility, we developed in vivo selective ESR agonist administration models. Adult male rats treated with ESR1 and ESR2 agonist for 60 days show spermatogenic defects leading to reduced sperm counts and fertility. While studying epigenetic changes in the male germ line that could have affected fertility, we earlier observed a decrease in DNA methylation and its machinery upon ESR2 agonist treatment. Here, we explored the effects on histone modifications, which could contribute to decreased male fertility upon ESR agonist administration. ESR1 agonist treatment affected testicular levels of histone modifications associated with active and repressed chromatin states, along with heterochromatin marks. This was concomitant with deregulation of corresponding histone modifying enzymes in the testis. In addition, there was increased retention of histones along with protamine deficiency in the caudal spermatozoa after ESR1 agonist treatment. This could be due to the observed decrease in several chromatin remodeling proteins implicated in mediating histone-to-protamine exchange during spermiogenesis. The activating and repressing histone marks in spermatozoa, which play a critical role in early embryo development, were deregulated after both the ESR agonist treatments. Together, these epigenetic defects in the male germ line could affect the spermatozoa quality and lead to the observed decrease in fertility. Our results thus highlight the importance of ESRs in regulating different epigenetic processes during spermatogenesis, which are crucial for male fertility.


PD-L1 and Tumor Infiltrating Lymphocytes as Prognostic Markers in Resected NSCLC.
Immune checkpoint inhibition has shifted treatment paradigms in non-small cell lung cancer (NSCLC). Conflicting results have been reported regarding the immune infiltrate and programmed death-ligand 1 (PD-L1) as a prognostic marker. We correlated the immune infiltrate and PD-L1 expression with clinicopathologic characteristics in a cohort of resected NSCLC. A tissue microarray was constructed using triplicate cores from consecutive resected NSCLC. Immunohistochemistry was performed for CD8, FOXP3 and PD-L1. Strong PD-L1 expression was predefined as greater than 50% tumor cell positivity. Matched nodal samples were assessed for concordance of PD-L1 expression. Of 522 patients, 346 were node-negative (N0), 72 N1 and 109 N2; 265 were adenocarcinomas (AC), 182 squamous cell cancers (SCC) and 75 other. Strong PD-L1 expression was found in 24% cases. In the overall cohort, PD-L1 expression was not associated with survival. In patients with N2 disease, strong PD-L1 expression was associated with significantly improved disease-free (DFS) and overall survival (OS) in multivariate analysis (HR 0.49, 95%CI 0.36-0.94, p = 0.031; HR 0.46, 95%CI 0.26-0.80, p = 0.006). In this resected cohort only 5% harboured EGFR mutations, whereas 19% harboured KRAS and 23% other. KRAS mutated tumors were more likely to highly express PD-L1 compared to EGFR (22% vs 3%). A stromal CD8 infiltrate was associated with significantly improved DFS in SCC (HR 0.70, 95%CI 0.50-0.97, p = 0.034), but not AC, whereas FOXP3 was not prognostic. Matched nodal specimens (N = 53) were highly concordant for PD-L1 expression (89%). PD-L1 expression was not prognostic in the overall cohort. PD-L1 expression in primary tumor and matched nodal specimens were highly concordant. The observed survival benefit in N2 disease requires confirmation.


Inhibition of epidermal growth factor receptor improves antitumor efficacy of vemurafenib in BRAF-mutant human melanoma in preclinical model.
Oncogenic activation of the epidermal growth factor receptor (EGFR) signaling pathway occurs in a variety of tumor types, albeit in human melanoma, the contribution of EGFR is still unclear. The potential role of EGFR was analyzed in four BRAF-mutant, one NRAS-mutant and one wild-type NRAS-BRAF-carrying human melanoma cell lines. We have tested clinically available reversible tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, irreversible EGFR-TKI pelitinib and a reversible experimental compound PD153035 on in-vitro proliferation, apoptosis, migration as well as in-vivo metastatic colonization in a spleen-liver model. The presence of the intracellular domain of EGFR protein and its constitutive activity were demonstrated in all cell lines. Efficacies of EGFR-TKIs showed significant differences, and irreversible inhibition had the strongest antitumor potential. Compared with BRAF-mutant cells, wild-type BRAF was associated with relative resistance against gefitinib. In combination with gefitinib, selective mutant BRAF-inhibitor vemurafenib showed additive effect in all BRAF-mutant cell lines. Treatment of BRAF-mutant cells with gefitinib or pelitinib attenuated in-vitro cell migration and in-vivo colonization. Our preclinical data suggest that EGFR is a potential target in the therapy of BRAF-mutant malignant melanoma; however, more benefits could be expected from irreversible EGFR-TKIs and combined treatment settings.


Persistent Cardiac Magnetic Resonance Imaging Features of Myocarditis Detected Months After COVID-19 Infection.
Acute myocarditis is commonly caused by viral infections resulting from viruses such as adenovirus, enteroviruses, and, rarely, coronavirus. It presents with nonspecific symptoms like chest pain, dyspnea, palpitation, or arrhythmias and can progress to dilated cardiomyopathy or heart failure. Fulminant myocarditis is a potentially life-threatening form of the condition and presents as acute, severe heart failure with cardiogenic shock. In this report, we discuss a case of a 41-year-old female who presented with cough and chest pain of two days' duration. The patient had a new-onset atrial flutter. Her chest auscultation revealed bilateral crackles. Laboratory workup revealed elevated troponin levels, and the patient tested positive for coronavirus disease 2019 (COVID-19) by nasopharyngeal swab polymerase chain reaction (PCR). Transthoracic echocardiogram revealed a low left ventricular (LV) ejection fraction of 35-40% compared to 55% one year prior, as well as a granular appearance of LV myocardium. The patient's condition subsequently improved clinically and she was discharged home. Due to cardiac involvement and characteristic myocardial appearance on the echocardiogram, cardiac magnetic resonance (CMR) imaging was performed for further evaluation about two months from the date of admission. CMR showed extensive myocardial inflammation with a typical pattern of sub-epicardial and mid-wall delayed enhancement, confirming the diagnosis of myocarditis. This case highlights myocarditis as a potential complication of COVID-19 that requires early diagnosis and proper management to improve patients' quality of life. Additionally, we highlight the features of myocarditis on CMR in the acute phase and two months after clinical recovery.


Atlantoaxial Osteoarthritis: A Well-Established Entity that Remains Frequently Overlooked.
Painful atlantoaxial (C1-2) osteoarthritis (AAOA) has been described over 40 years ago. The condition may cause severe pain symptoms and disability related to the unilateral suboccipital pain and, in some cases, occipital neuralgia. One of the greatest challenges with AAOA is making the diagnosis. Diagnosis is commonly missed or delayed when headaches are treated in isolation or when pain is attributed to subaxial spondylosis. Here we present an illustrative case involving a 67-year-old male presenting with classic painful AAOA. After failing conservative treatments, he was evaluated with morphologic, radiological studies and a diagnostic injection. He was successfully treated with bilateral, navigation guided C1 lateral mass and C2 pedicle screw fixation and fusion. To conclude, when there is clinical suspicion for painful AAOA, providers have numerous diagnostic modalities, including newer hybrid techniques, that can be used to solidify the diagnosis. When conservative efforts fail, C1-2 fusion is an effective and enduring treatment for most patients.


PRMT5 disruption drives antitumor immunity in cervical cancer by reprogramming T cell-mediated response and regulating PD-L1 expression.
Rationale: Protein arginine methyltransferase 5 (PRMT5) is an oncogene that promotes tumor cell proliferation, invasion and metastasis. However, the underlying mechanisms by which PRMT5 contributes to the progression of cervical cancer and especially the tumor microenvironment remain poorly understood. Methods: PRMT5 expression level was analyzed by Q-PCR, western blot, immunohistochemistry, and TCGA database. The role of PRMT5 in tumor growth was observed by transplanted tumor models, and the function of T cells in tumor microenvironment and in vitro co-culture system was investigated through flow cytometry. The transcriptional regulation of PRMT5 was analyzed using luciferase reporter and chromatin immunoprecipitation (ChIP) assay. The therapeutic effect of PRMT5 inhibitor was evaluated in a cervical cancer cell line transplanted tumor model. Results: We observed that the mRNA and protein expression levels of PRMT5 were increased in cervical cancer tissues, and the high expression of PRMT5 was associated with poor outcomes in cervical cancer patients. The absence of PRMT5 significantly inhibited tumor growth in a cervical cancer transplanted tumor model, and importantly, PRMT5 absence in tumors led to increase the number and enhance the function of tumor infiltrating T cells. Mechanistically, PRMT5 enhanced the transcription of STAT1 through symmetric dimethylation of histone H3R2 and thus promoted PD-L1 expression in cervical cancer cells. Moreover, in an in vitro co-culture system, knockdown of PRMT5 in tumor cells could directly enhance the expression of IFN-γ, TNF-α and granzyme B in T cells. These results suggested that PRMT5 promoted the development of cervical cancer by the crosstalk between tumor cells and T cells. Furthermore, the PRMT5 inhibitor EPZ015666 treatment could suppress tumor growth in a cervical cancer transplanted tumor model. Conclusion: Our results clarify a new mechanism which PRMT5 knockdown in cervical cancer cells drives an antitumor function via reprogramming T cell-mediated response and regulating PD-L1 expression. Thus, our study highlights that PRMT5 may be a potential target for cervical cancer therapy.


