tbuckley/cabot-search huggingface dataset:
Relationship Between the Physicochemical Properties of Lipid Nanoparticles and the Quality of siRNA Delivery to Liver Cells
Authors: Yusuke Sato, Hiroto Hatakeyama, Mamoru Hyodo, Hideyoshi Harashima
Journal: Molecular Therapy (2015)

While a variety of short interfering RNA (siRNA) delivery compounds have been developed, a deep understanding of the key parameters that determine the quality of siRNA delivery are not known with certainty. Therefore, an understanding of the factors required for the efficient, selective, and safe delivery of siRNA is a great challenge for successful siRNA delivery. Herein, we report on the development of two pH-sensitive cationic lipids and their use in examining the impact of the acid dissociation constant (pKa) value, lipase sensitivity and the size of lipid nanoparticles on the biodistribution, and efficiency and cell specificity of gene silencing in the liver. An increase in the pKa value resulted in a significant change in the intrahepatic localization of siRNA and gene-silencing efficiency in hepatocytes and liver sinusoidal endothelial cells (LSECs). The sensitivity of the pH-sensitive cationic lipid to lipases was a major factor in achieving hepatocyte-specific gene silencing. Increasing the particle size can improve the LSEC specificity of gene silencing. As a consequence, we succeeded in developing both a highly efficient, hepatocyte-specific formulation, and the most efficacious LSEC-targeted formulation reported to date. These findings will facilitate the development of more sophisticated siRNA delivery systems. While a variety of short interfering RNA (siRNA) delivery compounds have been developed, a deep understanding of the key parameters that determine the quality of siRNA delivery are not known with certainty. Therefore, an understanding of the factors required for the efficient, selective, and safe delivery of siRNA is a great challenge for successful siRNA delivery. Herein, we report on the development of two pH-sensitive cationic lipids and their use in examining the impact of the acid dissociation constant (pKa) value, lipase sensitivity and the size of lipid nanoparticles on the biodistribution, and efficiency and cell specificity of gene silencing in the liver. An increase in the pKa value resulted in a significant change in the intrahepatic localization of siRNA and gene-silencing efficiency in hepatocytes and liver sinusoidal endothelial cells (LSECs). The sensitivity of the pH-sensitive cationic lipid to lipases was a major factor in achieving hepatocyte-specific gene silencing. Increasing the particle size can improve the LSEC specificity of gene silencing. As a consequence, we succeeded in developing both a highly efficient, hepatocyte-specific formulation, and the most efficacious LSEC-targeted formulation reported to date. These findings will facilitate the development of more sophisticated siRNA delivery systems.
Case 45-1993
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Patricia M. Joseph, Eugene J. Mark
Journal: New England Journal of Medicine (1993)

Presentation of CaseA 23-year-old man with asthma was admitted to the hospital because of an increased cough with pulmonary infiltrates.There was a history of mild asthma since childhood, which was managed occasionally with short courses of prednisone. More recently, the patient required medication for asthma approximately once a year for exacerbations that were provoked by upper respiratory tract infections or by swimming and that were treated with a corticosteroid inhaler. He had never required admission to a hospital because of wheezing. He had a chronic morning cough productive of scanty clear secretions.The patient was well otherwise until . . .
A New Genetic Basis for Hemoglobin-H Disease
Authors: Lynne Pressley, D. R. Higgs, J. B. Clegg, R. P. Perrine, M. E. Pembrey, D. J. Weatherall
Journal: New England Journal of Medicine (1980)

We studied 11 families with alpha-thalassemia from the Qatif population of eastern Saudi Arabia to determine the genetic and molecular basis of hemoglobin-H disease, which is being encountered in this area with increasing frequency. The results show that there are two common alpha-thalassemia haplotypes, a deletion (-alpha/) determinant and a nondeletion (alpha alpha T/) determinant, which interact to produce a series of overlapping phenotypes. The most severe, hemoglobin-H disease, results from the homozygous state for the nondeletion determinant--a pattern of inheritance not previously recognized for this condition. Its molecular and genetic properties are thus different from those that produce the condition in Oriental or Mediterranean populations.
Urinary Hydroxyproline as an Index of Collagen Turnover in Bone
Authors: Theodore A. Dull, Philip H. Henneman
Journal: New England Journal of Medicine (1963)

