tbuckley/cabot-search huggingface dataset:
Amplicon-based next-generation sequencing: an effective approach for the molecular diagnosis of epidermolysis bullosa
Authors: E. Tenedini, L. Artuso, I. Bernardis, V. Artusi, A. Percesepe, L. De Rosa, R. Contin, R. Manfredini, G. Pellacani, A. Giannetti, J. Pagani, M. De Luca, E. Tagliafico
Journal: British Journal of Dermatology (2015)

Epidermolysis bullosa (EB) is caused by mutations in genes that encode proteins belonging to the epidermal-dermal junction assembly. Due to the extreme clinical/genetic heterogeneity of the disease, the current methods available for diagnosing EB involve immunohistochemistry of biopsy samples and transmission electron microscopy followed by single-candidate gene Sanger sequencing (SS), which are labour-intensive and expensive clinical pathways.According to the recently published recommendations for the diagnosis and treatment of EB, the assessment of the mutational landscape is now a fundamental step for developing a comprehensive diagnostic path. We aimed to develop a customized, cost-effective amplicon panel for the complete and accurate sequencing of all the pathogenic genes already identified in EB, and to minimize the processing time required for the execution of the test and to refine the analysis pipeline to achieve cost-effective results from the perspective of a routine laboratory set-up. Next-generation sequencing (NGS) via the parallel ultra-deep sequencing of many genes represents a proper method for reducing the processing time and costs of EB diagnostics.We developed an EB disease-comprehensive AmpliSeq panel to accomplish the NGS on an Ion Torrent Personal Genome Machine platform. The panel was performed on 10 patients with known genetic diagnoses and was then employed in eight family trios with unknown molecular footprints.The panel was successful in finding the causative mutations in all 10 patients with known mutations, fully confirming the SS data and providing proof of concept of the sensitivity, specificity and accuracy of this procedure. In addition to being consistent with the clinical diagnosis, it was also effective in the trios, identifying all of the variants, including ones that the SS missed or de novo mutations.The NGS and AmpliSeq were shown to be an effective approach for the diagnosis of EB, resulting in a cost- and time-effective 72-h procedure.
Plasma chromogranin A: a marker of serotonin release and of emesis associated with cisplatin chemotherapy.
Authors: L X Cubeddu, D T O'Connor, R J Parmer
Journal: Journal of Clinical Oncology (1995)

PURPOSE Emesis is a common side effect of cancer chemotherapy. Serotonin released from gastrointestinal enterochromaffin cells (ECC) may mediate chemotherapy-induced emesis. Since chromogranin A (CgA) is colocalized in ECC storage granules with serotonin, we tested the hypothesis that plasma CgA could mark emesis and serotonin release from ECC. PATIENTS AND METHODS The relationships between plasma CgA, serotonin release, and the development of vomiting following the first course of cisplatin chemotherapy were evaluated in 60 patients. RESULTS CgA levels increased in 59 of 60 patients (245% +/- 18% increase above baseline levels, P &lt; .001). The time course of the increase in plasma CgA matched that of emesis and of urinary 5-hydroxyindoleacetic acid (5-HIAA). Significant (P &lt; .001) positive correlations were found between the dose of cisplatin and the increases in plasma CgA, and between the changes in plasma CgA and urinary 5-HIAA after cisplatin (r = .54, n = 39, P &lt; .001). The increase in plasma CgA after cisplatin did not correlate with changes in serum lactic dehydrogenase (LDH) activity, a marker of cell toxicity or lysis. CONCLUSION Plasma CgA marks emesis and serotonin release induced by cisplatin. Since both CgA and serotonin are costored in ECC granules, we suggest that the source of release of each may be the ECC. Increases in plasma CgA are not explained by drug cytotoxicity. Exocytosis appears as the main mechanism by which cisplatin releases serotonin. This work further supports the role of serotonin as a mediator of emesis associated with cisplatin and suggests that plasma CgA level is a valuable tool in studies of chemotherapy-induced emesis.
Topical NSAIDs are better than placebo
Authors: M. Duerden, S. Barton, E. Johnstone, K. MacLean, J. Underhill, T. Walley, R A Moore, M R Tramer, D Carroll, P J Wiffen, H J McQuay
Journal: BMJ (1998)

Editor—Moore et al concluded in their study that topical non-steroidal anti-inflammatory drugs are better than placebo in acute and chronic musculoskeletal pain.1 Does this help to define their role in practice? 