Association between Hyperhomocysteinemia and Thyroid Hormones in Euthyroid Diabetic Subjects.
The concept now emerging is that higher thyroid-stimulating hormone (TSH) and lower thyroid hormone levels within the euthyroid range may adversely affect atherosclerosis. The present study aimed to investigate the potential associations between thyroid parameters and hyperhomocysteinaemia in a cohort of euthyroid diabetic subjects. Two hundred and seventy-three euthyroid diabetic subjects (167 males and 106 females) were consecutively recruited in this cross-sectional study. Clinical and biomedical data was collected. TSH level was higher in females than males. Compared to normal-homocysteine group, hyperhomocysteinaemia group was more likely to be elderly, males, with longer diabetes history, and with lower diastolic blood pressure. Free thyroxine (FT4) level was lower in hyperhomocysteinaemia group than in normal-homocysteine group; however, it was not statistically significant. Adjusted for age, sex, body mass index, duration of diabetes, blood pressure, fasting glucose, total cholesterol, and triglyceride in logistic regression analyses, hyperhomocysteinaemia was significantly correlated with FT4 (P = 0.021). No significant association was found with TSH or free triiodothyronine. When analyzed in subjects with TSH < 2.5 uIU/mL separately, we got similar results. In conclusion, we identified a relation between hyperhomocysteinemia and FT4 in a group of euthyroid diabetic patients.


Contribution of mutations in the cytochrome P450 14alpha-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans.
The cytochrome P450 14alpha-demethylase, encoded by the ERG11 (CYP51) gene, is the primary target for the azole class of antifungals. Changes in the azole affinity of this enzyme caused by amino acid substitutions have been reported as a resistance mechanism. Nine Candida albicans strains were used in this study. The ERG11 base sequence of seven isolates, of which only two were azole-sensitive, were determined. The ERG11 base sequences of the other two strains have been published previously. In these seven isolates, 12 different amino acid substitutions were identified, of which six have not been described previously (A149V, D153E, E165Y, S279F, V452A and G4655). In addition, 16 silent mutations were found. Two different biochemical assays, subcellular sterol biosynthesis and CO binding to reduced microsomal fractions, were used to evaluate the sensitivity of the cytochromes for fluconazole and itraconazole. Enzyme preparations from four isolates showed reduced itraconazole susceptibility, whereas more pronounced resistance to fluconazole was observed in five isolates. A three-dimensional model of C. albicans Cyp51p was used to position all 29 reported substitutions, 98 in total identified in 53 sequences. These 29 substitutions were not randomly distributed over the sequence but clustered in three regions from amino acids 105 to 165, from 266 to 287 and from 405 to 488, suggesting the existence of hotspot regions. Of the mutations found in the two N-terminal regions only Y132H was demonstrated to be of importance for azole resistance. In the C-terminal region three mutations are associated with resistance, suggesting that the non-characterized substitutions found in this region should be prioritized for further analysis.


Social anxiety disorder: common, disabling, and treatable.
Social anxiety disorder (also known as social phobia) is characterized by extreme fear, avoidance, or both of one or more social or performance situations, such as making a presentation, meeting new people, or eating in front of others. This condition is common, with a lifetime prevalence of up to 13%, and one third of affected persons have major dysfunction. The English-language literature on social anxiety disorder indexed on MEDLINE was searched using the phrases "social phobia" or "social anxiety disorder;" this search was supplemented with other data sources, such as recent textbooks, to determine common clinical symptoms, differential diagnosis, and management in the primary care setting. Recognition and treatment of social anxiety disorder is poor; only a small minority of patients with this condition have it appropriately diagnosed or treated. Primary care physicians should suspect social anxiety disorder in patients who have specific symptoms and signs (such as hyperhidrosis, flushing, tremor, and white-coat hypertension), in patients who have symptoms of anxiety (such as chest pain, palpitations, or dizziness), or in patients who have another known anxiety disorder, depression, or substance abuse. Drug treatment consists of serotonin-reuptake inhibitors, monoamine oxidase inhibitors, or high-potency benzodiazepines. A specific type of psychotherapy called cognitive behavioral therapy is another effective treatment, but it is not acceptable or accessible to most patients. Because social anxiety disorder is common, disabling, and treatable, primary care physicians should intensify their efforts to recognize it.


[Pediatric emergencies].
Management of acute emergencies in children has a number of specific aspects, with which the first person providing medical care needs to be familiar. For example, intubation requires knowledge of the particular anatomy of infants and young children. In addition, a specific and flexible approach to such matters as oxygen requirement, blood volumes, thermoregulation and the venous system is essential. Administration of adrenaline should initially be via inhalation, since this can be done rapidly and easily. Among the causes of cardiac arrest, sudden infant death predominates in babies, while in young and pre-school children, trauma and near-drowning accidents represent the most common events requiring reanimation measures. Of decisive importance for clarifying the cause of death is an accurate documentation of the course of reanimation and the situation initially presenting to the care provider.


RNase L contributes to experimentally induced type 1 diabetes onset in mice.
The cause of type 1 diabetes continues to be a focus of investigation. Studies have revealed that interferon α (IFNα) in pancreatic islets after viral infection or treatment with double-stranded RNA (dsRNA), a mimic of viral infection, is associated with the onset of type 1 diabetes. However, how IFNα contributes to the onset of type 1 diabetes is obscure. In this study, we found that 2-5A-dependent RNase L (RNase L), an IFNα-inducible enzyme that functions in the antiviral and antiproliferative activities of IFN, played an important role in dsRNA-induced onset of type 1 diabetes. Using RNase L-deficient, rat insulin promoter-B7.1 transgenic mice, which are more vulnerable to harmful environmental factors such as viral infection, we demonstrated that deficiency of RNase L in mice resulted in a significant delay of diabetes onset induced by polyinosinic:polycytidylic acid (poly I:C), a type of synthetic dsRNA, and streptozotocin, a drug which can artificially induce type 1-like diabetes in experimental animals. Immunohistochemical staining results indicated that the population of infiltrated CD8(+)T cells was remarkably reduced in the islets of RNase L-deficient mice, indicating that RNase L may contribute to type 1 diabetes onset through regulating immune responses. Furthermore, RNase L was responsible for the expression of certain proinflammatory genes in the pancreas under induced conditions. Our findings provide new insights into the molecular mechanism underlying β-cell destruction and may indicate novel therapeutic strategies for treatment and prevention of the disease based on the selective regulation and inhibition of RNase L.


[Prostatic pathology imaged by magnetic resonance. 58 cases].
Forty-eight patients with prostatic disease (benign prostatic hyperplasia (B.P.H.), carcinoma, cysts, myoma and prostatitis) and 10 normal volunteers underwent magnetic resonance imaging (M.R.I.) of the prostate. The prostatic parenchyma was best evaluated by a T2-weighted spin-echo pulse sequence. The prostate in patients with B.P.H. often had a homogeneous or more rarely a nodular appearance on T2-weighted images. In most cases, a peripheral dark rim is observed. All prostate in patients with carcinoma had an heterogeneous appearance on T2-weighted images. While most of the prostatic carcinomas appeared hypo-intense relative to adjacent prostatic parenchyma, some of the neoplasms had a high or mixed-high and low signal. The myoma showed a low-signal nodule like carcinoma. The cyst appears as a liquid tumor. The prostatitis had an homogeneous bright signal. With the used methodology, MRI can differentiate prostatic diseases in many cases. Nevertheless the technique has to be optimized to improve its accuracy.


Developing nontraditional community health placements.
Building capacity for student clinical experiences has become a key concern for nurse educators in the 21st century. For community health faculty, traditional placements at public health departments or other health-affiliated organizations often do not provide adequate numbers or types of placement opportunities. Wishing to expand experiences for its undergraduate program, faculty at a midwestern university have developed and nurtured long-standing collaborative relationships with organizations not typically used by schools of nursing. Such partnerships are often called "nontraditional," with the understanding that they are not affiliated with the typical health sector organizations. This article introduces two of these partnerships, describes the process used to establish and maintain them, and identifies the outcomes achieved by students, clients, and organizations.


Self-Cleaning, Thermoresponsive P (NIPAAm-co-AMPS) Double Network Membranes for Implanted Glucose Biosensors.
A self-cleaning membrane that periodically rids itself of attached cells to maintain glucose diffusion could extend the lifetime of implanted glucose biosensors. Herein, we evaluate the functionality of thermoresponsive double network (DN) hydrogel membranes based on poly(N-isopropylacrylamide) (PNIPAAm) and an electrostatic co-monomer, 2-acrylamido-2-methylpropane sulfonic acid (AMPS). DN hydrogels are comprised of a tightly crosslinked, ionized first network [P(NIPAAm-co-AMPS)] containing variable levels of AMPS (100:0-25:75 wt% ratio of NIPAAm:AMPS) and a loosely crosslinked, interpenetrating second network [PNIPAAm]. To meet the specific requirements of a subcutaneously implanted glucose biosensor, the volume phase transition temperature is tuned and essential properties, such as glucose diffusion kinetics, thermosensitivity, and cytocompatibility are evaluated. In addition, the self-cleaning functionality is demonstrated through thermally driven cell detachment from the membranes in vitro.