HYDROXYPROLINE, a nonessential imino acid, occurs in the body almost exclusively in collagen, where it accounts for 13 per cent of the total amino acids.1 Man excretes hydroxyproline in the urine in bound and free forms.2 , 3 The free state of the imino acid accounts for less than 4 per cent of the total amount excreted. Bound hydroxyproline, presumably in a polypeptide, is released by acid hydrolysis and accounts for nearly all the urinary excretion of hydroxyproline.2 , 3 A peptide-containing hydroxyproline has been isolated from human urine.4 Guinea pigs with osteolathyrism, a disorder of bone and collagen, excrete increased quantities of hydroxyproline . . .
Oxidative stress in obese children with sleep-disordered breathing
Authors: Kim Van Hoorenbeeck, Hilde Franckx, Luc Van Gaal, Kristine Desager, Wilrfied De Backer, Stijn Verhulst
Journal: European Respiratory Journal (2011)

Background: Sleep-disordered breathing (SDB) is prevalent in obese children. It is an independent risk factor for the metabolic syndrome. Oxidative stress is a possible linking mechanism and is reflected by serum uric acid (UA).  Aim: In this prospective follow-up study we focused on the effects of SDB on oxidative stress in childhood obesity, before and after weight loss treatment.  Methods: Obese children, attending an in-patient weight reduction program, between 10 and 18 years were included consecutively. All subjects had 1 baseline and 1 follow-up visit after 4-6 months of weight loss. UA was measured at both visits. A polygraphy was performed at baseline and repeated in case of oxygen desaturation index (ODI) ≥ 2 at admission.  Results: 132 obese patients participated. Median age was 15.4 years (10.1-18.0). Mean BMI z-score was 2.72±0.42. SDB was diagnosed in 39%. At baseline, UA concentration correlated negatively with mean nocturnal SaO2 (r=-0.29; P=0.001). There was a positive correlation between UA and ODI (r=0.18; P=0.04). Regression analysis showed a significant relation between UA and ODI, also after adjusting for BMI z-score (partial r=0.18; P=0.04). Median decrease in BMI z-score was 32%. Weight loss treatment was successful in 71% of the subjects with SDB at baseline. UA concentration dropped in all patients. Improvements in UA were associated with improvements in ODI in linear regression analysis, after controlling for decrease in BMI z-score (partial r=0.41; P=0.01).  Conclusion: There exists a significant association between UA and ODI at baseline, even after controlling for BMI z-score. Changes in ODI after treatment are reflected by changes in UA, independent of the degree of weight loss.
OC-021 Monocyte oxidative burst defect is associated with susceptibility to infection in severe alcoholic hepatitis
Authors: N Vergis, W Khamri, K Beale, F Sadiq, S Atkinson, S James, R Abeles, J Ryan, A O’Brien, M Foxton, J Wendon, D Shawcross, Y Ma, C Antoniades, M Thursz
Journal: Gut (2015)

