Stratification of ovarian tumor pathology by expression of programmed cell death-1 (PD-1) and PD-ligand- 1 (PD-L1) in ovarian cancer.
Ovarian cancer is the major cause of death among gynecologic cancers with 75% of patients diagnosed with advanced disease, and only 20% of these patients having a survival duration of five years. Treatments blocking immune checkpoint molecules, programmed cell death (PD-1) or its ligand PD-ligand- I (PD-L1) have produced a beneficial and prolonged effect in a subgroup of these patients. However, there is debate in the literature concerning the prognostic value of the expression of these molecules in tumors, with immunotherapy responsiveness, and survival. We evaluated the immune landscape of the ovarian tumor microenvironment of patients, by measuring the impact of the expression of tumor PD-1, PD-L1 and infiltrating lymphocytes on stage and grade of tumors and survival, in a cohort of 55 patients with gynecologic malignancies. Most patients under study were diagnosed with advanced disease ovarian cancer. Our studies revealed that a low density of PD-1 and of PD-L1 expressing cells in tumor tissue were significantly associated with advanced disease (P = 0.028 and P = 0.033, respectively). Moreover, PD-L1 was expressed significantly more often in high grade tumors (41.5%) than in low grade tumors of patients (7.7%) (P = 0.040). The presence of CD3 or of FoxP3 infiltrating cells with PD-L1 in patient tumors did not impact the significance of the association of PD-L1 with high grade tumors (P = 0.040), and our analyses did not show an association between the presence of PD-1 or PD-L1 and survival. We conclude that a subgroup of advanced disease ovarian cancer patients with high grade tumors, expressing PD-L1, may be prime candidates for immunotherapy targeting PD-1 signaling.


Postoperative Pain Outcomes After Nuss Procedures: Comparison of Epidural Analgesia, Continuous Infusion of Local Anesthetic, and Preoperative Self-Hypnosis Training.
The Nuss procedure to correct pectus excavatum is associated with severe postoperative pain. The purpose of this retrospective study was to compare pain management outcomes of thoracic epidural analgesia and continuous infusion of local anesthetic (CILA) with and without preoperative self-hypnosis training (SHT) after Nuss procedure (4 treatment groups). Between February 2010 and December 2013, 24 of 53 adolescents who underwent Nuss procedure received SHT. Of these, 16 received thoracic epidural analgesia and 8 received CILA postoperatively. Of the 29 patients who did not receive SHT, 19 received thoracic epidural analgesia and 10 received CILA. All patients received intravenous patient-controlled opioid analgesia and intravenous nonsteroidal anti-inflammatory drugs (IVNSAIDs) and then were transitioned to oral opioids and NSAIDs. Postoperative mean and maximum pain scores, opioid (morphine equivalents) use and side effects, and hospital length of stay (LOS) were compared between groups. Patients who received SHT reported lower mean (P = .0047) and maximum (P = .0028) pain scores and used less morphine equivalents/hour over time (P = .046) compared to patients who did not receive SHT. Patients who received thoracic epidural analgesia reported lower mean (P = .0092) and maximum (P = .0083) postoperative pain scores and used more morphine equivalents/hour (P = .01) compared to those who received CILA. In addition, patients who received SHT and CILA had shorter LOS (P = .0013) than patients who received thoracic epidural analgesia without SHT. SHT before pectus excavatum repair by Nuss procedure results in less postoperative pain and requires less morphine equivalents over time for postoperative pain management. Opioid-sparing CILA, when paired with SHT, results in shorter LOS.


[Bone tumor macroelements].
Neutron-activation method was employed to determine the concentration of magnium, sodium, chlorine, phosphorus and calcium in different bone tumors. In relation to normal skeletal tissue in tumor tissues higher concentrations of chlorine and sodium but lower concentrations of calcium and phosphorus were found. The greatest changes in the macromolecular content were noted in sarcoma tissues. Bone tumors differ reliably one from the other by concentrations or ratios of macroelements concentrations, this fact may be used for the differential diagnosis.


Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide.
Many tyrosine kinase inhibitors (TKI) undergo extensive hepatic metabolism, but mechanisms of their hepatocellular uptake remain poorly understood. We hypothesized that liver uptake of TKIs is mediated by the solute carriers OATP1B1 and OATP1B3. Transport of crizotinib, dasatinib, gefitinib, imatinib, nilotinib, pazopanib, sorafenib, sunitinib, vandetanib, and vemurafenib was studied in vitro using artificial membranes (PAMPA) and HEK293 cell lines stably transfected with OATP1B1, OATP1B3, or the ortholog mouse transporter, Oatp1b2. Pharmacokinetic studies were conducted with Oatp1b2-knockout mice and humanized OATP1B1- or OATP1B3-transgenic mice. All 10 TKIs were identified as substrates of OATP1B1, OATP1B3, or both. Transport of sorafenib was investigated further, as its diffusion was particularly low in the PAMPA assay (<4%) than other TKIs that were transported by both OATP1B1 and OATP1B3. Whereas Oatp1b2 deficiency in vivo had minimal influence on parent and active metabolite N-oxide drug exposure, plasma levels of the glucuronic acid metabolite of sorafenib (sorafenib-glucuronide) were increased more than 8-fold in Oatp1b2-knockout mice. This finding was unrelated to possible changes in intrinsic metabolic capacity for sorafenib-glucuronide formation in hepatic or intestinal microsomes ex vivo. Ensuing experiments revealed that sorafenib-glucuronide was itself a transported substrate of Oatp1b2 (17.5-fold vs. control), OATP1B1 (10.6-fold), and OATP1B3 (6.4-fold), and introduction of the human transporters in Oatp1b2-knockout mice provided partial restoration of function. These findings signify a unique role for OATP1B1 and OATP1B3 in the elimination of sorafenib-glucuronide and suggest a role for these transporters in the in vivo handling of glucuronic acid conjugates of drugs.


Parent and child usual source of care and children's receipt of health care services.
PURPOSE In the United States, children who have a usual source of care (USC) have better access to health care than those who do not, but little is known about how parental USC affects children's access. We examined the association between child and parent USC patterns and children's access to health care services. METHODS We undertook a secondary analysis of nationally representative, cross-sectional data from children participating in the 2002-2007 Medical Expenditure Panel Survey (n = 56,302). We assessed 10 outcome measures: insurance coverage gaps, no doctor visits in the past year, less than yearly dental visits, unmet medical and prescription needs, delayed care, problems getting care, and unmet preventive counseling needs regarding healthy eating, regular exercise, car safety devices, and bicycle helmets. RESULTS Among children, 78.6% had a USC and at least 1 parent with a USC, whereas 12.4% had a USC but no parent USC. Children with a USC but no parent USC had a higher likelihood of several unmet needs, including an insurance coverage gap (adjusted risk ratio [aRR] 1.33; 95% confidence interval [CI], 1.21-1.47), an unmet medical or prescription need (aRR 1.70; 95% CI 1.09-2.65), and no yearly dental visits (aRR 1.12; 95% CI 1.06-1.18), compared with children with a USC whose parent(s) had a USC. CONCLUSIONS Among children with a USC, having no parent USC was associated with a higher likelihood of reporting unmet needs when compared with children whose parent(s) had a USC. Policy reforms should ensure access to a USC for all family members.


[VIGILA: a tool for the epidemiologic surveillance of transmissible diseases].
It is described an instrument for the epidemiological surveillance of communicable diseases (VIGILA) that is based on the generalization of a modification of the statistical model proposed by Serfling for the prognosis of the endemic levels of the rates of communicable diseases in a period of 52 weeks (1 year). The comparison made between the observed rates and the prognosticated rates allows to detect unusual patterns of this indicator. The observation of rates over the higher limit of the prognosis interval during successive periods is suggested as a signal of alert. The introduction of this method in a computer program allows its application in the epidemiological surveillance units at the different levels of the health system.


Tropism of Tanapox virus infection in primary human cells.
Tanapox virus (TPV) belongs to the genus Yatapoxvirus and causes a relatively benign zoonotic disease in man, with symptoms that resemble a mild version of human monkeypox. In order to investigate the underlying mechanisms of TPV pathogenesis, the tropism and replication characteristics of TPV were examined in a variety of primary human cells. A GFP expressing TPV (TPV-GFP) was constructed and used to infect primary human dermal fibroblasts (pHDFs) and peripheral blood mononuclear cells (PBMCs), both of which are believed to be major in vivo targets of poxvirus infection. pHDFs fully supported productive replication and cell-cell spread of TPV-GFP. However, induction of cell cycle arrest in pHDFs by contact mediated inhibition or rapamycin treatment eliminated the ability of TPV to fully stimulate cell cycle progression and dramatically reduced viral replication. TPV-GFP-infected human PBMCs were screened for permissiveness by FACS analysis. CD14+ cells (monocytes) were the primary cellular target for TPV infection. A small proportion of CD3+ cells (T cells) were positive for GFP expression, yet TPV was not able to replicate and spread in cultured peripheral blood lymphocytes, regardless of their state of activation. Primary human monocytes, however, demonstrated robust TPV replication, yet these cells no longer supported replication of TPV once they differentiated into macrophages. This unique ex vivo tropism of TPV gives key insights into the basis for the self-limiting pathogenicity of TPV in man.


Atypical presentation of spine bone metastasis in prostate cancer mimicking Pott's disease.
A 55-year-old man was hospitalized for a low back pain lasting for 3 months. Spinal MRI revealed a suggestive aspect of multilevel discitis L5-S1-S2 with paravertebral abscess. A thoraco-abdominal CT scan confirmed the presence of multiple pathological lymph nodes in several locations, bilateral micronodular pulmonary infiltrate; it also showed mirror bone erosions of vertebral L5 and S1 endplates, suggestive of disseminated tuberculosis with lung involvement and lymphadenopathy. A discovertebral L5-S1 biopsy was performed confirming the diagnosis of metastatic prostatic adenocarcinoma including a tumor infiltration of the intervertebral disc, without arguments for a septic processus superimposed without tuberculosis granuloma. Although rare, cases of metastases located at the disco-vertebral junction including prostatic cancer have already been described, and should be known to the clinician. The differential diagnosis with an infectious spondylodiscitis can be difficult in some case around the vertebral disc and in case of epiduritis and soft tissues involvement on MRI sequences. Disco-vertebral biopsy remains the cornerstone of the diagnosis.