While we accept that these agents are better than placebo (this is considered during drug licensing), this does not help to decide how clinically effective they are. To define a therapeutic role for these preparations2 we need comparisons with other interventions, such as oral non-steroidal anti-inflammatory drugs, topical rubefacients, or paracetamol. Of the 87 trials reviewed by Moore et al only five compared topical with oral non-steroidal anti-inflammatory drugs, and none had adequate design or power to enable comparison. 

We are also concerned about the methodology used in this review. Moore et al conclude that the trials reviewed were of a good quality. We recently reviewed this area and found that many trials had poor methodology, low numbers of patients, and short durations of treatment.3 The quality analysis used by Moore et al is simplistic and may not fully evaluate the quality of the studies. We do, however, recognise the need to use some objective quantification of quality. 

Secondly, combining results from different studies of patients with varied musculoskeletal conditions may introduce errors, and a reliable meta-analysis of these agents could be difficult.4 One of the reasons for this is that the heterogeneity of conditions being studied makes it difficult to compare one study with another. We are not sure whether using the random effects model compensates sufficiently. 

Thirdly, the authors were unable to eliminate positive publication bias. As drug companies were asked to volunteer their trial data, this bias may extend to unpublished studies. The small number of trials volunteered by drug companies reinforces this concern. 

While the authors concede that further comparisons of topical with oral non-steroidal anti-inflammatory drugs are required, their conclusion that topical agents are effective and safe is not supported by their paper. Furthermore, it gives no guidance on when these drugs should be used. Not only may this review give the wrong messages to prescribers but it may be used inappropriately to promote non-evidence based prescribing. Until data are published that compare these agents with other alternatives—such as paracetamol, other much cheaper rubefacients, and interventions such as rest, ice, compression, and elevation—their therapeutic role remains unclear. Without this evidence it is difficult to justify a large proportion of the £33 million spent on these drugs over the past year (Prescription Pricing Authority, data on file, Oct 1997).
Red blood cells affect the margination of microparticles in synthetic microcapillaries and intravital microcirculation as a function of their size and shape
Authors: Rosa D'Apolito, Giovanna Tomaiuolo, Francesca Taraballi, Silvia Minardi, Dickson Kirui, Xuewu Liu, Armando Cevenini, Roberto Palomba, Mauro Ferrari, Francesco Salvatore, Ennio Tasciotti, Stefano Guido
Journal: Journal of Controlled Release (2015)
Modelling of 3He gas diffusion in realistic 3D models of human acinar airways obtained from micro-CT images
Authors: Juan Parra-Robles, Dragos Vasilescu, James C. Hogg, Jim M. Wild
Journal: European Respiratory Journal (2014)

Introduction: Theoretical models of gas diffusion can provide information about lung microstructure from hyperpolarized 3He MRI. Current models are based on computational simulation in simplified geometries that do not reflect the complex geometry of acinar airways.

Objective: To develop a new framework for computer simulations of 3He diffusion in realistic 3D models of acinar airways generated from microCT images.

Methods: 3D MicroCT images of samples of human lungs obtained in a previous study (McDonough et al NEJM 2011) were segmented to produce a 3D airways model. Simulations of gas diffusion were performed using finite element solution of the Bloch-Torrey diffusion MR equation [Parra-Robles and Wild, J Magn Res 2013]

Results: Figure 1 shows microCT data (A), corresponding to a typical 3He MRI voxel size (7x7x7mm) and the segmented volume from a single acinus (D). A cross-section of segmented airspace mask (C) and a 3D 3He diffusivity distribution map (cm2/s) obtained from the computer simulations (D) are also shown. The diffusivity values are similar to those measured in vivo with 3He MRI. These results showed effects from branching geometry and localized diffusion that are not accounted for in current simple geometric models.

![Figure][1] 



Conclusion: MicroCT images can be used to generate models of acinar airways which allow computer simulations of gas diffusion which account for the complexity of lung microstructure.