<h3>Introduction</h3> Infection is a common cause of mortality in severe alcoholic hepatitis (SAH). Monocytes are innate immune cells that play a key role in fighting infection. We sought to characterise monocyte phenotype and function in SAH and relate defects to the development of infection. <h3>Method</h3> We analysed pre-treatment blood samples from 73 patients admitted to hospital suffering from SAH (DF &gt;32), 34 healthy controls (HC) and 17 abstinent compensated cirrhotic patients (CLD). Flow cytometry was used to measure monocyte phenotype, cytokine production, phagocytosis and oxidative burst <i><i>ex vivo</i></i>. Production of superoxide (O<sub>2</sub><sup>-</sup>) was measured by luminometry and bacterial killing was assessed by counting viable <i>E. coli </i>colonies growing on agar plates after incubation with monocytes. Additionally, we evaluated the impact of <i><i>in vivo</i></i>steroid therapy on monocyte function via the <i>Steroids or Pentoxyfilline for Alcoholic Hepatitis </i>(STOPAH) clinical trial. <h3>Results</h3> The proportion of CD14<sup>+</sup><sup>+</sup>CD16<sup>+</sup><sup>+ </sup>monocytes was increased in SAH and CLD vs HC (<i>P </i>&lt; 0.003). These cells expressed elevated levels of activation marker HLA-DR (<i>P </i>&lt; 0.01) and chemokine receptor CCR-5 (.01). In addition, they produced greater TNF-α in response to lipopolysaccharide vs CD14<sup>+</sup><sup>+</sup>CD16<sup>- </sup>cells (.03). Conversely, patrolling CD14<sup>+</sup>CD16<sup>+</sup><sup>+ </sup>monocytes were reduced in SAH vs CLD and HC (.01). Phagocytosis was preserved in SAH for all subsets but monocyte oxidative burst (mOB) (<i>P </i>&lt; 0.001), O<sub>2</sub><sup>-</sup>production (.02) and bacterial killing (.01) were markedly impaired vs CLD and HC. Importantly, pre-treatment mOB defect predicted the development of infection within the subsequent two weeks of sampling with area under receiver-operator curve of 0.86 (<i>P </i>&lt; 0.02) (Figure 1). Accordingly, defective mOB was associated with death at 28 and 90 days (one-tailed .04 for both). <i>Ex vivo</i>mOB was unchanged in patients who had received 7 days steroid therapy. <h3>Conclusion</h3> Defective mOB is prevalent in patients with SAH and is strongly associated with the development of infection within the subsequent two weeks. In addition, CD14<sup>+</sup><sup>+</sup>CD16<sup>+</sup><sup>+</sup>monocytes are expanded in SAH and bear features suggestive of an inflammatory role in disease pathogenesis. Further work should seek the molecular mechanisms of these defects and components that might be amenable to therapeutic intervention. <h3>Disclosure of interest</h3> None Declared.
Emergency departments should provide range of out-of-hours services, conference hears
Authors: Nigel Hawkes
Journal: BMJ (2015)

Emergency departments should make the most of their strong brand and become the home for out-of-hours primary care and community pharmacy, nursing, and mental health teams, a King’s Fund conference in London on 22 September was told.

Clifford Mann, president of the Royal College of Emergency Medicine, said that emergency departments, universally recognised by the public, should become a hub for a range of services. Then patients attending emergency departments could have immediate access to whatever service was appropriate to their needs.

“People know all about the alternatives but still choose to use A&E [emergency departments],” he said. “The more we say don’t use it, the more it reinforces brand recognition.”

There was now a large mismatch between what …
Epidemic Measles in a Highly Vaccinated Population
Authors: D. Michael Shasby, Thomas C. Shope, Harry Downs, Kenneth L. Herrmann, Jane Polkowski
Journal: New England Journal of Medicine (1977)

During November, 1975, to May, 1976, measles occurred at a rate of 20.3 cases per 1000 in a purported immunized population, of whom historical and serologic survey revealed that 9 per cent had no history of either measles illness or vaccination and 18 per cent did not have detectable measles antibody. Antibody was detectable in 92 per cent of those vaccinated at greater than or equal to 13 months, 80 per cent at 12 months and 67 per cent of those vaccinated when less than one year old (P less than 0.001), but no significant differences existed with increasing years since vaccination (P greater than 0.1). A second vaccination increased detectable antibody prevalence only in those originally vaccinated when less than nine months old (42 to 80 per cent, P less than 0.02). During a measles outbreak, more cases occurred in those receiving vaccine when less than 12 months old than in those vaccinated at greater than or equal to 12 months (37 per cent vs. 9 per cent, P less than 0.001). A second vaccination protected those originally vaccinated at less than 12 months (35 per cent ill without a second vaccination vs. 2 per cent with, P less than 0.001). Thus, a single measles vaccination of children less than 12 months old does not protect; a second vaccination will protect this group.
Diagnostic Significance of Abdominal Murmurs
Authors: S. Julius, B. H. Stewart
Journal: New England Journal of Medicine (1967)