Ductal carcinoma in situ (DCIS) in Karachi.
To study the frequency of ductal carcinoma in situ (DCIS) in a large pathology series. DCIS is a proliferation of non-invasive, malignant epithelial cells within the ductolobular system of the breast. It is a heterogeneous entity with several morphologic variants that differ in gross appearance, growth pattern, cytologic features, mammography, and malignant potential. The data of The Aga Khan University' Pathology Department, diagnosed on the basis of histopathology, during a 6-year period (1st January 1998 to 31st December 2003) was reviewed, all cases of DCIS studied, and data was analyzed with the help of analytical software SPSS. Thirty-eight cases of DCIS were reported to the Aga Khan University Pathology Department, during a 6-year period (1998 to 2003), comprising approximately 1% of all breast cancers reported to the unit in the same period. The mean age of the patients at diagnosis was 48.95 years (CI 95% 44.6; 53.3). Approximately half the cases occurred in the 45-54 year age group (figure 1). Two cases (5.3%) were recurrences with previous lumpectomy scars. Comedo necrosis was observed in five (13.2%) cases, whereas 33 (86.8%) cases were non-comedo type. The clinical presentation was a palpable mass (92.1%), nipple discharge (5.3%) or clinically occult lesions diagnosed on mammography (2.6%). Approximately half the patients presented with a grade 2 disease. Atypical ductal hyperplasia was observed in a third of the cases, predominantly associated with a grade 1 and 2 disease. The estrogen and, progesterone receptor status was studied in 12 (31.6%) cases. Estrogen positivity was observed in 11 (91.7%) cases and progesterone positivity in 7 (58.3%) cases. Microcalcification was observed in four (10.6%) cases. The cases reported in this study are the indolent grade 1 or 2 cases with a non-comedo pattern, and a positive estrogen and progesterone receptor status. If untreated, only 40% of these innocuous forms of DCIS become invasive over a time span of approximately 25-30 years. In Pakistan we are missing the more aggressive forms of DCIS which have a shorter transition to invasive carcinoma.


Dimensional accuracy of computer-aided design/computer-assisted manufactured orbital prostheses.
The aim of this research was to assess the dimensional accuracy of orbital prostheses based on reversed images generated by computer-aided design/computer-assisted manufacturing (CAD/CAM) using computed tomography (CT) scans. CT scans of the faces of 15 adults, men and women older than 25 years of age not bearing any congenital or acquired craniofacial defects, were processed using CAD software to produce 30 reversed three-dimensional models of the orbital region. These models were then processed using the CAM system by means of selective laser sintering to generate surface prototypes of the volunteers' orbital regions. Two moulage impressions of the faces of each volunteer were taken to manufacture 15 pairs of casts. Orbital defects were created on the right or left side of each cast. The surface prototypes were adapted to the casts and then flasked to fabricate silicone prostheses. The establishment of anthropometric landmarks on the orbital region and facial midline allowed for the data collection of 31 linear measurements, used to assess the dimensional accuracy of the orbital prostheses and their location on the face. The comparative analyses of the linear measurements taken from the orbital prostheses and the opposite sides that originated the surface prototypes demonstrated that the orbital prostheses presented similar vertical, transversal, and oblique dimensions, as well as similar depth. There was no transverse or oblique displacement of the prostheses. From a clinical perspective, the small differences observed after analyzing all 31 linear measurements did not indicate facial asymmetry. The dimensional accuracy of the orbital prostheses suggested that the CAD/CAM system assessed herein may be applicable for clinical purposes.


Interaction between propofol and sulfisoxazole in mice an in vivo and in vitro study.
The effect of sulfisoxazole on the propofol response has been investigated in an animal model. Doses of propofol (0, 50, 75 and 100 mg/Kg intraperitoneal route) were administered to control (n = 36) and sulfisoxazole pretreated mice (n = 36). The impairment of righting reflex and struggle response were evaluated before and 5, 10, 15, 20, 30, 40, 50 and 60 minutes after propofol administration. Ten minutes after administration of the different doses of propofol, total plasma concentration was measured in both groups by high performance liquid chromatography Protein binding displacement was evaluated in vitro by the ultrafiltration technique. Pretreatment with sulfisoxazole produced an important enhancement in the effect of propofol in both tests. This change was reflected in a significant increase in the area under the time-effect curve (p < 0.001) and in a shift of the log dose-effect relationship to the left. Sulfisoxazole itself did not produce any effect on either test. ED50 for the righting reflex was significantly reduced from 114 mg/kg to 64 mg/kg in sulfisoxazole pretreated groups and it fell from 87 mg/kg to 43 mg/kg for the struggle response test. No changes in the total plasma concentration and protein binding were observed. On the basis of these results, it was concluded that a clinical interaction could be expected but this cannot be explained by an alteration in the protein binding.


A possible etiological role for ascorbate in calculi formation.
Studies of recurrent stone formers indicated that they have significantly increased urinary oxalate and decreased ascorbate excretions. Results of oral and intravenous administration of ascorbate indicate an enhanced production of oxalate from ascorbate in recurrent calcium stone formers as compared with normal persons and that most of this oxalate is generated in the gut.


Gastric cancer. Treatment of advanced disease and new drugs.
Gastric cancer is most chemosensitive among gastrointestinal tumors. However, the role of chemotherapy in advanced disease and its advantage over best supportive care has been adequately addressed only in the last decade. First generation regimens, such as 5-Fluorouracil (5-FU), Doxorubicin, Mitomycin C (FAM) have been used until early 90's, when evidence from randomized studies came up in favour of second generation regimens, such as 5-FU, Doxorubicin, high-dose Methotrexate (FAMTX), which in turn was proven less active than a third generation regimen, such as epirubicin, cisplatin, continuous infusion 5-FU (ECF) in a randomized study. Newer treatment options came up over last years. The Swiss Group for Clinical Cancer Research has carried out a randomized three-arm phase II study with ECF or docetaxel, cisplatin (TC), or docetaxel, cisplatin, 5-FU (TCF) in advanced gastric cancer. TCF has been selected as the combination to be further evaluated in a formal comparison with ECF. Oxaliplatin is being tested in advanced gastric cancer. Two recently published phase II studies of biweekly infusional 5-FU, folinic acid, and oxaliplatin have shown a considerable therapeutic activity. Irinotecan is another drug under investigation in advanced gastric cancer, both as single agent and in combination. A randomized phase II-III study of irinotecan plus cisplatin or irinotecan plus folinic acid/5-FU has recently been completed; the latter arm was proven worth undergoing a formal comparison with a standard CF regimen. Oral fluoropyrimidines represent a suitable therapeutic option in selected groups of patients. Marimastat is a matrix metalloproteinase inhibitor, whose main toxicity is musculoskeletal. A randomized phase III study of marimastat versus placebo as maintenance therapy in advanced gastric cancer has shown a significant survival advantage for the marimastat arm, both in the total patient population and in the subgroup of patients who had previously received chemotherapy. Since a clear gold standard for advanced gastric cancer does not yet exist, the inclusion of patients in well designed clinical trials is to be considered the best treatment option.


Caregiver openness in emotionally focused family therapy: A critical shift.
Through the application of a discovery-oriented task analysis, this research delineated specific therapist behaviors that resulted in a successful caregiver openness event in emotionally focused family therapy (EFFT). EFFT experts were recruited via email and asked to submit family therapy recordings where they believed a caregiver openness event occurred. Ten family therapy recordings were submitted by three experts. Within these recordings, 12 caregiver openness events were discovered and critically analyzed. Nine themes were identified and interventions therapists applied to accomplish these themes were delineated using the emotionally focused therapy-coding scheme (EFT-CS). These themes included: (1) validating and reframing the child's protected stance, (2) processing the impact of the child's unmet attachment longings, (3) validating the caregiver's blocked relational stance, (4) expanding caregiving intentions, (5) enacting the caregiver's intentions to meet the child's attachment longings, (6) processing the enactment, (7) processing and promoting caregiver accessibility to the child's response, (8) heightening the caregiver's accessible stance, and (9) enhancing shifting family dynamics. Additional findings, implications for clinical practice, training, and future research are discussed.


The effects of hyperosmosis or high pH on a dual-species biofilm of Enterococcus faecalis and Pseudomonas aeruginosa: an in vitro study.
To investigate the effect of hyperosmotic hyperosmosis or alkaline stress on a dual-species biofilm of Enterococcus faecalis and Pseudomonas aeruginosa. Biofilms were grown on glass cover slips suspended in bacterial inoculate for 96 h, after which the cover slips with attached biofilms were immersed in brain heart infusion broth (BHI-broth) with 6 mol L(-1) sodium chloride (NaCl) representing the hyperosmotic group or Ca(OH)(2), pH 12.1, representing the alkaline group. Two per cent sodium hypochlorite and BHI- broth served as positive and negative controls, respectively. After treatment, the biofilms were washed, harvested and plated on blood-agar plates after serial dilution. The bactericidal effect was assessed by determining the colony-forming units (CFU). The effect on the biofilm mass was imaged with confocal laser scanning microscopy (CLSM). Hyperosmosis reduced the CFU of both species significantly after 72 h (P < 0.0001). After 168 h, P. aeruginosa was eradicated and the E. faecalis reduction was more than 99%. High pH could not induce a significant bacterial reduction. CLSM revealed dense flocculation of the biofilms incubated in alkaline broth. Hyperosmosis effectively reduced a dual-species biofilm of E. faecalis and P. aeruginosa, whilst high pH had limited bactericidal effect in this model.


Long Noncoding RNA ZFPM2-AS1 Enhances the Malignancy of Cervical Cancer by Functioning as a Molecular Sponge of microRNA-511-3p and Consequently Increasing FGFR2 Expression.
A long noncoding RNA called ZFPM2 antisense RNA 1 (ZFPM2-AS1) has been verified as a key modulator in multiple human cancer types. Nonetheless, the expression and functions of ZFPM2-AS1 in cervical cancer remain poorly understood. Therefore, our purpose was to characterize the expression pattern, clinical value, and detailed roles of ZFPM2-AS1 in cervical cancer. Reverse-transcription quantitative PCR was carried out to measure ZFPM2-AS1 expression in cervical cancer. A Cell Counting Kit-8 assay, flow cytometry, Transwell migration and invasion assays, and a tumor xenograft experiment were conducted to determine the influence of ZFPM2-AS1 on cervical cancer cell proliferation, apoptosis, migration, and invasion in vitro and on tumor growth in vivo, respectively. ZFPM2-AS1 was found to be aberrantly upregulated in cervical cancer, and its upregulation was associated with unfavorable values of clinical parameters. A ZFPM2-AS1 knockdown significantly reduced cervical cancer cell proliferation, migration, and invasion and increased apoptosis in vitro. The ZFPM2-AS1 knockdown decelerated tumor growth of cervical cancer cells in vivo. Molecular investigation indicated that ZFPM2-AS1 acts as a molecular sponge of microRNA-511-3p (miR-511-3p) in cervical cancer cells. Fibroblast growth factor receptor 2 (FGFR2) mRNA was validated as a direct target of miR-511-3p in cervical cancer, and its expression was positively modulated by ZFPM2-AS1. The effects of the ZFPM2-AS1 knockdown on malignant characteristics of cervical cancer cells were greatly attenuated by miR-511-3p inhibition. ZFPM2-AS1 promotes cervical cancer progression through upregulation of miR-511-3p-FGFR2 axis output, thereby pointing to possible diagnostics and therapeutics based on the ZFPM2-AS1-miR-511-3p-FGFR2 pathway.