Identification of nuclear factors that enhance binding of the thyroid hormone receptor to a thyroid hormone response element.
Using a gel shift assay, we analyzed the binding of in vitro translated alpha- and beta-thyroid hormone (T3) receptors to a T3-response element (TRE) derived from the rat GH gene. No receptor-TRE complexes were observed when translated receptor alone was incubated with the TRE. However, addition of a nuclear extract from liver to the translational products resulted in the formation of two receptor-DNA complexes for both the alpha- and beta-receptors. These complexes were shown to contain translated receptor by comigration of 32P-labeled TRE and 35S-labeled receptor in the gel shift assay. A competition experiment demonstrated that formation of the complexes was sequence specific. Preincubation of the liver nuclear extract at 60 C abolished formation of both complexes indicating that receptor-TRE binding required a heat-labile nuclear factor. Phosphocellulose chromatography of the nuclear extract resulted in separation of the activities required for formation of the two complexes. Analysis of nuclear extracts from different tissues revealed that one complex formed in the presence of all extracts, whereas the second complex appeared predominantly with a nuclear extract from liver. Addition of T3 to the binding reaction had no effect on receptor-TRE complex formation. We suggest that nuclear factors interact with the T3 receptor to enhance hormone-independent binding to a TRE.


A Retrospective Study to Evaluate the Effect of Concentration of Hypertonic Saline on Efficacy and Safety of Epidural Adhesiolysis.
Percutaneous epidural adhesiolysis (PEA) is a minimally invasive procedure that is performed to relieve low back and/or lower limb pain secondary to adhesions or scarring in the epidural space that is refractory to conservative treatment. The optimal concentration of hypertonic saline might be an important factor in the safety and efficacy of PEA. We evaluated differences in the efficacy and safety of 2 concentrations of hypertonic saline (5% and 10%) used in lumbar PEA at our institutions in a retrospective study. Patients who received lumbar PEA between January 2009 and June 2014 at either of 2 large civilian teaching institutions in South Korea were assigned to the 5% or 10% groups according to the osmolality of saline. The primary outcome of this study was the difference in change in the 11-point numerical rating scale (NRS) scores of low back and leg pain from baseline to 6 months after PEA between patients in the 2 groups. The number of additional epidural injections, patients' satisfaction with PEA, and any complications that occurred within 6 months after PEA were reviewed. This study included 543 patients (5% group, 333; 10% group, 210). Post-PEA NRS pain scores were significantly lower compared with those at baseline in both groups; however, there were no significant differences between the 2 groups at 6 months or any time point after PEA with regard to any of the clinical characteristics, except infusion-related pain, which exhibited borderline significance for greater scores in the 10% group compared with those in the 5% group (P = .041). Multivariable linear regression analysis with adjustments for covariates, including the number of additional epidural injections, revealed no significant association between patient group and the decrease in NRS pain scores at 6 months of follow-up. Transient adverse events related to PEA were recorded in 3 patients (10% group, 2; 5% group, 1). In PEA, 5% hypertonic saline exhibited similar positive outcomes after 6 months of follow-up as 10% hypertonic saline, with less infusion-related pain. This result suggests that infusion of 5% hypertonic saline may be considered as an alternative to 10% hypertonic saline in lumbar PEA. Further prospective randomized studies are required to better appreciate the outcome with regard to the use of different concentrations of hypertonic saline for PEA.


Australian academic primary health-care careers: a scoping survey.
This study was undertaken to provide a snapshot of the academic primary health-care workforce in Australia and to provide some insight into research capacity in academic primary health care following changes to funding for this sector. A convenience sample of individuals self-identifying as working within academic primary health care (n=405) completed an anonymous online survey. Respondents were identified from several academic primary health-care mailing lists. The survey explored workforce demographics, clarity of career pathways, career trajectories and enablers/barriers to 'getting in' and 'getting on'. A mix of early career (41%), mid-career (25%) and senior academics (35%) responded. Early career academics tended to be female and younger than mid-career and senior academics, who tended to be male and working in 'balanced' (teaching and research) roles and listing medicine as their disciplinary background. Almost three-quarters (74%) indicated career pathways were either 'completely' or 'somewhat unclear', irrespective of gender and disciplinary backgrounds. Just over half (51%) had a permanent position. Males were more likely to have permanent positions, as were those with a medical background. Less than half (43%) reported having a mentor, and of the 57% without a mentor, more than two-thirds (69%) would like one. These results suggest a lack of clarity in career paths, uncertainty in employment and a large number of temporary (contract) or casual positions represent barriers to sustainable careers in academic primary health care, especially for women who are from non-medicine backgrounds. Professional development or a mentoring program for primary health-care academics was desired and may address some of the issues identified by survey respondents.


A prospective study of MRI biomarkers in the brain and lower limb muscles for prediction of lower limb motor recovery following stroke.
The aim of this prospective observational longitudinal study was to explore and decipher the predictive value of prospective MRI biomarkers in the brain and lower limb muscles for 3-month lower limb motor recovery following stroke. In the brain, we measured the integrity of the corticospinal tract (fractional anisotropy/"FA"). In the muscles, we measured volume, fatty replacement (fat fraction analysis and proton spectroscopy) and oedema. Measurements were taken at two time points: (1) within 4 weeks of stroke (baseline measurement, clinical and imaging) and (2) 3 months following stroke (follow up measurement, clinical only). Clinical measurements consisted of assessments of functional ability and strength (Fugl-Meyer score, motor NIHSS, Functional Ambulation Category/"FAC", and muscle dynamometry). Twenty-three patients completed imaging and clinical assessments at baseline and follow-up; five patients had partial imaging assessment. The results provided some evidence that damage to the corticospinal tract would result in less motor recovery: recovery of the Fugl-Meyer score and dynamometric ankle plantarflexion, ankle dorsiflexion, and knee extension correlated positively and significantly with fractional anisotropy (0.406-0.457; p = 0.034-p = 0.016). However, fractional anisotropy demonstrated a negative correlation with recovery of the Functional Ambulation Category (-0.359, p = 0.046). For the muscle imaging, significant inverse correlation was observed between vastus lateralis fat fraction vs. NIHSS recovery (-0.401, p = 0.04), and a strong positive correlation was observed between ratio of intra- to extra-myocellular lipid concentrations and the recovery of knee flexion (0.709, p = 0.007). This study supports previous literature indicating a positive correlation between the integrity of the corticospinal tract and motor recovery post-stroke, expanding the limited available literature describing this relationship specifically for the lower limb. However, recovery of functional ambulation behaved differently to other clinical recovery markers by demonstrating an inverse relationship with corticospinal tract integrity. The study also introduces some muscle imaging biomarkers as potentially valuable in the prediction of 3-month lower limb motor recovery following stroke.


Innate Immune Signaling in Hearts and Buccal Mucosa Cells of Patients with Arrhythmogenic Cardiomyopathy.
We sought to determine if persistent innate immune signaling via NFκB occurs in cardiac myocytes in patients with arrhythmogenic cardiomyopathy and if this is associated with myocardial infiltration of pro-inflammatory cells expressing CCR2. We also determined if buccal mucosa cells from young subjects with inherited disease alleles exhibit NFκB signaling. NFκB signaling in cardiac myocytes causes disease in a mouse model of arrhythmogenic cardiomyopathy by mobilizing CCR2-expressing macrophages which promote myocardial injury and arrhythmias. Buccal mucosa cells exhibit pathologic features similar to those seen in cardiac myocytes in patients with arrhythmogenic cardiomyopathy. We analyzed myocardium from arrhythmogenic cardiomyopathy patients who died suddenly or required cardiac transplantation. We also analyzed buccal mucosa cells from young subjects with inherited disease alleles. The presence of immunoreactive signal for RelA/p65 in nuclei of cardiac myocytes and buccal cells was used as a reliable indicator of active NFκB signaling. We also counted myocardial CCR2-expressing cells. NFκB signaling was seen in cardiac myocytes in 34 of 36 cases of arrhythmogenic cardiomyopathy but in none of 19 age-matched controls. Cells expressing CCR2 were increased in patient hearts in numbers directly correlated with the number of cardiac myocytes showing NFκB signaling. NFκB signaling also occurred in buccal cells in young subjects with active disease. Patients with clinically active arrhythmogenic cardiomyopathy exhibit persistent innate immune responses in cardiac myocytes and buccal mucosa cells reflecting an inflammatory process that fails to resolve. Such individuals may benefit from anti-inflammatory therapy. NFκB signaling in cardiac myocytes causes arrhythmias and myocardial injury in a mouse model of arrhythmogenic cardiomyopathy by mobilizing pro-inflammatory CCR2-expressing macrophages to the heart. Based on these new mechanistic insights, we analyzed hearts of arrhythmogenic cardiomyopathy patients who died suddenly or required cardiac transplantation. We observed active NFκB signaling in cardiac myocytes associated with marked infiltration of CCR2-expressing cells. We also observed NFκB signaling in buccal mucosa cells obtained from young subjects with active disease. Thus, anti-inflammatory therapy may be effective in arrhythmogenic cardiomyopathy. Screening buccal cells may be a reliable way to identify patients most likely to benefit. Inflammation likely contributes to the pathogenesis of arrhythmogenic cardiomyopathy but the responsible mechanisms and the roles of specific classes of immune cells remain undefined.NFκB signaling in cardiac myocytes is sufficient to cause disease in a mouse model of arrhythmogenic cardiomyopathy by mobilizing injurious myeloid cells expressing CCR2 to the heart.Here, we provide evidence of persistent NFκB signaling in cardiac myocytes and increased CCR2-expressing cells in hearts of patients with arrhythmogenic cardiomyopathy. We observed a close correlation between the number of cardiac myocytes with active NFκB signaling and the number of CCR2-expressing cells in patient hearts.We also provide evidence of active NFκB signaling in buccal mucosa cells associated with initial onset of disease and/or disease progression in young subjects with arrhythmogenic cardiomyopathy alleles.