ABDOMINAL murmurs have been reported as occurring in renal-artery stenosis associated with hypertension1 2 3 4 5 6 7 8 9 and also over enlarged spleens,10 with tortuous splenic arteries,11 tumors of the liver,12 , 13 carcinoma of the pancreas14 , 15 and abdominal arteriovenous aneurysms.16 A characteristic venous hum frequently accompanies cirrhosis of the liver.13 It is always assumed that abdominal murmurs are absent under normal conditions, and their presence is taken as a sign of abnormality. However, this assumption has not been carefully tested. There are no systematic data on the frequency of abdominal murmurs in the normal population.It is also not known whether the murmurs indeed originate in . . .
The Stud Gun — An Industrial and Public-Health Hazard
Authors: Sigmund Mage, Kenneth Chiache Sze
Journal: New England Journal of Medicine (1962)

AS the mechanization of industry has advanced it has been necessary to maintain a constant vigilance to protect the industrial worker and the general public against any accompanying hazards of injury and disease. Despite such precaution, occasionally it is only with time and experience that an unforeseen danger associated with the use of a mechanical device may become evident. Unless attention is promptly called to such a menace it is apt to receive slow recognition and belated correction, particularly if it is revealed by infrequent and isolated accidental occurrences. We believe such a situation to prevail with the powder-actuated tools . . .
Case 33-2007
Authors: Eyal C. Attar, Suzanne L. Aquino, Robert P. Hasserjian
Journal: New England Journal of Medicine (2007)

A 49-year-old HIV-positive man was seen in the hematology clinic because of rapidly progressive anemia. He had been HIV-positive for 20 years and had discontinued antiretroviral therapy 6 months earlier. The hemoglobin level was 6 g per deciliter, the hematocrit 16.9%, the reticulocyte count 0.2%, and the white-cell count 2600 per cubic millimeter, with a normal differential count. Diagnostic procedures were performed.
Pretreatment nomogram predicting the long-term risk of metastatic progression of prostate cancer after radical prostatectomy
Authors: A. J. Stephenson, P. T. Scardino, J. A. Eastham, F. J. Bianco, M. W. Kattan
Journal: Journal of Clinical Oncology (2005)

4545 Background: Biochemical recurrence as an endpoint for predictive models has been criticized as patients with a rising prostate specific antigen (PSA) level after definitive local therapy are not all at risk of dying from prostate cancer or suffering morbidity from recurrent disease. We have developed a preoperative nomogram that predicts the risk of metastatic disease after radical prostatectomy (RP). Methods: Between 1983 and 2002, 4590 consecutive patients with clinically localized prostate cancer underwent RP with (N=727) or without (N=3863) neoadjuvant androgen deprivation therapy (ADT). Information was obtained from a prospective database. The median follow-up for patients free of metastases was 61 months. Using Cox proportional hazards regression analysis, the disease characteristics and clinical follow-up were modeled to predict the probability of remaining free of metastases. The predictive accuracy of the nomogram was internally validated by means of bootstrapping. Results: Metastases developed in 209 patients (4.5%) overall, 95 of who received prior salvage ADT. The overall 13-year metastasis-free probability was 88% (95% confidence interval, 86–90). Significant variables in the multivariable model included pre-biopsy PSA (P=.0003), primary (P.0001) and secondary (P.0001) biopsy Gleason grade, clinical stage (P.0001), year of treatment (P=.0001) and neoadjuvant ADT (P=.002). Neoadjuvant ADT was an adverse predictor of metastatic progression (hazard ratio 1.7). The model was accurate and discriminating with a concordance index of 0.79. Conclusions: A preoperative nomogram has been developed that can be used to predict the 13-year probability of metastatic progression among men with clinically localized prostate cancer treated by RP. The nomogram is a useful tool for patient counseling and to identify high-risk patients for investigational neoadjuvant therapy. The adverse prognostic significance of neoadjuvant ADT for subsequent metastatic progression is an intriguing finding of our nomogram. Potentially, neoadjuvant ADT may diminish the response of prostate cancer to ADT when it is administered for progressive disease. No significant financial relationships to disclose.
Infectious Complications After Unrelated Donor Allogeneic Hematopoietic Cell Transplantation With Or Without Alemtuzumab Based In Vivo Lymphocyte Depletion
Authors: Brian C. Shaffer, Andrew Flynn, David Moorshead, Zach Powell, Jennifer Hsu, Rachel B Salit, Frances T. Hakim, Ronald E. Gress, Michael Bishop, Juan Gea-Banacloche, Steven Z. Pavletic
Journal: Blood (2013)
PWE-053 Development of data linkage techniques to support the uk ibd registry: making the most of routine nhs datasets
Authors: K Bodger, M Shawihdi, M Pearson, R Driscoll, F Cummings, S Bloom
Journal: Gut (2015)