Effect of Surface Texture on the Structural Adhesive Joining Properties of Aluminum 7075 and TEPEX®.
In the process of continuous improvement of manufacturing processes, this study was developed within the framework of the Ecovoss project, based on the inclusion of lightweight and new materials parts in the automotive sector. The objective was based on the replacement of aluminum welding operations with the option of adhesive operations with other types of materials such as polyamides or, in this case, a TEPEX® composite material (Dynalite 202-c200/50% TYP 13). The aim of this work is to test the best texturing of substrate made in 7075 aluminum specimens manufactured by robotic polishing with an ABB 6640 robot. Another substrate is TEPEX composite. A structural adhesive film AF-163-2 from the 3M company (St Paul, MN, USA) is used, which must be applied according to the manufacturing procedure. The tests carried out are based on the topographic measurement of the surfaces to be joined with an Alicona focus variation microscope, and the uniaxial shear tests of adhesive samples have been analyzed. The texture of the surface failure has been analyzed, and the results confirm a significant correlation between the texture parameters of initial surfaces and maximum shear stress. The expected results should provide a better understanding of the surfaces aimed to optimize the adhesion of the studied materials.


Effect of thromboxane A2 synthetase inhibitor, OKY-046, on sputum in chronic bronchitis and diffuse panbronchiolitis.
The mechanisms of excessive sputum production are only partially understood. We speculated that a selective thromboxane (Tx) A2 synthetase inhibitor, OKY-046, now used in the treatment of asthma in Japan, could decrease excess sputum production in patients with chronic airways disease. To test this hypothesis, we carried out a double-blind, placebo-controlled study of the effects of OKY-046, administered orally at 400 mg.day-1, on the sputum of patients with chronic bronchitis and patients with diffuse panbronchiolitis. Patients treated with OKY-046 showed a significant decrease (22%) in sputum volume after 1 month, and a 39% decrease after 3 months. Although the rheological properties of the sputum and the concentrations of fucose and immunoglobulin (Ig) A in the sputum remained unchanged, significant decreases were observed in the concentrations of total protein, albumin, sialic acid and phospholipid. Since albumin and fucose are chemical markers of plasma exudation and mucus secretion, respectively, whilst sialic acid and phospholipid are derived both from serum and mucus, our results indicate that this TxA2 synthetase inhibitor reduced sputum volume by inhibiting microvascular leakage in the airway. OKY-046 may, therefore, be of value in the treatment of chronic bronchitis and diffuse panbronchiolitis.


Integrative analysis of gene expression and copy number alterations using canonical correlation analysis.
With the rapid development of new genetic measurement methods, several types of genetic alterations can be quantified in a high-throughput manner. While the initial focus has been on investigating each data set separately, there is an increasing interest in studying the correlation structure between two or more data sets. Multivariate methods based on Canonical Correlation Analysis (CCA) have been proposed for integrating paired genetic data sets. The high dimensionality of microarray data imposes computational difficulties, which have been addressed for instance by studying the covariance structure of the data, or by reducing the number of variables prior to applying the CCA. In this work, we propose a new method for analyzing high-dimensional paired genetic data sets, which mainly emphasizes the correlation structure and still permits efficient application to very large data sets. The method is implemented by translating a regularized CCA to its dual form, where the computational complexity depends mainly on the number of samples instead of the number of variables. The optimal regularization parameters are chosen by cross-validation. We apply the regularized dual CCA, as well as a classical CCA preceded by a dimension-reducing Principal Components Analysis (PCA), to a paired data set of gene expression changes and copy number alterations in leukemia. Using the correlation-maximizing methods, regularized dual CCA and PCA+CCA, we show that without pre-selection of known disease-relevant genes, and without using information about clinical class membership, an exploratory analysis singles out two patient groups, corresponding to well-known leukemia subtypes. Furthermore, the variables showing the highest relevance to the extracted features agree with previous biological knowledge concerning copy number alterations and gene expression changes in these subtypes. Finally, the correlation-maximizing methods are shown to yield results which are more biologically interpretable than those resulting from a covariance-maximizing method, and provide different insight compared to when each variable set is studied separately using PCA. We conclude that regularized dual CCA as well as PCA+CCA are useful methods for exploratory analysis of paired genetic data sets, and can be efficiently implemented also when the number of variables is very large.


Safety and efficacy of intraperitoneal drain placement after emergency colorectal surgery: An international, prospective cohort study.
Intraperitoneal drains are often placed during emergency colorectal surgery. However, there is a lack of evidence supporting their use. This study aimed to describe the efficacy and safety of intraperitoneal drain placement after emergency colorectal surgery. COMPlicAted intra-abdominal collectionS after colorectal Surgery (COMPASS) is a prospective, international, cohort study into which consecutive adult patients undergoing emergency colorectal surgery were enrolled (from 3 February 2020 to 8 March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included rate and time-to-diagnosis of postoperative intraperitoneal collections, rate of surgical site infections (SSIs), time to discharge and 30-day major postoperative complications (Clavien-Dindo III-V). Multivariable logistic and Cox proportional hazards regressions were used to estimate the independent association of the outcomes with drain placement. Some 725 patients (median age 68.0 years; 349 [48.1%] women) from 22 countries were included. The drain insertion rate was 53.7% (389 patients). Following multivariable adjustment, drains were not significantly associated with reduced rates (odds ratio [OR] = 1.56, 95% CI: 0.48-5.02, p = 0.457) or earlier detection (hazard ratio [HR] = 1.07, 95% CI: 0.61-1.90, p = 0.805) of collections. Drains were not significantly associated with worse major postoperative complications (OR = 1.26, 95% CI: 0.67-2.36, p = 0.478), delayed hospital discharge (HR = 1.11, 95% CI: 0.91-1.36, p = 0.303) or increased risk of SSIs (OR = 1.61, 95% CI: 0.87-2.99, p = 0.128). This is the first study investigating placement of intraperitoneal drains following emergency colorectal surgery. The safety and clinical benefit of drains remain uncertain. Equipoise exists for randomized trials to define the safety and efficacy of drains in emergency colorectal surgery.


Identification, characterization, and cell specificity of a human LINE-1 promoter.
A constructed human LINE-1 (L1Hs) element containing intact 5' and 3' untranslatable regions and an in-frame fusion between the L1Hs open reading frame 1 and the bacterial lacZ gene (p1LZ) was found to promote the expression of beta-galactosidase in a variety of transiently transfected cell types in tissue culture. Full-length RNA was detected in the transfected cells. Most of the RNA transcripts initiated at or near the beginning of the L1Hs segment. Sequences within the L1Hs segment of p1LZ were sufficient for expression of the reporter gene; however, modulation of the transcriptional regulatory region by upstream sequences was not ruled out. Deletion analysis revealed that the sequences most critical for transcription were located within the first 100 bp of L1Hs. Other sequences within the first 668 bp of L1Hs also contributed to overall expression. Expression of p1LZ was high in human teratocarcinoma cells and low in all other cell types. This pattern of cell-type-specific expression matches the known pattern of endogenous L1Hs transcription in cultured cells.


Dual Antiplatelet Therapy De-escalation Strategies.
Dual antiplatelet therapy (DAPT), the combination of aspirin (ASA), and a P2Y12 inhibitor, protects against stent thrombosis and new atherothrombotic events after a stent implantation or an acute coronary syndrome, but exposes patients to an increased risk of bleeding. In most current practices, the P2Y12 inhibitor is stopped at 6 to 12 months and ASA is continued indefinitely. The advent of safer stents, with less risk of stent thrombosis, has challenged this standard of care, however. A number of alternative strategies involving earlier de-escalation of the antiplatelet therapy have therefore been proposed. In these approaches, standard DAPT is switched to a less potent antithrombotic combination at an earlier time-point than recommended by guidelines. Three different de-escalation variations have been tested to date. The first one maintains DAPT but switches from the potent P2Y12 inhibitors ticagrelor or prasugrel to either a lower dose or to clopidogrel, while maintaining ASA. The 2 other approaches involve changing DAPT to a single antiplatelet at some earlier time-point after the percutaneous coronary intervention procedure, by stopping either the P2Y12 inhibitor or ASA. These strategies have all demonstrated some benefit in clinical trials so far, but especially the contribution of ASA in secondary prevention is clearly evolving as its role in increasing bleeding complications while not providing increased ischemic benefit is becoming more and more clear. In contemporary practice, the type and duration of DAPT should now be based on an individualized decision, and the de-escalation strategies, if used wisely, can be added to the existing options.


Training medical myocologists in developing countries.
Although there has over recent years been a marked rise in the incidence of serious fungal infections, many of which are prevalent in developing countries, few facilities exist for diagnosis and research in medical mycology. In most countries, medical mycology is not taught adequately to medical students and consequently there is little awareness of the importance of fungal infections. Model teaching programmes need to be developed. Practical knowledge of mycoses, their diagnosis and treatment and also basic mycology can be disseminated through well-constructed courses and workshops. Formalized training in mycology research also needs to be introduced. To achieve all of this, expertise and additional resources need to be made available. In this regard, ISHAM can and should help.


Investigation on CT-DNA and Protein Interaction of New Pd(II) Complexes Involving Ceftazidime and 3-Amino-1,2,3-triazole: Synthesis, Characterization, Biological Impact, Anticancer Evaluation, and Molecular Docking Approaches.
Two new palladium (II) complexes, [Pd(CAZ)(OH2 )2 ]2+ (1) and [Pd(3-AT)(OH2 )2 ]2+ (2), (CAZ=ceftazidime, and 3-AT=amitrole) were synthesized and studied for their potential as anticancer drugs with low toxicity and high potency. To fully characterize these complexes, we conducted elemental analysis and FT-IR studies. Furthermore, we irradiated the complexes with Indian 60 Co gamma rays and thoroughly evaluated their antimicrobial properties. Our results demonstrate that the inhibitory activity of complexes was significantly enhanced against (G+) bacteria and fungi. Additionally, we probed the complexes' interaction with CT-DNA and BSA using various techniques, including UV-vis spectroscopy, thermal denaturation, viscometry, gel electrophoresis, and molecular docking studies. Our findings conclusively demonstrate that these complexes possess a strong binding interaction with CT-DNA via minor groove binding and/or electrostatic interactions, as well as excellent binding affinity to BSA. Finally, we conducted a cytotoxicity assay that clearly indicates these complexes hold immense promise as cell growth inhibitors against MCF-7 and HCT-116.