Assessment of Manual Dexterity in VR: Towards a Fully Automated Version of the Box and Blocks Test.
In recent years, the possibility of using serious gaming technology for the automation of clinical procedures for assessment of motor function have captured the interest of the research community. In this paper, a virtual version of the Box and Blocks Test (BBT) for manual dexterity assessment is presented. This game-like system combines the classical BBT mechanics with a play-centric approach to accomplish a fully automated test for assessing hand motor function, making it more accessible and easier to administer. Additionally, some variants of the traditional mechanics are proposed in order to fully exploit the advantages of the chosen technology. This ongoing research aims to provide the clinical practitioners with a customisable, intuitive, and reliable tool for the assessment and rehabilitation of hand motor function.


SP600125 inhibits Orthopoxviruses replication in a JNK1/2 -independent manner: Implication as a potential antipoxviral.
The pharmacological inhibitor SP600125 [anthra(1,9-cd)pyrazol-6(2H)-one 1,9-pyrazoloanthrone] has been largely employed as a c-JUN N-terminal kinase (JNK1/2) inhibitor. In this study, we evaluated whether pretreatment with SP600125 was able to prevent Orthopoxviruses Vaccinia virus (VACV), Cowpox virus (CPXV) and modified Vaccinia virus Ankara (MVA) replication. We found that incubation with SP600125 not only blocked virus-stimulated JNK phosphorylation, but also, significantly reduced virus production. We observed 1-3 log decline in viral yield depending on the cell line infected (A31, BSC-40 or BHK-21). The reduction in viral yield correlated with a dramatic impact on virus morphogenesis progress, intracellular mature viruses (IMV) were barely detected. Despite the fact that SP600125 can act as an efficient anti-orthopoxviral compound, we also provide evidence that this antiviral effect is not specifically exerted through JNK1/2 inhibition. This conclusion is supported by the fact that viral titers measured after infections of JNK1/2 knockout cells were not altered as compared to those of wild-type cells. In contrast, a decline in viral titers was verified when the infection of KO cells was carried out in the presence of the pharmacological inhibitor. SP600125 has been the focus of recent studies that have evaluated its action on diverse viral infections including DNA viruses. Our data support the notion that SP600125 can be regarded as a potential antipoxviral compound.


Association of infertility and fertility treatment with mammographic density in a large screening-based cohort of women: a cross-sectional study.
Ovarian stimulation drugs, in particular hormonal agents used for controlled ovarian stimulation (COS) required to perform in vitro fertilization, increase estrogen and progesterone levels and have therefore been suspected to influence breast cancer risk. This study aims to investigate whether infertility and hormonal fertility treatment influences mammographic density, a strong hormone-responsive risk factor for breast cancer. Cross-sectional study including 43,313 women recruited to the Karolinska Mammography Project between 2010 and 2013. Among women who reported having had infertility, 1576 had gone through COS, 1429 had had hormonal stimulation without COS and 5958 had not received any hormonal fertility treatment. Percent and absolute mammographic densities were obtained using the volumetric method Volpara™. Associations with mammographic density were assessed using multivariable generalized linear models, estimating mean differences (MD) with 95 % confidence intervals (CI). After multivariable adjustment, women with a history of infertility had 1.53 cm(3) higher absolute dense volume compared to non-infertile women (95 % CI: 0.70 to 2.35). Among infertile women, only those who had gone through COS treatment had a higher absolute dense volume than those who had not received any hormone treatment (adjusted MD 3.22, 95 % CI: 1.10 to 5.33). No clear associations were observed between infertility, fertility treatment and percent volumetric density. Overall, women reporting infertility had more dense tissue in the breast. The higher absolute dense volume in women treated with COS may indicate a treatment effect, although part of the association might also be due to the underlying infertility. Continued monitoring of cancer risk in infertile women, especially those who undergo COS, is warranted.


Mechanism of long-term potentiation of transmitter release induced by adrenaline in bullfrog sympathetic ganglia.
A mechanism of the long-term potentiation of transmitter release induced by adrenaline (ALTP) was studied by recording intracellularly the fast excitatory postsynaptic potentials (fast EPSPs). The ALTP was produced during the blockade of K+ channels at the presynaptic terminals by tetraethylammonium (TEA). The synaptic delay, possibly reflecting a relative change in the duration of an action potential at the presynaptic terminal, was not changed during the course of the ALTP. By contrast, it was significantly lengthened by TEA and other K+ channel inhibitors (4-aminopyridine and Cs+) that markedly enhanced the evoked release of transmitter. The magnitude of facilitation of the fast EPSP, induced by a conditional stimulus to the preganglionic nerve, was decreased during the generation of the ALTP, but was unchanged during the potentiation of transmitter release caused by TEA. These results, together with theoretical considerations applying the residual Ca2+ hypothesis to the facilitation, suggest that the enhancement of transmitter release during the ALTP is not caused by an increased Ca2+ influx during a presynaptic impulse owing to the blockade of K+ channel or the modulation of Ca2+ channel, but presumably is induced by a rise in the basal level of free Ca2+ in the presynaptic terminal.


The influence of delay in mononuclear cell isolation on acute myeloid leukemia phosphorylation profiles.
Mass-spectrometry (MS) based phosphoproteomics is increasingly used to explore aberrant cellular signaling and kinase driver activity, aiming to improve kinase inhibitor (KI) treatment selection in malignancies. Phosphorylation is a dynamic, highly regulated post-translational modification that may be affected by variation in pre-analytical sample handling, hampering the translational value of phosphoproteomics-based analyses. Here, we investigate the effect of delay in mononuclear cell isolation on acute myeloid leukemia (AML) phosphorylation profiles. We performed MS on immuno-precipitated phosphotyrosine (pY)-containing peptides isolated from AML samples after seven pre-defined delays before sample processing (direct processing, thirty minutes, one hour, two hours, three hours, four hours and 24 h delay). Up to four hours, pY phosphoproteomics profiles show limited variation. However, in samples processed with a delay of 24 h, we observed significant change in these phosphorylation profiles, with differential phosphorylation of 22 pY phosphopeptides (p < 0.01). This includes increased phosphorylation of pY phosphopeptides of JNK and p38 kinases indicative of stress response activation. Based on these results, we conclude that processing of AML samples should be standardized at all times and should occur within four hours after sample collection. SIGNIFICANCE: Our study provides a practical time-frame in which fresh peripheral blood samples from acute myeloid patients should be processed for phosphoproteomics, in order to warrant correct interpretation of in vivo biology. We show that up to four hours of delayed processing after sample collection, pY phosphoproteomic profiles remain stable. Extended delays are associated with perturbation of phosphorylation profiles. After a delay of 24 h, JNK activation loop phosphorylation is markedly increased and may serve as a biomarker for delayed processing. These findings are relevant for biomedical acute myeloid leukemia research, as phosphoproteomic techniques are of particular interest to investigate aberrant kinase signaling in relation to disease emergence and kinase inhibitor response. With these data, we aim to contribute to reproducible research with meaningful outcomes.


Genetics of mandible form in the mouse.
The underlying determination of phenotypic variability and covariability is described for 14 traits that define the morphological size and shape of the mature mouse mandible. Variability is partitioned into components due to direct additive and dominance genetic effects, indirect maternal additive genetic effects, genetic covariance between direct additive and indirect maternal additive effects and common and residual environmental effects. Multivariate analyses of the dimensionality of genetic variability indicate several complex and independent genetic components underlie the morphological form of the mandible. The multidimensional nature of the genetic components suggests a complex picture with regard to the consequences of selection on mandibular form.


Differential spontaneous killing of human and murine tumour cell lines by leucocyte subpopulations from carp peripheral blood leucocytes.
Cell populations from carp (Cyprinus carpio L.) peripheral blood leucocytes (PBLs) were examined for nonspecific cytotoxicities. By using monoclonal antibodies (MAbs) against carp thrombocytes (TCL-HB8) and both neutrophils and monocytes (TCL-BE8), PBLs with a density of 1.08 g ml-1 were separated into three fractions: thrombocytes, a mixture of neutrophils and monocytes, and other cells (mainly lymphocytes), and the separated cells were tested for cytotoxic activities against mammalian tumour cell lines (K562, HeLa, P815 and Yac-1 cell). Consequently, the mixture of neutrophils and monocytes exhibited cytolysis against these target cells, whereas the lymphocyte-rich and thrombocyte fractions did not show any cytolysis. To isolate only neutrophils, which do not contain monocytes, the MAb (TCL-BE8) positive cells from PBLs with a density of 1.08-1.09 g ml-1 were separated. Pure isolated neutrophils showed cytotoxic activities against K562 cells, but not P815 cells. Furthermore, analysis of the cytolytic mechanisms indicated that killing of these cells depended on H2O2 or HOCl. These results suggest that both neutrophils and monocytes are effectors for nonspecific cytotoxicity in carp PBLs, and neutrophils may be distinct from monocytes in their reactivity in cytolysis, including target cell selectivity and/or target cell sensitivity, and the cytolytic pathway. In carp, cytotoxicity of target cells can be mediated by several populations of their leucocytes which have cytotoxic capacities with various recognition and cytolytic mechanisms.


