tbuckley/cabot-search huggingface dataset:
Issues at the interface between primary and secondary care in the management of common respiratory disease bullet 4: Providing better care for patients who may have pneumonia
Authors: W. F Holmes, M. Woodhead
Journal: Thorax (1999)

“It is not as easy to elicit abnormal physical signs in a bedroom of traditional English winter temperature as in a well heated hospital ward.”1 

Pneumonia is common throughout the world, and although its presentation to health care services will vary, many of the difficulties which physicians and patients face are common. This paper deals with meeting this challenge within the British National Health Service (NHS) but the issues discussed have implications for other health care systems.

Pneumonia accounts for 5–12% of all cases of lower respiratory tract infections which UK general practitioners (GPs) treat with antibiotics.2 Based on prospective studies,3a British GP with an average list of 2000 patients would expect to see 4–12 cases of community acquired pneumonia (CAP) per year and to manage most of them at home. Annually in the UK there are some 250 000 episodes of CAP, about one third of which (approximately 83 000 patients) are admitted to hospital. These admissions account for 96% of the £440 million which CAP costs the NHS.4 CAP is therefore an important problem.

The diagnosis of pneumonia is not always easy. Even when patients with respiratory tract infection are examined in satisfactory conditions and with ready access to radiology, experienced physicians may still find the diagnosis sufficiently uncertain as to need treatment to cover several conditions. One may therefore have some sympathy for the plight of the GP who may have to examine the patient in less than satisfactory circumstances and early in the course of what can be an unpredictable disease.

The presence of abnormal physical signs on examination of the chest in an unwell patient with cough and breathlessness usually suggests pneumonia, but confusion, coping less well at home, or being thought not to be their usual self in a residential home …
Congenital Pulmonary Lymphangiectasia
Authors: Cornelia Hagmann, Thomas M. Berger
Journal: New England Journal of Medicine (2003)

Children’s Hospital of Lucerne CH-6000 Lucerne 16, Switzerland female infant was born at 40 weeks and 3 days of gestation, weighing 2970 g. The Apgar scores were 8, 10, and 10 at 1, 5, and 10 minutes, respectively. Within one hour after birth, severe respiratory distress with profound cyanosis developed while the infant was breathing room air, and intubation and mechanical ventilation were required. An initial chest radiograph showed normal lung volumes with diffuse, bilateral nodular changes, and a subsequent chest radiograph obtained on the 17th day of life showed that these changes had become more prominent (Panel A). Surfactant and antibiotics were administered. Lung compliance remained poor, and high-frequency oscillatory ventilation was begun. Congenital heart disease was ruled out, and cultures of blood and tracheal aspirates were unrevealing. After surfactant protein B deficiency was ruled out, an open-lung biopsy was performed, on the 18th day of life. On gross examination, the lung had an irregular surface with scattered nodular changes (Panel B). On microscopical examination, there was subpleural and septal cystic lymphangiectasia (L, Panel C; hematoxylin and eosin, ¬150). A denotes artery. These findings are consistent with a diagnosis of congenital pulmonary lymphangiectasia, which is a uniformly fatal disease when it manifests in the newborn period. The infant died on the 20th day of life.
The safety and quality of endobronchial biopsy in children under five years old
Authors: S Saglani
Journal: Thorax (2003)

Little is known about the airway pathology of wheezing disorders in infants and preschool children, partly owing to the difficulty of undertaking invasive studies in this age group. The safety of endobronchial biopsy and the quality of biopsies obtained were reviewed in infants and preschool children.Case notes of children under five years of age who underwent bronchoscopy and endobronchial biopsy were reviewed. The safety of the procedure was compared in a control group matched for weight and age, undergoing bronchoscopy without endobronchial biopsy. A consultant histopathologist assessed biopsy quality.33 patients (mean age 31 months, range 4 to 59) underwent bronchoscopy and endobronchial biopsy, and were matched with 33 controls (mean age 28 months, range 3 to 52). There was no significant difference between groups in the number, type, or severity of complications occurring during or after the procedure. Biopsies from 30 of the 33 subjects could be assessed. Reticular basement membrane was identified in all 30; inflammation could be assessed in 26; areas of smooth muscle were present in 23.In a group of preschool children undergoing bronchoscopy under general anaesthetic, performance of endobronchial biopsy carried no extra risk. The quality of biopsies obtained was usually sufficient to allow an assessment of remodelling and inflammation.
Gene Profiling Changes in Cytoskeletal Proteins During Clinical Recovery After Left Ventricular–Assist Device Support
Authors: Emma J. Birks, Jennifer L. Hall, Paul J.R. Barton, Suzanne Grindle, Najma Latif, James P. Hardy, James E. Rider, Nicholas R. Banner, Asghar Khaghani, Leslie W. Miller, Magdi H. Yacoub
Journal: Circulation (2005)