TNF superfamily protein-protein interactions: feasibility of small- molecule modulation.
The tumor necrosis factor (TNF) superfamily (TNFSF) contains about thirty structurally related receptors (TNFSFRs) and about twenty protein ligands that bind to one or more of these receptors. Almost all of these cell surface protein-protein interactions (PPIs) represent high-value therapeutic targets for inflammatory or immune modulation in autoimmune diseases, transplant recipients, or cancers, and there are several biologics including antibodies and fusion proteins targeting them that are in various phases of clinical development. Small-molecule inhibitors or activators could represent possible alternatives if the difficulties related to the targeting of protein-protein interactions by small molecules can be addressed. Compounds proving the feasibility of such approaches have been identified through different drug discovery approaches for a number of these TNFSFR-TNFSF type PPIs including CD40-CD40L, BAFFR-BAFF, TRAIL-DR5, and OX40-OX40L. Corresponding structural, signaling, and medicinal chemistry aspects are briefly reviewed here. While none of these small-molecule modulators identified so far seems promising enough to be pursued for clinical development, they provide proof-of-principle evidence that these interactions are susceptible to small-molecule modulation and can serve as starting points toward the identification of more potent and selective candidates.


Length oscillation induces force potentiation in infant guinea pig airway smooth muscle.
Deep inspiration counteracts bronchospasm in normal subjects but triggers further bronchoconstriction in hyperresponsive airways. Although the exact mechanisms for this contrary response by normal and hyperresponsive airways are unclear, it has been suggested that the phenomenon is related to changes in force-generating ability of airway smooth muscle after mechanical oscillation. It is known that healthy immature airways of both humans and animals exhibit hyperresponsiveness. We hypothesize that the profile of active force generation after mechanical oscillation changes with maturation and that this change contributes to the expression of airway hyperresponsiveness in juveniles. We examined the effect of an acute sinusoidal length oscillation on the force-generating ability of tracheal smooth muscle from 1 wk, 3 wk, and 2- to 3-mo-old guinea pigs. We found that the length oscillation produced 15-20% initial reduction in active force equally in all age groups. This was followed by a force recovery profile that displayed striking maturation-specific features. Unique to tracheal strips from 1-wk-old animals, active force potentiated beyond the maximal force generated before oscillation. We also found that actin polymerization was required in force recovery and that prostanoids contributed to the maturation-specific force potentiation in immature airway smooth muscle. Our results suggest a potentiated mechanosensitive contractile property of hyperresponsive airway smooth muscle. This can account for further bronchoconstriction triggered by deep inspiration in hyperresponsive airways.


[Nucleotide composition and homology of the DNA of parasitic Leptospira].
The study of DNA in parasitic leptospirae of different serovariants by the method of molecular hybridization has revealed two groups differing in their homology level. The homology of nucleic acids has been found to correlate with serological properties. The serovariants ensuring cross immunity are characterized by the high level of homology of their DNA.


Particle entrainment in dead-end pores by diffusiophoresis.
The transport of particulate matter to and from dead-end pores is difficult to achieve due to confinement effects. Diffusiophoresis is a phenomenon that results in the controlled motion of colloids along solute concentration gradients. Thus, by establishing an electrolyte concentration gradient within dead-end pores, it is possible to induce the flow of particles into and out of the pores via diffusiophoresis, as has been demonstrated recently. In this paper, we explain the pore-scale mechanism by which individual colloids are entrained in dead-end pores by diffusiophoresis. We flow particles past a series of dead-end pores in the presence of a solute concentration gradient. Our results reveal that particles execute pore-to-pore hops before ultimately being captured. We categorize an event as particle capture when the particle's trajectory terminates within the dead-end pore. Experiments and numerical simulations demonstrate that particle capture only occurs when flowing particles are positioned sufficiently close to the pore entry. Outside this capture region, the particles have insufficient diffusiophoretic velocities to induce capture and their dynamics are largely dominated by their free-stream advective velocities. We observe that the particles move closer to the device wall as they hop, thereby reducing the effect of flow advection and increasing that of diffusiophoresis. These results enhance our understanding of suspension dynamics in a driven system and have implications for the development, design, and optimization of diffusiophoretic platforms for drug delivery, cosmetics, and material recovery.


Isotopic study of L-Arginine kinetics in the lung during pseudomonas sepsis in an ovine model.
The objective of the study is to investigate how L-Arginine pulmonary metabolism is altered in response Pseudomonas aeruginosa (P. aeruginosa) induced septic conditions using an ovine model. Seven female sheep were infused with a primed-constant infusion of L-[(15)N2-guanidino, 5, 5, (2)H2] L-Arginine for 28 hs. After the initial 4 hs of the L-Arginine infusion, a continuous infusion of live Pseudomonas aeruginosa bacteria started for 24 hs. A NO synthase (NOS) inhibitor, N(G)-Methyl-L-arginine (L-NMA), infusion was added during the last 4 hs of the bacterial infusion. Blood samples were taken at specific time points for isotopic enrichment during control, septic and NOS blocking phases of the study. We observed that the level of total delivery of L-Arginine to the lungs was significantly decreased in septic phase after 24 hours of pseudomonas infusion. In contrast, the fractional uptake and metabolism of L-Arginine by the lungs was doubled during septic phase relative to the control phase (MARG-basal = 100% vs. MARG-septic = 220 ± 56%, P < 0.05). NO production in the lungs was also significantly increased. Infusion of L-NMA markedly blunted this elevated NO production and attenuated the total arginine metabolized in the septic lungs (Mnitrate-septic = 43.6 ± 5.7 vs. Mnitrate-septic + L-NMA = 13.4 ± 5.1 umol/kg/min; p < 0.05). We demonstrated sepsis induced by P. aeruginosa infusion caused an increase in the fractional uptake and metabolic rate of arginine in the lungs. Furthermore, our data suggests that arginine was mainly consumed via arginine - NO pathway, which might be responsible for this enhanced arginine metabolic activity in the septic lungs.


Bilateral posterior fracture dislocation of the shoulders following seizure.
Bilateral posterior fracture dislocation is a rare injury known to be associated with seizures. Convulsion was found to be the cause of fracture dislocation in 78% of the cases reported. The mechanism of injury was described by Shaw in 1971. The management depends largely on the severity of the injury. In many cases reported, the fracture was a large compression defect in the anteromedial aspect of the articular surface of the humeral head. It has been suggested that for defects that involve less than 20% of the articular surface closed reduction can be attempted. Rush nail or percutaneous K wires can be used to maintain reduction. Open reduction is necessary for defects that are involving 20-40% of the surface. The aim in these cases is to reconstruct the proximal humerus if possible by the use of internal fixation. If reconstruction is not feasible, a modified McLaughlin procedure can be used to prevent chronic instability of the shoulder. This procedure involves re-implanting the subscapularis tendon into the defect. Reconstructing fractures that involve more than 40% of the articular surface or 4-part fracture is not usually successful. These fractures are associated with a high the risk of avascular necrosis. Hemi-arthroplasty or total shoulder replacement is generally regarded as better option as they offer rapid recovery and eliminate the possibility of multiple procedures if fixation fails.


The effect of inhaled hexamethonium bromide and atropine sulphate on airway responsiveness to histamine.
The degree of protection against inhaled histamine achieved by inhalation of the ganglion blocker hexamethonium bromide plus placebo, hexamethonium plus atropine sulphate, and placebo plus placebo was examined in six atopic subjects, four of whom had current asthma. Hexamethonium was administered until there was systemic evidence of ganglionic blockade with a postural drop in blood pressure of 31 +/- 7.5 mm Hg (mean +/- SD) (p = 0.01) and an increase in heart rate of 30 +/- 3.1 bpm (mean +/- SD) (p = 0.01). Atropine was inhaled in a dose (18 mg nebulized during tidal breathing) known to produce systemic inhibition of cardiac and salivary cholinergic (muscarinic) receptors. The airway effects were measured by FEV1. Hexamethonium caused bronchoconstriction in all four subjects with asthma, which was reversed by atropine. The mean provocation concentration of histamine to provoke a 20% fall in FEV1 was 2.97 mg/ml after premedication with placebo, it was not different at 2.84 mg/ml after hexamethonium alone, and it increased slightly to 5.31 mg/ml after both hexamethonium and atropine (p = 0.06). The results suggest that the main effect of inhaled histamine is not by reflex bronchoconstriction but rather through stimulation of H1-receptors on airway smooth muscle. Therefore, histamine hyperresponsiveness in asthma is not primarily caused by a defect in the parasympathetic nervous supply to the airway.


Hypoglycemia in the treatment of hyperkalemia with insulin in patients with end-stage renal disease.
Hypoglycemia is common in patients with end-stage renal disease (ESRD). We identified the incidence and timing of hypoglycemia and its risk factors in hospitalized patients with ESRD after the treatment of hyperkalemia with insulin. We conducted a retrospective study of all hospitalized adult patients treated with hemodialysis who received intravenous insulin to treat hyperkalemia between 1 January 2011 and 31 December 2011. We identified patients who became hypoglycemic [blood glucose <3.3 mmol/L (60 mg/dL)] after insulin administration. Two hundred and twenty-one episodes of hyperkalemia were treated with insulin, resulting in 29 episodes of hypoglycemia (13%). Factors associated with a higher risk of hypoglycemia included no prior diagnosis of diabetes [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.0-5.1, P = 0.05], no use of diabetes medication prior to admission [OR 3.6, 95% CI 1.2-10.7, P = 0.02] and a lower pretreatment glucose level [mean 5.8 ± 0.7 mmol/L (104 ± 12 mg/dL) versus 9.0 ± 0.6 mmol/L (162 ± 11 mg/dL), P = 0.04]. Hypoglycemia occurred at a median of 2 h after insulin administration and persisted for a median of 2 h. The treatment of hyperkalemia with insulin in hospitalized patients with ESRD may be complicated by hypoglycemia. Patients with a history of diabetes are less susceptible to this complication. Our study supports the use of a protocol to provide dextrose support and blood glucose monitoring for at least 3 h after insulin treatment of hyperkalemia.