Tobramycin Liquid Crystal Nanoparticles Eradicate Cystic Fibrosis-Related Pseudomonas aeruginosa Biofilms.
Pseudomonas aeruginosa biofilms cause persistent and chronic infections, most known clinically in cystic fibrosis (CF). Tobramycin (TOB) is a standard anti-pseudomonal antibiotic; however, in biofilm infections, its efficacy severely decreases due to limited permeability across the biofilm matrix. Herewith, a biomimetic, nanostructured, lipid liquid crystal nanoparticle-(LCNP)-formulation is discovered to significantly enhance the efficacy of TOB and eradicate P. aeruginosa biofilm infections. Using an advanced, biologically-relevant co-culture model of human CF bronchial epithelial cells infected with P. aeruginosa biofilms at an air-liquid interface, nebulized TOB-LCNPs completely eradicated 1 × 109 CFU mL-1 of P. aeruginosa after two doses, a 100-fold improvement over the unformulated antibiotic. The enhanced activity of TOB is not observed with a liposomal formulation of TOB or with ciprofloxacin, an antibiotic that readily penetrates biofilms. It is demonstrated that the unique nanostructure of the LCNPs drives the enhanced penetration of TOB across the biofilm barrier, but not through the healthy lung epithelium barrier, significantly increasing the available antibiotic concentration at the site of infection. The LCNPs are an innovative strategy to improve the performance of TOB as a directed pulmonary therapy, enabling the administration of lower doses, reducing the toxicity, and amplifying the anti-biofilm activity of the anti-pseudomonal antibiotic.


Effects of prostaglandin E1 in diabetic heart.
Isolated perfused hearts from normal and alloxan-diabetic rats were studied to determine the effects of prostaglandin E1 (PGE1) on phosphorylase activation in the insulin-deficient state. Perfusion of hearts from normal and diabetic rats with 3 X 10(-5) M PGE1 for the final 2 min resulted in activation to the same extent of adenosine 3',5'-cyclic monophosphate (cAMP) accumulation, cAMP-sensitive protein kinase, and phosphorylase kinase. Although phosphorylase activation was somewhat suppressed in both the normal and diabetic heart, PGE1 produced a 36% increase in phosphorylase a in normal hearts and a 44% increase in phosphorylase a in diabetic hearts. The decreased effectiveness of phosphorylase activation by PGE1 appears to be located beyond activation of phosphorylase kinase and perhaps involves an alteration in phosphorylase sensitivity to phosphorylase kinase. Further, the activation of phosphorylase by phosphorylase kinase is hypersensitive in hearts of diabetic rats, perhaps due to a diabetes-related alteration in calcium metabolism.


Acute demyelinating optic neuritis: a review.
Acute demyelinating optic neuritis (ON) is a leading consideration in the differential diagnosis for young adults presenting with sudden onset of painful unilateral visual loss. Multiple sclerosis (MS) is believed to be the most common etiology for ON. Nearly 50% of MS patients will develop ON, and in 15-20% of cases, ON will be the initial manifestation of the illness. Conventional and emerging magnetic resonance imaging (MRI) techniques have provided greater insight into the pathophysiology of ON, and conventional MRI has also allowed clinicians to better estimate the future risk of MS. At 10 years after ON, patients with zero, one, or two or more brain lesions on T2-weighted MRI sequences demonstrated a 22%, 52%, and 56% risk of developing MS, respectively. Treatment with high dose intravenous methylprednisolone may accelerate visual recovery in patients with acute ON, but has little impact on long term visual outcome. Disease modifying therapies in patients with acute demyelinating ON should be considered as a treatment option at the time of initial presentation in those patients whose initial brain MRI shows demyelinating lesions as these therapies have been shown in to be effective at reducing the future risk of MS.


Postoperative adjuvant therapy for patients with resected non-small cell lung cancer: still controversial after all these years.
Patients with clinical stage I and II non-small cell lung cancer (NSCLC) generally are considered candidates for surgical resection, with cure rates as high as 80% reported for some subsets. Locoregional and systemic adjuvant therapies have been evaluated in patients with lymph node involvement or pathologic T3 status, although considerable controversy regarding an appropriate standard of care continues to exist. Several trials have evaluated postoperative radiation therapy, the majority of which suggest that overall survival may be only minimally improved with this adjuvant therapy, but local failure is probably reduced. Trials evaluating the role of adjuvant chemotherapy have been few, often enrolling small numbers of patients. Several recent reviews summarizing the results of these trials suggest that, although some adjuvant chemotherapy regimens may have biological activity, results have not been consistent, and further study is warranted for regimens that include newer chemotherapy agents. CNS relapse is one of the most common sites of metastasis in NSCLC, and prophylactic cranial irradiation (PCI) has been evaluated in a number of trials to reduce the risk of local failure at this site. Data from these trials strongly suggest that a prospective trial of PCI in patients with NSCLC at high risk for isolated CNS relapse is warranted. Future clinical trials evaluating new radiographic, immunologic, and molecular technologies for early detection of second primary tumors also should be considered, particularly in patients with resected T1N0M0 lesions.


Safety and dose-dependency of eptacog beta (activated) in a dose escalation study of non-bleeding congenital haemophilia A or B patients, with or without inhibitors.
Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide therapeutic options when treating bleeding in patients with congenital haemophilia who have developed inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX). This study evaluated escalated doses of a new rhFVIIa product as a prelude to selecting the doses for clinical efficacy evaluation in haemophilia patients. To assess the safety, pharmacokinetics, and laboratory pharmacodynamics of 3 doses of rhFVIIa in non-bleeding patients with congenital haemophilia A or B with or without inhibitors. Adult male patients (18-75 years old) with congenital haemophilia A or B (with or without inhibitors) received infusions of rhFVIIa at doses of 25, 75 or 225 μg/kg body weight. Ten patients were treated at each dose level, and each patient received 2 different dose levels. Descriptive methods were used to analyse the data. Administration of rhFVIIa at all doses was well tolerated. Pharmacokinetic analyses showed that peak FVIIa plasma levels (Cmax ) were approximately proportional to dose and correlated well with peak thrombin generation. Total AUC0-inf also was approximately dose proportional. Clot formation and duration correlated with FVIIa activity. Repeat doses did not produce an immunological response. In the first dose-escalation study of rhFVIIa to support product registration, eptacog beta at doses of 25, 75, and 225 μg/kg was pharmacodynamically active and well tolerated in non-bleeding patients with congenital haemophilia A or B.


Source and health implications of high toxic metal concentrations in illicit tobacco products.
A significant flux of heavy metals, among other toxins, reaches the lungs through smoking. Consequently, contaminated soil is usually avoided for tobacco cultivation. Here we compare the heavy metal concentrations in tobacco from a sample of 47 counterfeit products, representative of the substantial market for these products in the U.K., with their genuine equivalents and find significantly higher concentrations of heavy metals in the counterfeits. Trace element patterns suggest that over-application of fertilizers (phosphate and/or nitrate) is the most likely cause. Nitrogen isotopes showed no significant enrichment in 15N (delta15N range from +1.1 to +4.6% in counterfeits and from +2.5 to +3.3% in genuine tobaccos) as might be expected from a sewage or manure source of nitrate, and a mineral phosphate source is considered the more likely source of metals. Stable carbon isotopes in the same tobaccos have a wide range (delta13C -18.3 to -26.4%), indicating the influence of multiple controls during cultivation and possibly post-harvesting. A review of the health effects of heavy metal transfer from tobacco via smoke to the lungs indicates that habitual smokers of counterfeits may be risking additional harm from high levels of cadmium and possibly other metals.


Lactobacillus florum sp. nov., a fructophilic species isolated from flowers.
Three strains of fructophilic lactic acid bacteria were isolated from flowers in South Africa. The isolates formed a subcluster in the Lactobacillus buchneri phylogenetic group, closely related to Lactobacillus fructivorans, Lactobacillus homohiochii, Lactobacillus lindneri and Lactobacillus sanfranciscensis according to phylogenetic analysis based on the 16S rRNA gene sequences. Levels of DNA-DNA relatedness indicated that the three strains belonged to the same taxon and formed a genetically distinct group, well separated from their phylogenetic relatives. The three strains produced acids from only two of the 49 carbohydrates tested, i.e. D-glucose and D-fructose. D-Fructose was more rapidly fermented than D-glucose. Good growth was recorded on d-fructose or D-glucose in the presence of external electron acceptors. However, delayed growth was recorded on d-glucose without electron acceptors. The novel strains produced lactic acid, ethanol and acetic acid from D-glucose at a ratio of 1 : 0.8 : 0.2. These characteristics were distinct from other species of the genus Lactobacillus. Based on the data provided, the three isolates represent a fructophilic and novel species of the genus Lactobacillus, for which the name Lactobacillus florum sp. nov. is proposed. The type strain is F9-1(T) (=JCM 16035(T)=DSM 22689(T)=NRIC 0771(T)).


The Small RNA Repertoire of Small Extracellular Vesicles Isolated From Donor Kidney Preservation Fluid Provides a Source for Biomarker Discovery for Organ Quality and Posttransplantation Graft Function.
Delayed graft function (DGF) after kidney transplantation is negatively associated with long-term graft function and survival. Kidney function after transplantation depends on multiple factors, both donor- and recipient-associated. Prediction of posttransplantation graft function would allow timely intervention to optimize patient care and survival. Currently, graft-based predictions can be made based on histological and molecular analyses of 0-hour biopsy samples. However, such analyses are currently not implemented, as biopsy samples represent only a very small portion of the entire graft and are not routinely analyzed in all transplantation centers. Alternatives are thus required. We analyzed whether donor organ preservation fluid contain small extracellular vesicles (sEV) and whether the RNA content of these vesicles could be used as a source for potential biomarkers for posttransplantation kidney function. We provide proof of principle that sEVs are present in preservation fluid, which contain RNAs associated with donor origin. Furthermore, sEV micro RNA profiles could be associated with graft function during the first 7 days posttransplantation, but no significant correlation with DGF could be established based on the current dataset. Overall, the predictive potential of sEV RNA biomarkers together with relatively easy and noninvasive sample collection and analysis methods could pave the way towards universal screening of donor kidney-associated risk for DGF, optimized patient treatment, and subsequently improved short- and long-term graft function and survival.