<h3>Introduction</h3> The IBD Registry aims to provide the first ever UK-wide repository of anonymized, individual-level data to support service delivery, audit and research. We report the Registry’s progress with development of methodologies to analyse the routinely coded data collected by all NHS hospitals (Hospital Episode Statistics, Outpatient and A&amp;E attendances). <h3>Method</h3> National HES data were interrogated to identify all admissions ‘belonging’ to people coded with an IBD-specific ICD-10 code (2-yr period), exploring coding variations and devising algorithms to distinguish IBD-related from unrelated admissions. At one NHS Trust, a linked dataset containing HES, OPD and A&amp;E events (7-yr period) was merged in order to link all IBD-related activity. In collaboration with the HSCIC, we established the feasibility of linking individual (anonymized) patients from the UK IBD Registry with their routine HES data. <h3>Results</h3> National HES data 84,314 patients had ≥1 admission with an IBD-specific diagnostic code (any position). We extracted their all-cause admissions (271,567). Of these, 119,045 admissions had a primary diagnosis of IBD. A further 77,957 admissions had IBD codes in position 2 or 3, but 39,515 (50%) had a relevant primary diagnosis (e.g. symptom or complication) or a procedure code that would indicate an IBD-related admission. A further 25,978 admissions had no IBD diagnosis coded but a relevant primary diagnosis or procedure (e.g. a colonoscopy). Single Trust Datasets 1,941 IBD cases were identified by screening discharges over a 7 yr period, with 6,583 admissions categorised as IBD-related using the coding algorithms developed on national data. The activity rose to 7,507 by adding admissions recorded under an IBD consultant where relevant diagnosis or procedure codes were missing. We linked cases successfully to their OPD events (22,743 for GI specialists; 16,710 non-GI) and all-cause AED attendances (6,276; 39% discharged home). Reports of activity, patient characteristics, admission types, procedures and candidate metrics have been generated for IBD, UC and CD. Linkage between UK IBD Registry and HES has been achieved at patient-level, allowing outputs of routine data to be extracted and analysed for all registered cases. <h3>Conclusion</h3> The UK IBD Registry is developing and testing algorithms that interrogate routine NHS data in ways that account for the realities of coding quality and bring together information from inpatient, outpatient and AED sources. The linkage of routine data to registry information offers the potential to build powerful tools to support IBD care delivery, audit and research. <h3>Disclosure of interest</h3> None Declared.
Targeted delivery of CXCR4-siRNA by scFv for HER2+ breast cancer therapy
Authors: Kuo Jiang, Jia Li, Jipeng Yin, Qiong Ma, Bo Yan, Xiang Zhang, Lei Wang, Lifeng Wang, Tao Liu, Yinglong Zhang, Qingyu Fan, Angang Yang, Xiuchun Qiu, Baoan Ma
Journal: Biomaterials (2015)
Reducing Variation in the “Standard of Care” for Cancer Screening
Authors: Douglas A. Corley, Jennifer S. Haas, Sarah Kobrin
Journal: JAMA (2016)

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