 [1]: pending:yes
Using research findings in clinical practice
Authors: J. Main, S E Straus, D L Sackett
Journal: BMJ (1999)

Deprivation and emergency admissions for cancersOther possible explanations for findings need to be explored Editor-The reasons for Pollock and Vickers's findings about the relation between deprivation and emergency admissions for cancers remain speculative. 1To impute the differences in care to failures of primary care seems unfair at this stage.The authors discuss a range of possible explanations, but many other could also be relevant.Day case treatment may require a certain level of facilities at home that are less commonly available in deprived areas.The presence of another adult at home may also be a prerequisite.Single people may be more likely to live in deprived areas; patients from deprived areas may be more likely to have a working partner who cannot afford to take time off work or who has a job where such absences would be unacceptable.Patients with lung cancer due to smoking (more common in areas where smoking is more prevalent) may be less likely to have an operable malignancy because of concomitant disease related to smoking.The authors mention this in their discussion, but limiting the study to inpatient finished consultant episodes with a primary diagnosis of any of the three cancers of interest does not give any information about comorbidity.I hope further research will be carried out to help elucidate the reasons behind the apparently inequitable access and treatment decisions that Pollock and Vickers have found.Both qualitative and quantitative research methods could be used to study patients' and professionals' experiences as patients pass through the system.Perhaps allocation of blame should wait until such results are available.
Direct Antitumor Effect of the Polysaccharide Levan in Mice: Effects of Drug Concentration and Time and Temperature of Incubation&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN4"&gt;4&lt;/xref&gt;
Authors: Judith Leibovici, Yafit Stark
Journal: JNCI Journal of the National Cancer Institute (1984)

In vitro treatment of Lewis lung carcinoma cells with the polysaccharide levan was shown previously to reduce the oncogenicity of these cells by acting on the cell membrane. In the present study the direct effect of levan on the tumorigenicity of Lewis lung carcinoma in C57BL male mice was tested at different doses and intervals and temperatures of incubation. A dose-dependent decrease in tumorigenicity was observed: Doses of 0.5, 1, and 2 mg Ievan/2×105 cells/0.2 ml reduced tumor incidence by 30, 50, and 70%, respectively. Some degree of inhibition was observed even with a dose of 0.004 mg. The inhibitory effect was rapid; 5 minutes of incubation resulted in the same reduction in oncogenicity as 60 minutes. Inhibition at 0°C was as effective as inhibition at 37°C. The lack of temperature effect indicates that enzymatic activity probably is not involved. The data presented here, together with previous data, suggest that levan induces a physical, rather than a chemical, change in the affected tumor cells. The polysaccharide appears to be loosely, noncovalently bound to the cell membrane.
Rapid Diagnostic Testing for<i>Plasmodium vivax</i>and Nonfalciparum Malaria in Endemic Areas
Authors: Yemisi Takwoingi, Katharine Abba, Paul Garner
Journal: JAMA (2015)

<h3>Clinical Question</h3> How sensitive and specific are rapid diagnostic tests (RDTs) for diagnosing<i>Plasmodium vivax</i>and nonfalciparum malaria in endemic areas? <h3>Bottom Line</h3> Vivax-specific RDTs were highly sensitive and specific when compared with microscopy (the gold standard) for detecting<i>P vivax</i>malaria. RDTs that can only distinguish<i>Plasmodium falciparum</i>from nonfalciparum malaria were less sensitive.
Margaret McCartney: Honesty, placebos, and pain care
Authors: Margaret McCartney
Journal: BMJ (2015)

The medicine cabinet for chronic pain is-let's face it-poor.At the bottom of the ladder is paracetamol: ineffective for low back pain and, in the long term, for osteoarthritis. 1Observational data have linked the increased use of paracetamol to cardiovascular, renal, and gastrointestinal side effects and overall mortality.
High prevalence of esophageal acid exposure in very low birth weight infants presenting or not bronchopulmonary dysplasia
Authors: Thaís Mendes-Lopes, Mariana Veras, José Dirceu Ribeiro, Maria Aparecida Mezzacappa
Journal: European Respiratory Journal (2014)

Background:  A high frequency of treatment for gastroesophageal reflux (GER) disease is observed in neonates with bronchopulmonary dysplasia (BPD). The association between these illnesses is controversial. Objective : Determine by esophageal pH monitoring the prevalence of reflux index (RI ≥10%) in very low birth weight (VLBW) infants presenting or not BPD.  Methods:  A prospective cross-sectional study was conducted. Thirty-five newborns presenting BPD and 15 newborns not presenting BPD underwent distal esophageal pH monitoring during their stay in a university hospital neonatal unit. The frequency of symptoms and GER treatment were studied in both groups. Data were analyzed using Fisher9s Exact Test.  Results:  The prevalence of RI ≥10% did not differ between groups presenting (65.7%) and not BPD (93.3%); p=0.075. There was no significant difference between symptoms attributable to GER, occurred in 91.4% of newborns presenting BPD and in 73.3% of the group not presenting BPD. Antireflux treatment was introduced to 80% of the subjects presenting BPD and to 20% of patients not presenting BPD; (p Conclusions : There is a high prevalence of increased esophageal mucosal exposure to acid in VLBW infants presenting or not BPD. The symptoms attributable to GER are frequent in both groups; however, in VLBW infants not presenting BPD, a clinical progression complicated by GER is less frequent. Nevertheless, BPD is associated with a higher frequency of GER treatment, the indication of any therapeutic modality must be cautious, and the laboratory investigation associated with a clinical evaluation may contribute to a reduction in the number of unnecessary treatment.
Title of news article on zoledronic acid and bone density was misleading
Authors: S. Goh
Journal: BMJ (2015)