Fusion of the septic knee with external hybrid fixator.
Arthrodesis is a well-recognized salvage procedure in patients with septic destruction of knee joints. It offers the opportunity for restoring weight bearing capability and significant pain relief as well as eradication of infection, but at the expense of joint motion. However, arthrodesis in order to joint sepsis may be difficult to achieve because of poor bone stock, persistent infection and soft tissue compromise. From 2000 to June 2004, in 70 consecutive patients arthrodesis of the knee was indicated. Nineteen patients were considered to have external hybrid fixator (EHF) and were therefore included to the prospective study protocol. Forty-three stabilisations of destructed knee joints were done by a modular titanium rod. In these cases bony fusion was very unlikely to be achieved because of devastating defects due to infected total knee arthroplasties. Eight patients were treated by compression nailing. In these situations EHF was not indicated. In three patients minor complication occurred. In two out of 17 patients fusion failed because of primary underestimated bony defects (11.8%). The use of EHF for arthrodeses after septic destruction of knee joints can be recommended according to our results. However, EHF will not be successful or applicable in each case. Therefore, physicians and institutions that offer this special method should have not only experiences with EHF but also with arthrodeses and alternative procedures.


Ablation of Myeloid ADK (Adenosine Kinase) Epigenetically Suppresses Atherosclerosis in ApoE-/- (Apolipoprotein E Deficient) Mice.
Objective- Monocyte-derived foam cells are one of the key players in the formation of atherosclerotic plaques. Adenosine receptors and extracellular adenosine have been demonstrated to modulate foam cell formation. ADK (adenosine kinase) is a major enzyme regulating intracellular adenosine levels, but its functional role in myeloid cells remains poorly understood. To enhance intracellular adenosine levels in myeloid cells, ADK was selectively deleted in novel transgenic mice using Cre-LoxP technology, and foam cell formation and the development of atherosclerotic lesions were determined. Approach and Results- ADK was upregulated in macrophages on ox-LDL (oxidized low-density lipoprotein) treatment in vitro and was highly expressed in foam cells in atherosclerotic plaques. Atherosclerotic mice deficient in ADK in myeloid cells were generated by breeding floxed ADK (ADKF/F) mice with LysM-Cre (myeloid-specific Cre recombinase expressing) mice and ApoE-/- (apolipoprotein E deficient) mice. Mice absent ADK in myeloid cells exhibited much smaller atherosclerotic plaques compared with controls. In vitro assays showed that ADK deletion or inhibition resulted in increased intracellular adenosine and reduced DNA methylation of the ABCG1 (ATP-binding cassette transporter G1) gene. Loss of methylation was associated with ABCG1 upregulation, enhanced cholesterol efflux, and eventually decreased foam cell formation. Conclusions- Augmentation of intracellular adenosine levels through ADK knockout in myeloid cells protects ApoE-/- mice against atherosclerosis by reducing foam cell formation via the epigenetic regulation of cholesterol trafficking. ADK inhibition is a promising approach for the treatment of atherosclerotic diseases.


Age, vascular health, and Alzheimer disease biomarkers in an elderly sample.
To investigate the associations between age, vascular health, and Alzheimer disease (AD) imaging biomarkers in an elderly sample. We identified 430 individuals along the cognitive continuum aged >60 years with amyloid positron emission tomography (PET), tau PET, and magnetic resonance imaging (MRI) scans from the population-based Mayo Clinic Study of Aging. A subset of 329 individuals had fluorodeoxyglucose (FDG) PET. We ascertained presently existing cardiovascular and metabolic conditions (CMC) from health care records and used the summation of presence/absence of hypertension, hyperlipidemia, cardiac arrhythmias, coronary artery disease, congestive heart failure, diabetes mellitus, and stroke as a surrogate for vascular health. We used global amyloid from Pittsburgh compound B PET, entorhinal cortex tau uptake (ERC-tau) from tau-PET, and neurodegeneration in AD signature regions from MRI and FDG-PET as surrogates for AD pathophysiology. We dichotomized participants into CMC = 0 (CMC- ) versus CMC > 0 (CMC+ ) and tested for age-adjusted group differences in AD biomarkers. Using structural equation models (SEMs), we assessed the impact of vascular health on AD biomarker cascade (amyloid leads to tau leads to neurodegeneration) after considering the direct and indirect age, sex, and apolipoprotein E effects. CMC+ participants had significantly greater neurodegeneration than CMC- participants but did not differ by amyloid or ERC-tau. The SEMs showed that (1) vascular health had a significant direct and indirect impact on neurodegeneration but not on amyloid; and (2) vascular health, specifically the presence of hyperlipidemia, had a significant direct impact on ERC-tau. Vascular health had quantifiably greater impact on neurodegeneration in AD regions than on amyloid deposition. Longitudinal studies are warranted to clarify the relationship between tau deposition and vascular health. Ann Neurol 2017;82:706-718.


[Gynecological clinical study in girls and adolescent victims of sexual abuse].
In spite of a very important under-registration, sexual abuse represents a social and public health problem worldwide. In Mexico, estimated prevalence of sexual abuse in women is 17.3%, half of them in youngsters under 15 years old. Most of cases have a late gynecological evaluation, due to a delay in a formal complaint. Gynecologist or pediatrician are the specialists who most frequently perform the genital examination of girls suspected of sexual abuse, due to this a complete knowledge of the topic is necessary in order to make an accurate diagnosis, register the physical findings and give prompt medical and psychological treatment as well as follow up to the patient. Despite the low risk of acquiring a sexually transmitted infection, it is important to evaluate the use of prophylactic treatment and the prevention of unwanted pregnancy with emergency contraception. Big efforts are being made by preventive programs on sexual abuse, sexually transmitted infections and unwanted pregnancy, all of which are serious problems in Mexican children and youths, and should constitute a fundamental part of the public politics on sexual health.


Protein Kinase C Life Cycle: Explained Through Systems Biology Approach.
Protein kinase C (PKC) enzymes are a family of kinases that mediate signal transduction originating at the cell surface. Most cell membranes can contain functional PKC enzymes. Aberrations in the PKC life cycle may result in cellular damage and dysfunction. For example, some cancerous cells exhibit alterations in PKC activity. Here, we use a systems biology approach to describe a molecular model of the PKC life cycle. Understanding the PKC life cycle is necessary to identify new drug targets. The PKC life cycle is composed of three key regulatory processes: maturation, activation, and termination. These processes precisely control PKC enzyme levels. This model describes the fate of PKC during de novo synthesis and PKC's lipid-mediated activation cycle. We utilize a systems biology approach to show the PKC life cycle is controlled by multiple phosphorylation and dephosphorylation events. PKC processing events can be divided into two types: maturation via processing of newly synthesized enzyme and secondary messenger-dependent activation of dormant, but catalytically competent enzyme. Newly synthesized PKC enzyme is constitutively processed through three ordered phosphorylations and stored in the cytosol as a stable, signaling-competent inactive and autoinhibited molecule. Upon extracellular stimulation, diacylglycerol (DAG) and calcium ion (Ca2+) generated at the membrane bind PKC. PKC then undergoes cytosol-to-membrane translocation and subsequent activation. Our model shows that, once activated, PKC is prone to dephosphorylation and subsequent degradation. This model also describes the role of HSP70 in stabilization and re-phosphorylation of dephosphorylated PKC, replenishing the PKC pool. Our model shows how the PKC pool responds to different intensities of extracellular stimuli? We show that blocking PHLPP dephosphorylation replenishes the PKC pool in a dose-dependent manner. This model provides a comprehensive understanding of PKC life cycle regulation.


Commentary: a strategic agenda for IUHPE's scientific and technical development.
The growth in the scientific agenda for IUHPE has reflected both the growth of the membership globally as well as the rapid development of the field. Through the numerous projects, working groups and partnerships, it can be seen that IUHPE has made much progress in such areas as health promotion infrastructure and capacity mapping, and on health promotion evidence and effectiveness. Looking to the next few years, these issues will remain core to the IUHPE scientific agenda, but more attention is needed on low and middle income countries. An additional frontier for exploration is the translation of evidence into decision-making, both within and outside the health sector, and with particular attention to health equity and social determinants of health. The further development of the scientific agenda will require collaborative work across the IUHPE executive and with the staff.


The need to develop nursing practice through innovation and practice change.
This paper examines some of the strategies that can be used to produce change in nursing. These strategies range from the power-coercive through rational-empirical to the normative-re-educative. Strategies that promote a 'bottom-up' approach are advocated for clinical nursing and some of the principal factors towards success, such as team building, the presence of a clinical leader and planning are indicated. The paper will also expand on what needs to be changed in nursing, and what the purpose of such changes are. It is argued that externally focused efforts of change, such as the organization of care or new practices are only part of the picture. The journey of change also requires an inner exploration of who we are and what are we seeking to achieve in nursing.