On what evidence should education concerning depression be based?
Disease depresses. As a consequence depressed mood is almost ubiquitous in medicine. This is as true for physical disorders as it is for mental disorders. Depressed mood, moreover, seldom comes alone but is generally accompanied by other troublesome phenomena. In other words, the transition from distress towards depression is a gradual one, at least from the clinical point of view. One could therefore rightfully assume, that most physicians will be well versed in diagnosing and treating depression. Regrettably that is not the case. Depression is an under-diagnosed and under-treated disorder. Hence sophisticated educational programs to enhance the diagnostic and therapeutic skills of those frequently encountering depressive and depressed patients are much in need. The Dep Relief program is a CD-ROM program well suited for this purpose. It is wide-ranging, evidence-based, easily adaptable to various audiences and scrutinized by a panel of international experts. In short, it is an important tool to disseminate up-to-date information about mood disorders.


Effect of Electroacupuncture on Urea and Creatinine Levels in the Wistar Sepsis Model.
Objective: Sepsis is a life-threatening organ dysfunction caused by dysregulation of a host's response to infections. Sepsis-one of the most common contributing factors to acute kidney injuries in critically ill patients-is caused by bacterial endotoxins that lead to excessive production of proinflammatory cytokines. This condition can be treated with few side-effects by using electroacupuncture (EA) to regulate the neuroendocrine immune system to control the production of these cytokines. A number of studies have proven that EA stimulates the vagus nerve to manage inflammatory responses through the cholinergic pathway, slowing sepsis. This study was conducted to investigate the effect of bilateral EA at ST 36 (Zusanli) on rats' renal function by measuring their levels of plasma urea and creatinine. Materials and Methods: This study was a randomized, double-blinded, laboratory experimental post-test, with both subjects and laboratory investigators blinded. Twenty-eight male Wistar rats were divided randomly into 4 groups of 7 rats each: (1) a control group; (2) a sepsis group; (3) an EA + group; and (4) a sham EA + group. EA and sham EA was applied once for 30 minutes before intraperitoneal administration of live Eschericia coli bacteria ATCC 25922. Six hours after administration of the bacteria the rats' plasma urea and creatinine levels were measured. Results: There was a statistically significant difference in the mean levels of urea (P < 0.001, 95% confidence interval (CI): 57.1-76.6) and creatinine (P = 0.005, 95% CI: 0.14-0.62) between the sepsis and control groups. Conclusions: These findings suggest that EA pretreatment at ST 36 attenuated the induced inflammatory bacteria response and mitigated acute kidney injury.


Antibody against granulin-epithelin precursor sensitizes hepatocellular carcinoma to chemotherapeutic agents.
Granulin-epithelin precursor (GEP) overexpression has been shown in many cancers with functional role on growth, and recently on regulating chemoresistance and cancer stem cell (CSC) properties. Here, we investigate the combined effect of GEP antibody and chemotherapeutic agent. Combination therapy was compared with monotherapy using hepatocellular carcinoma (HCC) cells in vitro and orthotopic liver tumor models in vivo. CD133 and related hepatic CSC marker expressions were investigated by flow cytometry. Antiproliferative and apoptotic effects and signaling mechanisms were examined by immunohistochemistry, flow cytometry, and Western blot analysis. Secretory GEP levels in the serum and culture supernatant samples were measured by ELISA. We demonstrated that HCC cells that survived under chemotherapeutic agents showed upregulation of hepatic CSC markers CD133/GEP/ABCB5, and enhanced colony and spheroid formation abilities. Importantly, GEP antibody sensitized HCC cells to the apoptosis induced by chemotherapy for both HCC cell lines and the chemoresistant subpopulations, and counteracted the chemotherapy-induced GEP/ABCB5 expressions and Akt/Bcl-2 signaling. In human HCC orthotopic xenograft models, GEP antibody treatment alone was consistently capable of inhibiting the tumor growth. Notably, combination of GEP antibody with high dose of cisplatin resulted in the eradication of all established intrahepatic tumor in three weeks. This preclinical study demonstrated that GEP antibody sensitized HCC cells to apoptosis induced by chemotherapeutic agents. Combination treatment with GEP antibody and chemotherapeutic agent has the potential to be an effective therapeutic regimen for GEP-expressing cancers.


Plasma remnant-like lipoprotein particles or LDL-C as major pathologic factors in sudden cardiac death cases.
We have previously reported that the majority of sudden cardiac death (SCD) events were associated with postprandial hyperlipidemia in Japanese subjects. In this investigation, we have compared LDL-cholesterol (LDL-C) and remnant-like lipoprotein particles (RLP) as cardiovascular risk factors in SCD cases, especially in Pokkuri death syndrome (PDS) cases who had nearly normal coronary arteries. To predict the risk of plasma RLP-cholesterol, triglyceride (RLP-C, RLP-TG) and LDL-C in fatal clinical events associated with SCD cases with or without atherosclerosis (PDS), we calculated the cut-off values and likelihood ratio of these lipoproteins from ROC analysis. Sixty-eight percent of SCD cases were above cut-off value of RLP-C (>12.8 mg/dL) versus 32% for control death cases (P<0.0001) and the likelihood ratio of RLP-C was 2.12. Significantly higher incidence of RLP-C above cut-off value (>10.1 mg/dL) was seen in PDS compared to controls (P<0.0001) and the likelihood ratio was 3.13. Similarly, significantly higher incidence of RLP-TG above cut-off values, SCD>53 mg/dL and PDS>67 mg/dL, was seen compared to controls (P<0.0001) and the likelihood ratio was 1.86 and 2.73, respectively. Further, significantly higher incidence of LDL-C above cut-off value (>93 mg/dL) was seen in SCD compared to controls (P<0.0001) and the likelihood ratio was 1.68. However, the incidence of LDL-C above cut-off value (LDL-C>106 mg/dL) was not significantly different between PDS and controls and the likelihood ratio was 1.52. In conclusion, this study has shown high levels of plasma remnant lipoproteins in PDS and that PDS cases did not present with atherosclerotic lesions or elevated LDL-C. In contrast, SCD cases showed high levels of plasma remnant lipoproteins together with elevated plasma LDL-C. Accordingly, we believe that plasma remnant lipoproteins level rather than plasma LDL-C is a major pathologic factor in cardiovascular events.


Dose and time effects of caffeine intake on human platelet adenosine A(2A) receptors : functional and biochemical aspects.
BACKGROUND-We determined whether repeated caffeine administration at different dosages and for different periods of time (400 or 600 mg/d for 1 week or 400 mg/d for 2 weeks) upregulates human platelet adenosine A(2A) receptors and is accompanied by increases in cAMP accumulation and decreases in aggregation and calcium levels after stimulation of A(2A) receptors by the selective agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine (HE-NECA). METHODS AND RESULTS-Platelets were obtained from peripheral venous blood of 45 healthy human volunteers at the end of 2 weeks of caffeine abstinence and at 12, 60, and 108 hours after the last dose of caffeine. The lowest dose of caffeine, when given for only 7 days, had no effect. Increasing the total dose, either by giving 400 mg/d for 14 days or giving 600 mg/d, resulted in binding assays performed with the adenosine A(2A) receptor radioligand [(3)H]SCH 58261 [5-amino-7(phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1, 5-c]pyrimidine], in the upregulation of A(2A) receptors. Moreover, the potency of HE-NECA to produce antiaggregatory effects, a rise in cAMP accumulation, and a decrease in calcium levels was significantly increased. CONCLUSIONS-Chronic caffeine intake can lead to upregulation of adenosine A(2A) receptors, which is accompanied by sensitization, in a time- and dose-dependent manner, to the actions of the agonist HE-NECA.


Cost implication of an early invasive strategy on weekdays and weekends in patients with acute coronary syndromes.
Early invasive intervention is associated with shorter length of stay (LOS) and similar outcomes in a delayed strategy in lower-risk patients with non-ST segment elevation acute coronary syndromes (NSTEACS), but is superior in higher-risk patients. However, early invasive intervention might be constrained by the need to mobilize the on-call team on weekends. We evaluated costs associated with an early vs delayed invasive intervention strategy, including patients who present on weekends. Health care utilization was extracted from the Timing of Intervention in Acute Coronary Syndromes (TIMACS) trial for Canadian patients from case report forms. Only direct costs were considered and only hospitalization events were included. Canadian unit costs were applied to health care resources consumed for all patients. Sensitivity and subgroup analyses were performed. Early invasive intervention reduced LOS costs by $2808 (95% confidence interval [CI], $4,629-$987). Total costs per Canadian patient for early invasive intervention were $16,579 (95% CI, $14,949-$18,209) compared with $19,517 (95% CI, $17,897-$21,136) for the delayed invasive approach. This resulted in a savings of $2938 (95% CI, $5236-$640). Findings were confirmed using bootstrap simulation. Sensitivity analyses confirmed savings regardless of proportion of cases done on weekends. All subgroup costs favoured early intervention. Early invasive strategy was cost-saving, even on weekends, for Canadian NSTEACS patients because of significant LOS savings. Because many high-risk NSTEACS patients receive delayed intervention because of weekend catheterization laboratory status, these findings support opening catheterization laboratories on weekends to facilitate the use of early invasive intervention.


Predicting the Individual Risk of Acute Severe Colitis at Diagnosis.
Acute severe colitis [ASC] is associated with major morbidity. We aimed to develop and externally validate an index that predicted ASC within 3 years of diagnosis. The development cohort included patients aged 16-89 years, diagnosed with ulcerative colitis [UC] in Oxford and followed for 3 years. Primary outcome was hospitalization for ASC, excluding patients admitted within 1 month of diagnosis. Multivariable logistic regression examined the adjusted association of seven risk factors with ASC. Backwards elimination produced a parsimonious model that was simplified to create an easy-to-use index. External validation occurred in separate cohorts from Cambridge, UK, and Uppsala, Sweden. The development cohort [Oxford] included 34/111 patients who developed ASC within a median 14 months [range 1-29]. The final model applied the sum of 1 point each for extensive disease, C-reactive protein [CRP] > 10mg/l, or haemoglobin < 12g/dl F or < 14g/dl M at diagnosis, to give a score from 0/3 to 3/3. This predicted a 70% risk of developing ASC within 3 years [score 3/3]. Validation cohorts included different proportions with ASC [Cambridge = 25/96; Uppsala = 18/298]. Of those scoring 3/3 at diagnosis, 18/18 [Cambridge] and 12/13 [Uppsala] subsequently developed ASC. Discriminant ability [c-index, where 1.0 = perfect discrimination] was 0.81 [Oxford], 0.95 [Cambridge], 0.97 [Uppsala]. Internal validation using bootstrapping showed good calibration, with similar predicted risk across all cohorts. A nomogram predicted individual risk. An index applied at diagnosis reliably predicts the risk of ASC within 3 years in different populations. Patients with a score 3/3 at diagnosis may merit early immunomodulator therapy.