Basal insulin peglispro (BIL) comprises insulin lispro covalently bound to a 20-kDa polyethylene glycol (PEG) at lysine B28. The biologic fate of BIL and unconjugated PEG were examined in rats given a single 0.5-mg/kg i.v. or 2-mg/kg s.c. dose of BIL with <sup>14</sup>C label in 20-kDa PEG or <sup>125</sup>I label in lispro. Unconjugated <sup>14</sup>C-labeled 20-kDa PEG was dosed at 10 mg/kg i.v. or s.c. Blood, urine, and feces were collected up to 336 hours after dosing. Radioactivity was measured by scintillation spectrometry, and BIL was quantitated by enzyme-linked immunosorbent assay. Area under the curve and half-life for immunoreactive BIL were lower than those for both <sup>14</sup>C and <sup>125</sup>I after subcutaneous and intravenous administration. The half-lives of <sup>14</sup>C after BIL and PEG dosing were similar. The clearance of immunoreactive BIL was 2.4-fold faster than that of <sup>14</sup>C and 1.6-fold faster than <sup>125</sup>I. After a subcutaneous dose of BIL, immunoreactive BIL accounted for 31% of the circulating <sup>125</sup>I and 16% of the circulating <sup>14</sup>C, indicating extensive catabolism of BIL. Subcutaneous bioavailability of BIL was 23%–29%; bioavailability for unconjugated PEG was 78%. For unconjugated PEG, most of the <sup>14</sup>C dose was recovered in urine. For BIL, ≥86% of <sup>125</sup>I was eliminated in urine and <sup>14</sup>C was eliminated about equally in urine and feces. The major <sup>14</sup>C-labeled catabolism product of BIL in urine was 20-kDa PEG with lysine attached. The attachment of 20-kDa PEG to lispro in BIL led to a different elimination pathway for PEG compared with unconjugated 20-kDa PEG.
Abstract AS28: Phase Ib/II with expansion of patients at the mtd study of olaparib plus weekly (metronomic) carboplatin and paclitaxel in relapsed ovarian cancer
Authors: SE Rivkin, D Iriarte, H Sloan, C Wiseman, J Moon
Journal: Clinical Cancer Research (2015)

Abstract BACKGROUND: To establish the maximum-tolerated dose (MTD) and evaluate dose-limiting toxicities (DLTs) and response to therapy of combination therapy with carboplatin/paclitaxel and olaparib, an oral tablet inhibitor of poly ADP ribose polymerase (PARP), in advanced (Stage III or IV) relapsed ovarian cancer. METHODS: Eligibility required measurable disease, adequate organ function and ECOG performance status of ≤ 2. Patients had to have failed first line platinum containing chemotherapy. All patients were tested for BRCA 1 and 2 mutations. Patients received the metronomic therapy of paclitaxel 60mg/m2 IV and carboplatin AUC 2 IV weekly, 3 weeks out of 4 and increasing doses of olaparib until the maximum tolerated dose was obtained. Olaparib started at 50 mg bid administered orally for 3 consecutive days (D1-D3), every week for each cycle. Patients were assessed for toxicity and response according to the protocol. Patients received combination therapy until DLT or disease progression. RESULTS: The maximum tolerated dose was found to be olaparib 150 mg bid administered orally, three (D1-D3) consecutive days of each week of each cycle. Total number of patients enrolled in the phase 1b part of this study was 14. Median age was 58 (range 42-77). The median number of prior therapeutic regimens was 4 (range 3-8). Median number of cycles on study to date is 9.3 and the mean is 7.3. There were no grade 4 toxicities. The most common grade 3 toxicities were neutropenia (11), leukopenia (7), lymphopenia (4), anemia (4), fatigue (1) and MDS (1). There was no evidence of GI, cardiac, hepatic, pulmonary or dermatologic toxicities in any of these patients. Two patients had an allergic reaction prior to participating in the trial and once enrolled were desensitized to carboplatin for each study visit. One patient had a mild allergic reaction to the chemotherapy on trial, but did not require desensitization. 4 patients had a complete response (CR), 3 had partial response (PR), 3 had stable disease (SD), 2 had progressive disease (PD) and 2 were not evaluable. Of the 4 CR's three were BRCA mutant and 1 had no known BRCA mutation. Of the PD's one was BRCA mutant. CONCLUSION: Olaparib, an oral tablet can be safely administered with a weekly regimen of carboplatin and paclitaxel in heavily pretreated, ovarian cancer patients. This is early preliminary data. This study is ongoing with a planned total expansion of 40 additional patients at the MTD. Citation Format: Rivkin SE, Iriarte D, Sloan, H, Wiseman, C, Moon J,. Phase Ib/II with expansion of patients at the mtd study of olaparib plus weekly (metronomic) carboplatin and paclitaxel in relapsed ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS28.
Anxiety in asbestos exposed subjects involved chest CT-scan screening program
Authors: Isabelle Thaon, Ibrahim Mounchetrou-Njoya, Amandine Luc, Jean-Claude Pairon, Christophe Paris
Journal: European Respiratory Journal (2014)