Protective immunogenicity of group A streptococcal M-related proteins.
Many previous studies have focused on the surface M proteins of group A streptococci (GAS) as virulence determinants and protective antigens. However, the majority of GAS isolates express M-related protein (Mrp) in addition to M protein, and both have been shown to be required for optimal virulence. In the current study, we evaluated the protective immunogenicity of Mrp to determine its potential as a vaccine component that may broaden the coverage of M protein-based vaccines. Sequence analyses of 33 mrp genes indicated that there are three families of structurally related Mrps (MrpI, MrpII, and MrpIII). N-terminal peptides of Mrps were cloned, expressed, and purified from M type 2 (M2) (MrpI), M4 (MrpII), and M49 (MrpIII) GAS. Rabbit antisera against the Mrps reacted at high titers with the homologous Mrp, as determined by enzyme-linked immunosorbent assay, and promoted bactericidal activity against GAS emm types expressing Mrps within the same family. Mice passively immunized with rabbit antisera against MrpII were protected against challenge infections with M28 GAS. Assays for Mrp antibodies in serum samples from 281 pediatric subjects aged 2 to 16 indicated that the Mrp immune response correlated with increasing age of the subjects. Affinity-purified human Mrp antibodies promoted bactericidal activity against a number of GAS representing different emm types that expressed an Mrp within the same family but showed no activity against emm types expressing an Mrp from a different family. Our results indicate that Mrps have semiconserved N-terminal sequences that contain bactericidal epitopes which are immunogenic in humans. These findings may have direct implications for the development of GAS vaccines.


In utero exposure to di-(2-ethylhexyl)phthalate and duration of human pregnancy.
Di-(2-ethylhexyl)phthalate (DEHP), the most commonly used plasticizer in flexible polyvinylchloride formulations, is a ubiquitous environmental contaminant. To date, no information exists on the potential health hazards from exposure to DEHP and/or its main metabolite, mono-(2-ethylhexyl)phthalate (MEHP), in high-risk conditions, such as pregnancy and during the neonatal period. The aim of this study was to evaluate prenatal exposure to DEHP and/or MEHP and its possible biologic effects. We measured serum DEHP and MEHP concentrations in the cord blood of 84 consecutive newborns by high-performance liquid chromatography. Relationships between DEHP/MEHP and infant characteristics were tested using Fisher's exact test, unpaired t-tests, and univariate linear regression analyses, and significant differences on univariate analysis were evaluated using multiple logistic regression analysis. We found detectable cord blood DEHP and/or MEHP concentrations in 88.1% of the samples. Either DEHP or MEHP was present in 65 of 84 (77.4%) of the examined samples. Mean concentrations of DEHP and MEHP were 1.19 +/- 1.15 microg/mL [95% confidence interval (CI), 0.93-1.44, range = 0-4.71] and 0.52 +/- 0.61 microg/mL (95% CI, 0.39-0.66, range = 0-2.94), respectively. MEHP-positive newborns showed a significantly lower gestational age compared with MEHP-negative infants (p = 0.033). Logistic regression analysis results indicated a positive correlation between absence of MEHP in cord blood and gestational age at delivery (odds ratio = 1.50, 95% CI, 1.013-2.21; p = 0.043). These findings confirm that human exposure to DEHP can begin in utero and suggest that phthalate exposure is significantly associated with a shorter pregnancy duration.


Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia.
We report here on the long-term follow-up on 162 patients with high-risk chronic lymphocytic leukemia (CLL) who have undergone hematopoietic stem cell transplantation (SCT) at a single center from 1989 to 1999. Twenty-five patients with human leukocyte antigen (HLA)-matched sibling donors underwent T-cell-depleted allogeneic SCT, and 137 patients without HLA-matched sibling donors underwent autologous SCT. The 100-day mortality was 4% for both groups, but later morbidity and mortality were negatively affected on outcome. Progression-free survival was significantly longer following autologous than allogeneic SCT, but there was no difference in overall survival and no difference in the cumulative incidence of disease recurrence or deaths without recurrence between the 2 groups. At a median follow-up of 6.5 years there is no evidence of a plateau of progression-free survival. The majority of patients treated with donor lymphocyte infusions after relapse responded, demonstrating a significant graft-versus-leukemia effect in CLL. From these findings we have altered our approach for patients with high-risk CLL and are currently exploring the role of related and unrelated allogeneic SCT following reduced-intensity conditioning regimens.


The F-box protein AhSLF-S2 controls the pollen function of S-RNase-based self-incompatibility.
Recently, we have provided evidence that the polymorphic self-incompatibility (S) locus-encoded F-box (SLF) protein AhSLF-S(2) plays a role in mediating a selective S-RNase destruction during the self-incompatible response in Antirrhinum hispanicum. To investigate its role further, we first transformed a transformation-competent artificial chromosome clone (TAC26) containing both AhSLF-S(2) and AhS(2)-RNase into a self-incompatible (SI) line of Petunia hybrida. Molecular analyses showed that both genes are correctly expressed in pollen and pistil in four independent transgenic lines of petunia. Pollination tests indicated that all four lines became self-compatible because of the specific loss of the pollen function of SI. This alteration was transmitted stably into the T1 progeny. We then transformed AhSLF-S(2) cDNA under the control of a tomato (Lycopersicon esculentum) pollen-specific promoter LAT52 into the self-incompatible petunia line. Molecular studies revealed that AhSLF-S(2) is specifically expressed in pollen of five independent transgenic plants. Pollination tests showed that they also had lost the pollen function of SI. Importantly, expression of endogenous SLF or SLF-like genes was not altered in these transgenic plants. These results phenocopy a well-known phenomenon called competitive interaction whereby the presence of two different pollen S alleles within pollen leads to the breakdown of the pollen function of SI in several solanaceaous species. Furthermore, we demonstrated that AhSLF-S(2) physically interacts with PhS(3)-RNase from the P. hybrida line used for transformation. Together with the recent demonstration of PiSLF as the pollen determinant in P. inflata, these results provide direct evidence that the polymorphic SLF including AhSLF-S(2) controls the pollen function of S-RNase-based self-incompatibility.


Fish-oil supplementation induces antiinflammatory gene expression profiles in human blood mononuclear cells.
Polyunsaturated fatty acids can have beneficial effects on human immune cells, such as peripheral blood mononuclear cells (PBMCs). However, the mechanisms of action of polyunsaturated fatty acids on immune cells are still largely unknown. The objective was to examine the effects of supplementation with the polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on whole-genome PBMC gene expression profiles, in healthy Dutch elderly subjects participating in a double-blind trial, by using whole-genome transcriptomics analysis. The subjects were randomly allocated to 1 of 3 groups: 1) consumption of 1.8 g EPA+DHA/d (n = 36), 2) consumption of 0.4 g EPA+DHA/d (n = 37), or 3) consumption of 4.0 g high-oleic acid sunflower oil (HOSF)/d (n = 38). All supplements were given in capsules. Before and after 26 wk of intervention, blood samples were collected. Microarray analysis was performed on PBMC RNA from 23 subjects who received 1.8 g EPA+DHA/d and 25 subjects who received HOSF capsules. Quantitative real-time polymerase chain reaction was performed in all 111 subjects. A high EPA+DHA intake changed the expression of 1040 genes, whereas HOSF intake changed the expression of only 298 genes. EPA+DHA intake resulted in a decreased expression of genes involved in inflammatory- and atherogenic-related pathways, such as nuclear transcription factor kappaB signaling, eicosanoid synthesis, scavenger receptor activity, adipogenesis, and hypoxia signaling. These results are the first to show that intake of EPA+DHA for 26 wk can alter the gene expression profiles of PBMCs to a more antiinflammatory and antiatherogenic status. This trial was registered at clinicaltrials.gov as NCT00124852.


Oral Cryotherapy: Prevention of Oral Mucositis and Pain Among Patients With Colorectal Cancer Undergoing Chemotherapy.
Evidence remains mixed on the benefits of oral cryotherapy in the prevention of oral mucositis and pain associated with fluorouracil-based chemotherapy. The intent of this article is to evaluate the effect of oral cryotherapy on the prevention of oral mucositis and pain among patients with colorectal cancer undergoing fluorouracil-based chemotherapy. Using an experimental study design, the authors randomly assigned 80 patients to either the intervention (n = 40) or usual care group (n = 40). Intervention group participants received oral cryotherapy in the form of ice chips held in their mouths during chemotherapy infusion. Both groups used sodium bicarbonate mouthwash postchemotherapy until the next cycle. In the usual care group, most participants reported grade 2 (moderate to life-threatening) or greater mucositis. Pain associated with mucositis was lower using oral cryotherapy, with the majority of participants in the intervention group reporting no pain.


Mechanical properties of liquid-filled shellac composite capsules.
This paper describes the mechanical properties of thin-walled, liquid-filled composite capsules consisting of calcium pectinate and shellac. In a series of experiments we measured the deformation of these particles in a spinning drop apparatus. For different pH-values we studied the elastic properties of these particles and compared the obtained results with the mechanical response measured by squeezing capsule experiments. In analogy to these experiments, we also investigated liquid-filled unloaded calcium pectinate capsules without the addition of shellac. The deformation properties of these experiments and the surface Young moduli were in good agreement. Furthermore we investigated the liquid-filled calcium pectinate and the composite capsules by NMR microscopy. These experiments allowed investigations of the membrane thickness and the kinetics of membrane growing. Additional characterizations by stress controlled small amplitude surface shear experiments of similar composed gel layers provided coherent results for the surface Young modulus.