Researching Eyesight Trends IN ADHD (RETINA).
There has been limited exploration of the relationship between ADHD and vision impairment, especially in relation to ADHD medication regimens and age. This study aims to examine trends in visual disorders in young patients with ADHD. We analyzed deidentified patient records from TriNetX database. Patients under 22 years old were divided into cohorts based on ADHD status and medication regimen. We compared prevalence of vision disorders between cohorts. We studied over 1 million patients. The ADHD cohort had higher rates of all visual disorders than their non-ADHD peers. Medication usage was found to have a slight impact, with non-stimulants associating with higher rates for all outcomes. Our findings suggest that the higher occurrence of visual disorders in ADHD is not primarily due to misdiagnosis or medication effects. There is a need for regular eye care in ADHD patients and further investigation into the role of ADHD medications in eye health.


Liver metastases arising from well-differentiated pancreatic endocrine neoplasms demonstrate increased VEGF-C expression.
Pancreatic endocrine neoplasms (PENs) are uncommon, generally well-differentiated neoplasms that demonstrate prominent endocrine differentiation. Although the majority of PENs remain localized, malignant spread may occur via lymphatic or hematogenous routes. Angiogenic growth factors, including the vascular endothelial growth factor (VEGF) family, have been implicated in new vessel growth and hematogenous metastases, although this has not been studied in PENs. We therefore examined 19 primary well-differentiated PENs and 7 liver metastases to determine the expression of VEGF-A and its family member VEGF-C by immunolabeling analysis. VEGF-A immunoreactivity was evident only in scattered cells throughout all lesions. VEGF-C, however, demonstrated low-to-moderate expression in primary PENs by semiquantitative histoscore analysis (factor of labeling intensity by percentage of positive cells), with significantly increased expression in liver metastases (mean histoscore indices: primary PEN, 4.7 versus liver metastases, 9.5; Student's t test; P =.002773). Microvascular density of primary PENs and liver metastases did not appear to linearly correlate with VEGF-C expression. Examination of the VEGF-C-specific receptors VEGFR-2/KDR/Flk-1 and VEGFR-3/Flt-4 demonstrated intense endothelial immunoreactivity for VEGFR-2, as well as VEGFR-2 and -3 expression on the majority of neoplastic cells, suggesting a possible role in autocrine/paracrine neoplastic growth regulation. We postulate that the upregulation of VEGF-C may be involved in PEN progression and metastases, although not via a direct proangiogenic mechanism.


Chronic obstructive pulmonary disease: getting it right. Does optimal management of chronic obstructive pulmonary disease alter disease progression and improve survival?
We live in a world where people live longer lives. The standardized mortality rate for many diseases is decreasing. Chronic obstructive pulmonary disease (COPD) is not following this trend. Over the last 10 years, interventions for COPD have been developed, but have any changed the prognosis or trajectory of this modern epidemic? We review the most recent and classical literature in order to answer this question. Recent analyses of data have clarified which interventions are effective in COPD and which are not. New studies have defined what is achievable with the current therapies. Only two interventions have been demonstrated to improve survival: smoking cessation and long-term oxygen therapy. Other treatments do reduce exacerbations, improve lung function and improve the patient's quality of life, but do not affect physiological disease progression or mortality. There is much work to do, not only to improve the treatments we have for this disease, but also to diagnose it early, intervene at the right time, reduce the treatment side-effects and most importantly understand the pathophysiology better. Moreover, we are duty bound to look at each patient and review what we are trying to achieve for each one through appropriate phenotyping as well as sometimes taking a more palliative approach.


Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations. We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines. Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75). Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).


Accessible and informative sectioned images and surface models of a cadaver head.
The sectioned images and surface models of a cadaver head in the Visible Korean Project would be more beneficial if they were accessible and informative. To this aim, 3 policies were established: (1) the data are promptly obtainable and observable; (2) the graphic data are accompanied by explaining the anatomic terms; and (3) two-dimensional images and three-dimensional models are shown together. According to the policies, the following were attempted. Two hundred thirty-five couples of sectioned images and outlined images (intervals, 1 mm) of the head were prepared. Browsing software was developed where the 2 corresponding images were displayed simultaneously. In addition, the structures in the images were recognized with the aid of automatic labeling. From the outlined images, surface models of 178 head structures were constructed. The two-dimensional surface models including the sectioned images were embedded into the three-dimensional surface models. All the models were categorized into systems and arranged to be inputted to a PDF (portable document format) file. The finalized PDF file containing comprehensive head data could be explored on Adobe Reader. If the user clicked on the surface models, their anatomic names were highlighted. The sectioned images, outlined images, and surface models in the browsing software and PDF file can be downloaded from the homepage (anatomy.co.kr) free of charge. The state-of-the-art graphic information will hopefully assist medical students in learning head anatomy. In addition, the raw data are expected to contribute to the various clinical practice simulations.


An impedance threshold device increases blood pressure in hypotensive patients.
The impedance threshold device (ITD-7) augments the vacuum created in the thorax with each inspiration, thereby enhancing blood flow from the extrathoracic venous systems into the heart. To the best of our knowledge, the ITD-7 has not previously been investigated in hypotensive patients in the emergency department (ED) or the prehospital setting. The objective of this study was to determine whether the ITD-7 would increase systolic arterial pressures in hypotensive spontaneously breathing patients. The ED study was a prospective, randomized, double-blind, sham control design. Patients with a systolic blood pressure ≤ 95 mm Hg were randomized to breathe for 10 min through an active or sham ITD. The primary endpoint was the change in systolic blood pressure measured non-invasively. The prehospital study was a prospective, non-blinded evaluation of the ITD-7 in hypotensive patients. In the ED study, the mean ± standard deviation rise in systolic blood pressure was 12.9 ± 8.5 mm Hg for patients (n = 16) treated with an active ITD-7 vs. 5.9 ± 5.9 mm Hg for patients (n = 18) treated with a sham ITD-7 (p < 0.01). In the prehospital study, the mean systolic blood pressure before the ITD-7 was 79.4 ± 10.2 mm Hg and 107.3 ± 17.6 mm Hg during ITD-7 use (n = 47 patients) (p < 0.01). During this clinical evaluation of the ITD-7 for the treatment of hypotensive patients in the ED and in the prehospital setting, use of the device significantly increased systolic blood pressure and was safe and generally well tolerated.


Photoperiodic changes in hippocampal neurogenesis and plasma metabolomic profiles in relation to depression-like behavior in mice.
Photoperiod alters affective behaviors and brain neuroplasticity in several mammalian species. We addressed whether neurogenesis and signaling pathways of insulin-like growth factor-I (IGF-I), a key modulator of neuroplasticity, are regulated by photoperiod in C57BL/6 J mice, a putative model of seasonal affective disorder. We also examined the effects of photoperiod on plasma metabolomic profiles in relation to depression-like behavior to understand a possible linkage between peripheral metabolism and behavior. Mice that were maintained under long-day conditions (LD) exhibited a higher number of 5-bromo-2'-deoxyuridine-positive cells and higher levels of astrocyte marker in the dentate gyrus of the hippocampus compared to that of mice under short-day conditions (SD). Plasma IGF-I levels and levels/expression of IGF-I signaling molecules in the hippocampus (Brn-4, NeuroD1, and phospho-Akt) involved in neuronal proliferation and differentiation were higher in the mice under LD. Metabolome analysis using plasma of the mice under LD and SD identified several metabolites that were highly correlated with immobility in the forced swim test, a depression-like behavior. Negative correlations with behavior occurred in the levels of 23 metabolites, including metabolites related to neurogenesis and antidepressant-like effects of exercise, metabolites in the biosynthesis of arginine, and the occurrence of branched chain amino acids. Three metabolites had positive correlations with the behavior, including guanidinosuccinic acid, a neurotoxin. Taken together, photoperiodic responses of neurogenesis and neuro-glial organization in the hippocampus may be involved in photoperiodic alteration of depression-like behavior, mediated through multiple pathways, including IGF-I and peripheral metabolites.


Bilateral malposition of maxillary second premolars: report of case.
A case of bilateral malposition of maxillary second premolars is reported. Different approaches for management are considered. The possible causes of the rare abnormality are discussed.


Alfentanil-oxygen anaesthesia: plasma concentrations and clinical effects during variable-rate continuous infusion for coronary artery surgery.
A variable rate continuous infusion of alfentanil 12.5-50 mg h-1, commenced after tracheal intubation, was used as the sole opioid anaesthetic agent in 14 patients undergoing coronary artery surgery. The infusion rate was adjusted to somatic responses and to maintain a stable systolic arterial pressure. Plasma alfentanil concentrations were determined throughout anaesthesia, including peaks of surgical stress and for 5 h after operation. Before cardiopulmonary bypass (CPB), a mean infusion rate of 36.6 +/- 8.9 mg h-1 minimized the frequency of hypertensive episodes and resulted in high plasma alfentanil concentrations which reached a mean peak, 1.76 +/- 0.46 micrograms ml-1 at maximal sternal spread. After CPB, a slower infusion rate, 6.9 +/- 5.8 mg h-1, afforded cardiovascular stability. Patients recovered consciousness 3.1 +/- 1.4 h after operation at a mean plasma alfentanil concentration of 0.27 +/- 0.13 micrograms ml-1. Apart from clinical response, parameters have not yet been identified which may optimize infusion rates.


Cardiac mesothelial/monocytic-incidental-excrescence: more than an artifactual lesion?
Mesothelial/monocytic incidental cardiac excrescence (MICE) is a benign finding made up of a mixture of cuboidal mesothelial cells, histiocytes and fibrine and is mainly found incidentally during open heart surgery, commonly after cardiac catheterization. Clinical importance of this lesion has been emphasized because of its potential confusion with malignancies, especially with metastatic carcinoma. We report a case of an asymptomatic 72-year-old man with incidental finding of a pericardial effusion and a small mass attached to the left appendage.