Rationale: Only few data are available on psychological impact of asbestos exposure. The aim of this study was to examine the impact of delivering information on anxiety before and after CT-scan in the large Asbestos Related Disease COhort (ARDCO).  Methods: Between September 2011 and March 2012, the 4339 remaining subjects of the ARDCO cohort were invited to perform a CT-scan and to fill a Hospital Anxiety Depression (HAD) scale and a self-questionnaire concerning knowledge about asbestos-related risks. Half of them randomly selected received precise information on asbestos-related diseases incidence issued from the cohort previous analyses. Six months after CT-can all the subjects filled a 2 nd  HAD scale.  Results: At 10/01/2013, 1781 subjects had returned their 1 st  HAD scale and 321 (18.1%) of them were anxious (defined by an anxiety score equal or greater than 11). Eight hundred and forty three (47.3%) have received an information letter on asbestos-related diseases incidence issued from the cohort analyses. The information letter had a significant impact on knowledge about asbestos health risks and a non statistically significant impact on anxiety before CT-scan. Subjects who received and read the information letter had less anxiety after CT-scan than those who did not receive the letter or declared that they did not read it (13% versus 19% p=0.02).  Conclusion: Specific information about personal result after CT-scan must be provided to subjects involved in CT-scan surveillance to prevent anxiety. This should be particularly important in subjects with high level of self-perceived exposure as we had already found in this cohort of a strong correlation between asbestos exposure self-perception and anxiety.
Reduced Spinophilin But Not Microtubule-Associated Protein 2 Expression in the Hippocampal Formation in Schizophrenia and Mood Disorders: Molecular Evidence for a Pathology of Dendritic Spines
Authors: Amanda J. Law, Cynthia Shannon Weickert, Thomas M. Hyde, Joel E. Kleinman, Paul J. Harrison
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Aberrant synaptic connectivity may underlie the involvement of the hippocampus in schizophrenia. There is reasonable neuropathological evidence for a presynaptic pathology but few studies of the postsynaptic component. This study tested the hypothesis that hippocampal dendritic pathology is also present in schizophrenia. METHOD: Using in situ hybridization in sections of hippocampal formation from 10 patients with schizophrenia, 10 patients with mood disorders (three with bipolar disorder and seven with major depression), and 10 healthy comparison subjects, the authors examined the expression of two important dendritic genes: spinophilin, which serves as a marker of dendritic spines, and microtubule-associated protein 2 (MAP2), an overall dendritic marker. RESULTS: The patients with schizophrenia had lower levels of spinophilin mRNA in CA4 (hilus), CA3, the subiculum, and the entorhinal cortex than did the normal comparison subjects. The mood disorder group showed similar differences from the comparison group. MAP2 and cyclophilin mRNA did not differ between the groups in any subfield. CONCLUSIONS: Decreased spinophilin but unchanged MAP2 expression provides molecular evidence for a hippocampal dendritic pathology in schizophrenia that preferentially affects the spines. As spines are the target of most glutamatergic synapses, the data extend the evidence that excitatory synapses are particularly affected. Similar dendritic spine pathology may also occur in mood disorders.