Catechins suppress muscle inflammation and hasten performance recovery after exercise.
Catechins, abundant in green tea, exhibit many biological actions for potential clinical applications. Our purpose was to explore the potential benefits of catechin ingestion on recovery of physical performance after downhill running. Institute of Cancer Research mice were used to examine the effects of prior catechin ingestion (0.5% w/w in diet for 3 wk) on 1) wheel-running activity, 2) running endurance, 3) muscle force, and 4) muscle oxidative stress and inflammation after downhill running (16 m·min for 5 min, 18 m·min for 5 min, 20 m·min for 10 min, and 22 m·min for 130 min). Voluntary wheel-running activity and the contractile force of the isolated soleus muscle decreased (P < 0.05) after downhill running. Notably, catechin ingestion significantly alleviated the running-induced decrease in voluntary wheel-running activity by 35%; the catechin-treated mice maintained endurance running capacity (214 ± 9 vs 189 ± 10 min, P < 0.05). Furthermore, catechins alleviated (P < 0.05) the decrease in tetanic force evident in the soleus muscle after downhill running. Catechins suppressed the running-induced increases in plasma creatine phosphokinase levels by 52%; this was also true of the carbonylated protein content of the soleus muscle by 17% (P < 0.05), malondialdehyde levels by 32% in the gastrocnemius muscle, and myeloperoxidase activity of the gastrocnemius by 22% (P < 0.05). The levels of tumor necrosis factor-α, interleukin-1β, and monocyte chemoattractant protein-1 in the gastrocnemius muscle were significantly lower (P < 0.05) by 33%, 29%, and 35%, respectively, in treated mice; the expression levels of mRNAs encoding these fell in parallel. Our results suggest that long-term intake of catechins, perhaps through their antioxidant properties, attenuates downhill running-induced muscle damage by suppressing muscle oxidative stress and inflammation, hastening recovery of physical performance in mice.


Multifunctional Cinnamic Acid Derivatives.
Our research to discover potential new multitarget agents led to the synthesis of 10 novel derivatives of cinnamic acids and propranolol, atenolol, 1-adamantanol, naphth-1-ol, and (benzylamino) ethan-1-ol. The synthesized molecules were evaluated as trypsin, lipoxygenase and lipid peroxidation inhibitors and for their cytotoxicity. Compound 2b derived from phenoxyphenyl cinnamic acid and propranolol showed the highest lipoxygenase (LOX) inhibition (IC50 = 6 μΜ) and antiproteolytic activity (IC50 = 0.425 μΜ). The conjugate 1a of simple cinnamic acid with propranolol showed the higher antiproteolytic activity (IC50 = 0.315 μΜ) and good LOX inhibitory activity (IC50 = 66 μΜ). Compounds 3a and 3b, derived from methoxylated caffeic acid present a promising combination of in vitro inhibitory and antioxidative activities. The S isomer of 2b also presented an interesting multitarget biological profile in vitro. Molecular docking studies point to the fact that the theoretical results for LOX-inhibitor binding are identical to those from preliminary in vitro study.


Laparoscopic groin hernia surgery: the TAPP procedure. Transabdominal preperitoneal hernia repair.
To describe the technique and results of laparoscopic transabdominal preperitoneal (TAPP) hernia repair. A case series, with a detailed description of the operative technique. A university affiliated hospital. A consecutive series of 554 patients (494 male, 60 female) who underwent laparoscopic hernia repair in a single institution. The mean follow-up was 14 months. Laparoscopic TAPP hernia repair was performed in almost all patients. Simple closure was performed in a patient with a strangulated hernia, and a mesh-based repair was used in a patient with bilateral obturator hernias. Complications and recurrence. The laparoscopic TAPP repair was successful in 550 of the 554 patients who underwent 632 hernia repairs. conversion was necessary in 4 patients. Complications were infrequent and there were no recurrences. Only 3.4% of patients were lost to follow-up. The most frequent complications were urinary retention (27) and hematoma and seroma (38) in the early postoperative period. Neuralgia (11) and hydrocele (10) also occurred. Mesh infection occurred in only 1 patient and port-site hernias in 3 patients. there was 1 death from an acute myocardial infarction. Laparoscopic TAPP hernia repair is associated with an exceedingly low recurrence rate and an acceptable complication rate.


Cytoplasmic lipid droplets are translocated into the lumen of the Chlamydia trachomatis parasitophorous vacuole.
The acquisition of host-derived lipids is essential for the pathogenesis of the obligate intracellular bacteria Chlamydia trachomatis. Current models of chlamydial lipid acquisition center on the fusion of Golgi-derived exocytic vesicles and endosomal multivesicular bodies with the bacteria-containing parasitophorous vacuole ("inclusion"). In this study, we describe a mechanism of lipid acquisition and organelle subversion by C. trachomatis. We show by live cell fluorescence microscopy and electron microscopy that lipid droplets (LDs), neutral lipid storage organelles, are translocated from the host cytoplasm into the inclusion lumen. LDs dock at the surface of the inclusion, penetrate the inclusion membrane and intimately associate with reticulate Bodies, the replicative form of Chlamydia. The inclusion membrane protein IncA, but not other inclusion membrane proteins, cofractionated with LDs and accumulated in the inclusion lumen. Therefore, we postulate that the translocation of LDs may occur at IncA-enriched subdomains of the inclusion membrane. Finally, the chlamydial protein Lda3 may participate in the cooption of these organelles by linking cytoplasmic LDs to inclusion membranes and promoting the removal of the LD protective coat protein, adipocyte differentiation related protein (ADRP). The wholesale transport of LDs into the lumen of a parasitophorous vacuole represents a unique mechanism of organelle sequestration and subversion by a bacterial pathogen.


Screening for Obstructive Sleep Apnea in Children With Sickle Cell Disease: A Pilot Study.
Obstructive sleep apnea (OSA) and sickle cell disease (SCD) represent two complex disease processes. Current guidelines recommend that children with SCD receive polysomnography (PSG) after presenting with signs or symptoms of sleep-disordered breathing (SDB). Recent studies suggest a disproportionately elevated prevalence of SDB in the population of children with SCD, and traditional risk factors may not be evident within these patients. Further objective testing might be needed to screen all pediatric patients with SCD, even in the absence of overt signs or symptoms of OSA to prevent complications of both conditions. Prospective cohort study. Institutional review board approval was obtained. An eight-question OSA risk assessment screening questionnaire was presented prospectively to 100 consecutive patients with SCD in the pediatric hematology clinic regardless of complaints of SDB. Out of 100 patients, 51 were female. The average age, body mass index (BMI), BMI percentile, and I'M SLEEPY score of the entire cohort were 3.97 years, 15.97%, 55.4%, and 1.63%, respectively. Nineteen patients had a positive sleep apnea screening score and were referred for PSG. The average age BMI, BMI percentile, and I'M SLEEPY score for those 19 patients were 3.77%, 16.67%, 65%, and 3.95%, respectively. Ten patients completed PSG, with seven diagnosed with OSA. This pilot study demonstrates a higher incidence of SDB and OSA in children with SCD relative to the general pediatric population. Although more PSG reports and further testing is needed to determine whether the results hold, preliminary data indicate that children with SCD should at least undergo OSA screening in the office regardless of overt symptoms. 3 Laryngoscope, 131:E1022-E1028, 2021.


Insulin regulation of insulin-like growth factor-binding protein production in cultured HepG2 cells.
A human hepatoma cell line, HepG2, secretes a discrete insulin-like growth factor-binding protein (IGFBP-1) into serum-free medium, which is identical to the 25K mol wt BP in amniotic fluid and plasma. IGFBP-1 levels in vivo have been shown to be inversely correlated with circulating insulin concentrations. This study investigated the direct effects of insulin on IGFBP-1 production in vitro. Addition of insulin to HepG2 cultures induced a rapid dose-dependent decrease in IGFBP-1 synthesis and secretion independent of the glucose concentration in the medium. As assessed by ligand binding and specific RIA, levels of IGFBP-1 were 20-50% of control levels in 18-h conditioned medium from insulin-treated cells. Monoclonal antibody studies indicated that the suppressive effect of insulin on IGFBP-1 synthesis was mediated through specific interaction with the insulin receptor. Therefore, HepG2 cells respond to insulin by altering the synthesis and secretion of IGFBP-1 in a manner that mimics many of the changes in plasma IGFBP-1 levels observed in vivo and provide an in vitro model for studies of IGFBP-1 biosynthesis.


Obesity Severity and Duration Are Associated With Incident Metabolic Syndrome: Evidence Against Metabolically Healthy Obesity From the Multi-Ethnic Study of Atherosclerosis.
Although the health risks of obesity compared to normal weight have been well studied, the cumulative risk associated with chronic obesity remains unknown. Specifically, debate continues about the importance of recommending weight loss for those with metabolically healthy obesity. We hypothesized that relatively greater severity and longer duration of obesity are associated with greater incident metabolic syndrome. Design, Setting, Participants, and Measures: Using repeated measures logistic regression with random effects, we investigated the association of time-varying obesity severity and duration with incident metabolic syndrome in 2,748 Multi-Ethnic Study of Atherosclerosis participants with obesity (body mass index ≥30 kg/m2) at any visit. Obesity duration was defined as the cumulative number of visits with measured obesity and obesity severity by the World Health Organization levels I-III based on body mass index. Metabolic syndrome was defined using Adult Treatment Panel III criteria modified to exclude waist circumference. Higher obesity severity (level II odds ratio [OR], 1.32 [95% confidence interval, 1.09-1.60]; level III OR, 1.63 [1.25-2.14] vs level I) and duration (by number of visits: two visits OR, 4.43 [3.54-5.53]; three visits OR, 5.29 [4.21-6.63]; four visits OR, 5.73 [4.52-7.27]; five visits OR, 6.15 [4.19-9.03] vs one visit duration of obesity) were both associated with a higher odds of incident metabolic syndrome. Both duration and severity of obesity are positively associated with incident metabolic syndrome, suggesting that metabolically healthy obesity is a transient state in the pathway to cardiometabolic disease. Weight loss should be recommended to all individuals with obesity, including those who are currently defined as metabolically healthy.