PtBi-β-CD-Ce6 Nanozyme for Combined Trimodal Imaging-Guided Photodynamic Therapy and NIR-II Responsive Photothermal Therapy.
Combined photothermal/photodynamic therapy is a promising strategy to achieve an enhanced anticancer effect. However, hypoxia is one of the representative characteristics of the microenvironment of solid tumors, which not only attenuates the therapeutic effects but also promotes tumor invasion and metastasis. Herein, a PtBi-β-CD-Ce6 nanoplatform for the generation of sustained O2 was constructed for more effective tumor therapy. In detail, the catalase (CAT)-like nanozyme, PtBi, which could decompose H2O2 to produce O2, was modified with β-cyclodextrin (β-CD). O2 would be converted into 1O2 by PtBi-β-CD-Ce6 for enhanced photodynamic therapy (PDT) under 650 nm laser irradiation. In addition, by reason of excellent absorption in the near-infrared-II (NIR-II) region, PtBi-β-CD-Ce6 was used for photoacoustic imaging (PA) and photothermal imaging (PT)-guided photothermal therapy (PTT) in the NIR-II biowindow. Furthermore, PtBi-β-CD-Ce6 could be elected to serve as a contrast agent for X-ray computed tomography (CT) imaging due to the apparent X-ray attenuation capability of the Pt and Bi elements themselves. Therefore, by integrating the advantages of overcoming the hypoxia function and photothermal effect into a single nanoplatform, PtBi-β-CD-Ce6 showed an immense possibility in multimodal imaging-guided combined PDT/PTT.


The effects of parental control and warmth on problematic internet use in adolescents: A prospective cohort study.
Problematic internet use (PIU) is a highly prevalent condition with severe adverse effects. The literature suggests that parent-child bonding and parental behavioral control exert protective effects against PIU. However, the most relevant studies rely on simplistic measurement of parenting, cross-sectional designs and mixed-aged samples. Our study analyzed the effect of maternal and paternal parenting on PIU by using a prospective design and a cohort sample of same-aged children. Data from 1,019 Czech 12-year-old sixth-graders who were followed until ninth grade were used. Maternal and paternal responsiveness and strictness were reported by children using the Parental Acceptance-Rejection Questionnaire (PARQ) and the Parental Control Scale (PCS). PIU was measured by the Excessive Internet Use Scale (EIUS). The self-reported PIU prevalence in nine-graders (15-year-old) was 8.1%. Parenting, reported by adolescents 18 months before PIU screening, showed significant relationships with PIU: parental responsiveness was negatively and moderately associated, while maternal strictness showed a weak positive association; the authoritative parenting style in both parents decreased PIU, with a PIU probability of 3.21%, while a combination of maternal authoritarian and paternal neglectful parenting was associated with PIU probability as high as 20.9%. The self-reported prevalence of PIU in Czech adolescents was found to be high. The effects of parenting on PIU were similar to the effects of parenting on other problematic behavior among adolescents. Our findings showed the need for interventions to prevent PIU by helping parents to apply optimal parenting styles.


Efficacy of Acupuncture for Treating Opioid Use Disorder in Adults: A Systematic Review and Meta-Analysis.
To assess the efficacy of acupuncture in treating opioid use disorder (OUD). Systematic review and meta-analysis. PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, ProQuest Dissertation and Theses, Allied and Complementary Medicine Database (AMED), Clinicaltrials.gov, and who.int/trialsearch were searched from inception to 23 December 2017. The methodological quality of selected studies and the quality of evidence for outcomes were assessed, respectively, by the Cochrane risk of bias assessment tool and the GRADE approach. Statistical analyses were conducted by RevMan 5.3. A total of nine studies involving 1063 participants fulfilled the inclusion criteria. The results showed that acupuncture could be more beneficial than no treatment/sham acupuncture in terms of changes in craving for opioid (MD -2.18, 95% CI -3.10 to -1.26), insomnia (MD 2.31, 95% CI 1.97 to 2.65), and depression (SMD -1.50, 95% CI -1.85 to -1.15). In addition, these findings showed that, compared to sham electroacupuncture (EA), EA had differences in alleviating symptoms of craving (SMD -0.50, 95% CI -0.94 to -0.05) and depression (SMD -1.07, 95% CI -1.88 to -0.25) and compared to sham transcutaneous acupoint electrical stimulation (TEAS), TEAS had differences in alleviating symptoms of insomnia (MD 2.31, 95% CI 1.97 to 2.65) and anxiety (MD -1.26, 95% CI -1.60 to -0.92) compared to no treatment/sham TEAS. Acupuncture could be effective in treating OUD. Moreover, EA could effectively alleviate symptoms of craving for opioid and depression, and TEAS could be beneficial in improving symptoms of insomnia and anxiety. Nevertheless, the conclusions were limited due to the low-quality and small number of included studies. PROSPERO registration number is CRD42018085063.


[A case of primary diffuse leptomeningeal gliomatosis, clinically indistinguishable from metastatic meningeal carcinomatosis].
A 65-year-old woman presented with progressive gait disturbance. She complained of appetite loss for 3 months. Her gait gradually became unsteady, and she was admitted to our hospital. On admission, slow mentation, bathyhypesthesia in left upper and both lower extremites, positive Romberg sign and wide-based gait were observed. Gd-enhanced MRI revealed mass lesions in the left temporal fossa and the cervical spinal canal with focal meningeal enhancement. Besides lesions in the central nervous system (CNS), systematic examination detected no additional malignancy. Repeated cytology of the cerebrospinal fluid was negative. After admission, her consciousness became reduced gradually. At 2 months after admission, she died of central respiratory failure. On autopsy, diffuse extension of the tumor cells was observed on the surface of CNS, and the mass lesions observed by MRI were extra-parenchymal On microscopic examination, the mass was consisted of GFAP positive malignant cells, and included perivascular pseudorosette, pseudopalisading necrosis and many mitotic cells. The diagnosis of the case was made as primary diffuse leptomeningeal gliomatosis (PDLG). PDLG is a rare disorder that is difficult to diagnose by CSF cytology. The progress of PDLG is rapid, and appropriate treatment is rarely taken. However, the combination of temozolomide and the radiotherapy performed for a glioblastoma has been reported as a possible treatment for PDLG. We emphasize that, in possible cases of PDLG, a biopsy should be performed in the early stages, especially in cases showing features similar to those of metastatic meningeal carcinomatosis and have no malignant tumors by whole body examination.


Lactobacillus acidophilus Exerts Neuroprotective Effects in Mice with Traumatic Brain Injury.
Traumatic brain injury (TBI) causes dysbiosis and intestinal barrier disruption, which further exacerbate brain damage via an inflammatory pathway. Gut microbiota remodeling by Lactobacillus acidophilus (LA) is a potential intervention. The aim of this study was to investigate the neuroprotective effects of LA in TBI and elucidated underlying mechanisms. C57BL/6 male mice (aged 8-9 wk) were subjected to weight-drop impact and gavaged with saline (TBI + vehicle) or LA (1 × 1010 CFU) (TBI + LA) on the day of injury and each day after for 1, 3, or 7 d. The sham + vehicle mice underwent craniotomy without brain injury and were gavaged with saline. Sensorimotor functions were determined pre-TBI and 1, 3, and 7 d postinjury. Indexes of neuroinflammation, peripheral inflammation, and intestinal barrier function were measured on days 3 and 7. Microbiota composition was measured 3 d postinjury. The data were mainly analyzed by 2-factor ANOVA. Compared with sham + vehicle mice, the TBI + vehicle mice exhibited impairments in the neurological severity score (+692%, day 3; +600%, day 7) and rotarod test (-58%, day 3; -45%, day 7) (P < 0.05), which were rescued by LA. The numbers of microglia (total and activated) and astrocytes and concentrations of TNF-α and IL1-β in the perilesional cortex were elevated in the TBI + vehicle mice on day 3 or 7 compared with sham + vehicle mice (P < 0.05) and were normalized by LA. Compared with sham + vehicle mice, the TBI + vehicle mice exhibited increased serum concentrations of endotoxin and TNF-α, and intestinal barrier permeability (D-lactate) on days 3 and 7 (P < 0.05), and these changes were alleviated by LA. Three days postinjury, the microbiota composition was disrupted in the TBI + vehicle mice compared with sham + vehicle mice (P < 0.05), which was restored by LA. Our results demonstrate that LA exerts neuroprotective effects that may be associated with gut microbiota remodeling in TBI mice.


[Surgical treatment of dystonia].
Dystonia is a neurological syndrome which is often progressive and disabling. The pathophysiological basis is only partly understood. Medical treatment often fails. Peripheral surgical techniques can alleviate the symptoms of many patients with diverse forms of focal dystonia. In patients with generalized dystonia, central surgical techniques are preferable. Thalamotomy is the best known technique, although the target is not fully defined. Experience with surgery of the pallidum and subthalamus is very limited, but results are promising. More studies are necessary to discover the precise potential benefit of these techniques and define the ideal candidates. It is important that such studies should be done using rigorous methodology and be similar for all groups working on this.


Action of adenosine on energetics, protein synthesis and K(+) homeostasis in teleost hepatocytes.
In a comparative study, we analysed the effects of adenosine on the energetics, protein synthesis and K(+ )homeostasis of hepatocytes from the anoxia-tolerant goldfish Carassius auratus and the anoxia-intolerant trout Oncorhynchus mykiss. The rate of oxygen consumption did not respond immediately to the addition of adenosine to the cells from either species, but showed a significant decrease in trout hepatocytes after 30 min. The anaerobic rate of lactate formation was not significantly affected by adenosine in goldfish hepatocytes, but was increased in trout cells. We also studied the effects of adenosine on the two most prominent ATP consumers in these cells, protein synthesis and Na(+)/K(+)-ATPase activity. Under aerobic conditions, adenosine inhibited protein synthesis of hepatocytes from goldfish by 51% and of hepatocytes from trout by 32%. During anoxia, the rate of protein synthesis decreased by approximately 50% in goldfish hepatocytes and by 90% in trout hepatocytes, and this decrease was not altered by the presence of adenosine. Adenosine inhibited normoxic Na(+)/K(+)-ATPase activity and K(+ )efflux by 20-35% in the cells of both species. An investigation into the mechanism underlying the inhibition of protein synthesis by adenosine indicated that, in the goldfish cells, adenosine acts via a membrane receptor-mediated pathway, i.e. the effect of adenosine was abolished by applying the A1 receptor antagonist 8-phenyltheophylline. In the trout, however, the uptake of adenosine into hepatocytes seems to be required for an effect on protein synthesis. [Ca(2+)](i) does not seem to be involved in the inhibition of protein synthesis by adenosine.


Serum and saliva sialic acid in periodontitis patients with and without cardiovascular disease.
Serum total sialic acid (sTSA) has recently been shown to be a cardiovascular risk factor. However, there is little information about the role of sTSA and TSA in saliva in periodontitis, a chronic and inflammatory disease known to be a risk factor for cardiovascular disease (CVD). We aimed to investigate the changes in sTSA and TSA levels in saliva in patients having both periodontitis and CVD versus periodontitis patients without diagnosed CVD. The study group consisted of 26 patients with proven periodontitis and 26 controls with no diagnosed systemic disease but periodontitis. sTSA and saliva TSA levels were determined by the thiobarbituric acid method, and C-reactive protein (CRP) was evaluated by the nephelometric method. The severity of periodontitis has been determined by the community periodontal index of treatment needs (CPITN). TSA in blood and saliva and CRP levels in blood were significantly increased in CVD patients compared with the control group. CPITN ranged from 2 to 4 in both groups. Significant and positive correlations were found between sTSA and saliva SA levels in patients and controls and between tooth loss and TSA both in blood and saliva. Therefore, TSA in saliva may be a useful marker similar to sTSA in CVD patients.


Integrating aprepitant and palonosetron into clinical practice: a role for the new antiemetics.
Chemotherapy-induced nausea and vomiting (CINV) are among the most feared side effects of cancer treatment. With increasingly more complex chemotherapy treatments, CINV plays an important role in determining patients' quality of life, as well as when to halt potentially lifesaving therapy. Although significant progress has been made in the treatment of CINV, patients undergoing chemotherapy continue to report that this side effect is persistent and distressing. In 2003, two new agents were added to the armamentarium of antiemetic therapy. The U.S. Food and Drug Administration approved palonosetron, a longer-acting serotonin antagonist, and aprepitant, a neurokinin-1 antagonist and the first in a new class of antiemetics, for the treatment of CINV. Although the indications for both agents are similar, they have distinct differences. Decisions regarding placement of these agents into existing antiemetic protocols can be based on national guidelines, review of the literature, and clinical experience. This article will review current antiemetic therapy with an emphasis on the new additions to the treatment of CINV. Aprepitant and palonosetron represent significant changes in the treatment of CINV. Oncology nurses need to know current approaches to maximize effective antiemetic therapy.


Characterization of a Zika Virus Isolate from Colombia.
Zika virus (Flavivirus genus) is the first mosquito-borne virus known to cause high rates of microcephaly and abortion in humans. Typically, Zika virus causes a self-limiting, systemic illness; however, the current outbreak of Zika virus in the Americas has been associated with increased rates of fetal malformations and Guillain-Barré syndrome. Very few Zika virus isolates have been described in the literature, and live viruses are needed to perform studies of pathogenesis and to develop vaccines and treatments. We isolated Zika virus, strain FLR, directly from the serum of an individual infected in Barranquilla, Colombia (December, 2015). Here, we describe the patient's clinical course and characterize strain FLR by its growth characteristics in mosquito and mammalian cells and its partial resistance to UV-inactivation. The full genome sequence of FLR was also analyzed (including the 3' un-translated region), to determine its probable geographic origin, and to pinpoint structural differences from other Zika virus strains. We anticipate that the study of this low passage, clinical isolate of Zika virus, which is available for worldwide distribution, will help uncover the mechanisms of viral replication and host immune responses contributing to the varied and sometimes severe clinical presentations seen during the current epidemic in the Americas.


[When coitus produce pain: an exploration of female sexuality in northwest Mexico].
To determine the prevalence of dyspareunia among women aged 25-54 and its associated risk factors. A cross-sectional population-based study was carried out in the city of Hermosillo, Sonora and data from 1,183 sexually active women were analyzed. A multiple logistic regression was computed to analyze the association between dyspareunia and sociodemographic characteristics, medical conditions and sexual violence. The 12-month prevalence of dyspareunia was estimated to be 12.3% (95% CI 10.5, 14.4). After adjustment for working conditions, dyspareunia was associated with younger ages (25-34 years), history of sexually transmitted diseases/pelvic inflammatory disease, chronic urinary tract infections, colitis and history of sexual violence. Increased attention to this condition by reproductive health programs and primary care services is urgently needed in Mexico.


Identification of Plant Compounds Involved in the Microbe-Plant Communication During the Coinoculation of Soybean with Bradyrhizobium elkanii and Delftia sp. strain JD2.
Delftia sp. strain JD2 is a betaproteobacterium characterized as a plant growth-promoting bacterium with a 'helper' function, enhancing the performance of rhizobial inoculant strains during the coinoculation of alfalfa and clover. In this work we analyzed i) the effect of the coinoculation with Bradyrhizobium elkanii and Delftia sp. strain JD2 strains on the performance of soybean plants and ii) the production of a few secondary plant metabolites that would explain the positive effect of coinoculation on the growth and development of soybean plants. The results showed a beneficial effect of coinoculation on soybean growth, nodulation rate, and pulse yield, with the concomitant benefit for the agricultural economy. In addition, based on a metabolomics approach, we demonstrated that a different pattern of plant metabolites is being produced at different stages of plant growth. The new information suggests that the coinoculation of soybean changes the primary and secondary metabolism of the plant, including changes in the metabolic status of main and secondary nodules within the plant. The relevance of producing a different pattern of photosynthetic and photoprotective pigments, flavonoids, organic acids, and carbohydrates are discussed. Finally, we propose that JD2 could be used together with bradyrhizobia to manipulate the chemical composition of plant tissues, promoting the nutritional benefits and health of soybean.


Δ9-Tetrahydrocannabinol (Δ9-THC) Improves Ischemia/Reperfusion Heart Dysfunction and Might Serve as a Cardioprotective Agent in the Future Treatment.
Ischemia/reperfusion (I/R) is a pivotal mechanism of organ injury during clinical stetting for example for cardiopulmonary bypasses. The generation of reactive oxygen species (ROS) during I/R induces oxidative stress that promotes endothelial dysfunction, DNA dissociation and local inflammation. In turn, those processes induce cytokine release, resulting in damage to cellular structures and cell death. One of the major psychoactive compounds of Cannabis is delta-9-tetrahydrocannabinol (Δ9-THC), which is known as an anti-inflammatory mediator. Our research aimed to test if Δ9-THC may be protective in the treatment of cardiovascular system dysfunction arising from I/R heart injury. Two experimental models were used: isolated rat hearts perfused with the Langendorff method and human cardiac myocytes (HCM) culture. Rat hearts and HCM underwent ex vivo/chemical in vitro I/R protocol with/without Δ9-THC treatment. The following parameters were measured: cell metabolic activity, morphology changes, cell damage as lactate dehydrogenase (LDH) activity, ceramide kinase (CERK) activity, ROS level, total antioxidant capacity (TAC) and heart hemodynamic parameters. Δ9-THC protected the heart, as evidenced by the improved recovery of cardiac function (p < 0.05, N = 3-6). Cells subjected to I/R showed lower cytoplasmic LDH activity, and 10 μM Δ9-THC treatment reduced cell injury and increased LDH content (p = 0.019, N = 6-9). Morphology changes of HCM-spherical shape, vacuolisation of cytoplasm and swollen mitochondria-were inhibited due to Δ9-THC treatment. I/R condition affected cell viability, but 10 μM Δ9-THC decreased the number of dead cells (p = 0.005, N = 6-9). The total level of CERK was lower in the I/R group, reflecting oxidative/nitrosative stress changes. The administration of Δ9-THC effectively increased the production of CERK to the level of aerobic control (p = 0.028, N = 6-9). ROS level was significantly decreased in I/R cells (p = 0.007, N = 6-8), confirming oxidative stress, while administration of 10 μM Δ9-THC enhanced TAC in cardiomyocytes subjected to I/R (p = 0.010, N = 6-8). Δ9-THC promotes the viability of cardiomyocytes, improves their metabolic activity, decreases cell damage and restores heart mechanical function, serving as a cardioprotective. We proposed the use of Δ9-THC as a cardioprotective drug to be, administered before onset of I/R protocol.


Burns induced by cupping therapy in a burn center in northeast china.
Cupping therapy as a curative skill has been developed and applied throughout history. Despite reports of adverse effects, this therapy is considered to be relatively safe with no systemic reviews documenting negative side effects. The aim of this study was to explore methods that avoid the adverse effects sometimes associated with this therapy. Clinical records of 14 outpatients and inpatients that visited the First Hospital of Jilin University (Changchun, China) for management of burn injuries caused by cupping therapy were retrospectively reviewed. Characteristics, history of injury, and treatment of each patient was collected and analyzed. Burn injury induced by cupping therapy was not uncommon. Most of the injuries were mild to moderate and cured by conservative methods without severe complications. The use of wet cupping was more prevalent among injured patients than dry cupping. Cupping therapy as an ancient alternative treatment is still popular with a large number of devoted practitioners. Although there is the potential for injury during the application of this therapy, this is mostly preventable. Standardized training for health care professionals and increased the awareness among the public about the proper methods to administer this therapy to avoid adverse effects is important.


Ultrasound-guided injection of polidocanol microfoam in the management of venous leg ulcers.
Venous leg ulceration is a frequent and severe complication of lower limb venous insufficiency. Compression therapy is associated with a protracted course of healing and multiple recurrences. Minimally invasive surgery (subfascial endoscopic perforating surgery) is only possible in a subset of patients with leg ulcers. Low-cost and noninvasive therapeutic procedures are needed as alternative treatments. To evaluate the efficacy and safety of sclerosant in microfoam in treating venous leg ulceration. A retrospective study of medical records, pretreatment and posttreatment color photographs, and echo Doppler in patients with venous leg ulceration. All patients were evaluated at 6 months after therapy, 70% were also evaluated at 2 years, 25% at 3 years, and 14% at 4 or more years after treatment. They were assessed for complete (100%) ulcer healing, time to wound closure, and recurrence. Private vascular surgery clinic in Granada and dermatology department at a hospital in Pamplona, Spain. Over 115 months, 116 consecutive patients (mean age [range], 57 [25-85] years) treated with ultrasound-guided injection of polidocanol microfoam (UIPM). To reduce venous hypertension, UIPM was used to selectively and progressively sclerose sources of incompetence. The number of sessions per patient varied between 1 and 17 (mean, 3.6). Complete ulcer healing, defined as full reepithelialization of the wound with absence of drainage. Recurrence was defined as epithelial breakdown in the healed limb. At 6-months' follow-up, treatment with UIPM achieved complete healing in 83% of patients (96/116), with median time to healing of 2.7 months; 7 patients were never cured, and 1 patient was lost to follow-up. There were recurrences in 10 patients. The use of UIPM to selectively and progressively sclerose incompetent veins produced by venous hypertension is highly effective to achieve a stable ulcer healing with minimal invasion, even in elderly patients. Recurrences are easily treatable with this approach. This technique may become a first-line treatment in the management of leg venous ulcers.