Background— After left ventricular–assist device (LVAD) support, a proportion of patients recover sufficient ventricular function to enable explantation of the device. The exact molecular mechanisms involved in myocardial recovery remain unknown. Cytoskeletal proteins are essential for the structure and function of the cardiac myocyte and might play a major role. Methods and Results— A total of 15 patients with nonischemic cardiomyopathy who required LVAD implantation were studied; 6 recovered sufficiently to allow explantation of the device compared with 9 who did not recover and required transplantation. LV myocardial samples were collected at implantation and explantation/transplantation. Affymetrix microarray analysis was performed on the paired samples and analyzed with reference to sarcomeric and nonsarcomeric cytoskeletal proteins. In the recovery group, of the nonsarcomeric proteins, lamin A/C increased 1.5-fold ( P &lt;0.05) and spectrin 1.6-fold ( P &lt;0.05) between the times of implantation and explantation. Integrins β1, β6, and α7 decreased 1.7-fold (P&lt;0.05), 2.4-fold (P&lt;0.05), and 1.5-fold (P&lt;0.05), respectively, but integrins α5 and β5 increased 2.3-fold (P&lt;0.01) and 1.2-fold ( P &lt;0.01) at explantation. The following sarcomeric proteins changed in the recovered group only: β-actin increased 1.4-fold ( P &lt;0.05); α-tropomyosin, 1.3-fold ( P &lt;0.05); α1-actinin, 1.8-fold ( P &lt;0.01); and α-filamin A, 1.6-fold ( P &lt;0.05). Both troponin T3 and α 2-actinin decreased by 1.6-fold at the time of explantation ( P &lt;0.05). Vinculin decreased 1.7-fold ( P =0.001) in the recovered group but increased by 1.7-fold ( P &lt;0.05) in the nonrecovered group. Vinculin protein levels decreased 4.1-fold in the recovered group. Conclusions— Myocardial recovery was associated with a specific pattern of changes in sarcomeric, nonsarcomeric, and membrane-associated proteins, which could have important implications in understanding the mechanisms involved.
Endothelium-Derived Hyperpolarizing Factor–Mediated Renal Vasodilatory Response Is Impaired During Acute and Chronic Hyperhomocysteinemia
Authors: An S. De Vriese, Henk J. Blom, Sandra G. Heil, Siska Mortier, Leo A.J. Kluijtmans, Johan Van de Voorde, Norbert H. Lameire
Journal: Circulation (2004)

Endothelial dysfunction is an early event in the development of vascular complications in hyperhomocysteinemia. Endothelial cells release a number of vasodilators, including NO and prostacyclin. Several lines of evidence have indicated the existence of a third vasodilator pathway, mediated by endothelium-derived hyperpolarizing factor (EDHF). EDHF is a major determinant of vascular tone in small resistance vessels. The influence of hyperhomocysteinemia on EDHF is unknown. The present in vivo study evaluates the integrity of the EDHF pathway in the renal microcirculation of rats with acute and chronic hyperhomocysteinemia.EDHF-mediated vasodilation was evaluated as the renal blood flow (RBF) response to intrarenal acetylcholine during systemic NO synthase and cyclooxygenase inhibition. Acute hyperhomocysteinemia induced by intravenous homocysteine did not affect EDHF-mediated vasodilation. In contrast, intravenous methionine with subsequent hyperhomocysteinemia impaired the EDHF-mediated RBF response. When the methionine infusion was preceded by adenosine periodate oxidized to prevent the cleavage of S-adenosylhomocysteine to homocysteine and adenosine, a similar impairment of EDHF was observed, but with normal homocysteine levels. Animals with chronic hyperhomocysteinemia induced by a high-methionine, low-B vitamin diet during 8 weeks had a severely depressed EDHF-mediated vasodilation compared with those on a standard diet. Endothelium-independent vasodilation to deta-NONOate and pinacidil was not affected in acute and chronic hyperhomocysteinemia, demonstrating intact vascular smooth muscle reactivity.EDHF-dependent responses are impaired in the kidney of hyperhomocysteinemic rats. Because EDHF is a major regulator of vascular function in small vessels, these findings have important implications for the development of microangiopathy in hyperhomocysteinemia.
Density and function of inward currents in right atrial cells from chronically fibrillating canine atria
Authors: T Yagi
Journal: Cardiovascular Research (2002)

Objective: To determine whether INa and ICaL are altered in function/density in right atrial (RA) cells from dogs with chronic atrial fibrillation (cAF dogs, episodes lasting at least 6 days) and whether the changes that occur differ from those in dogs with nonsustained or brief episodes of fibrillation (nAF dogs). Methods: Using whole cell voltage clamp, sodium and calcium current density and function were determined in disaggregated RA cells from nAF, cAF and control atria (Con). Ca2+ currents were studied with either Ca2+ or Ba2+ as charge carrier, as well as with either EGTA or BAPTA as the internal solution Ca2+ chelator. Results: After rapid atrial pacing, dogs can either fibrillate for short periods of time (nAF) or longer, more sustained periods (cAF). Both the Na+ and Ca2+ current decrease in cells of the nAF atria. Na+ current density remains reduced in cAF cells with some slowing of recovery kinetics. Ca2+ current density does not further decrease with persistent atrial fibrillation (cAF cells) remaining significantly different from Con cells. However, the difference in density of Ca2+ currents between nAF and Con cells is negligible when Ba2+ is charge carrier and when Cai is quickly and effectively chelated with BAPTA. On the contrary, cAF IBaL densities remain significantly reduced compared to Con and nAF values when Ba2+/BAPTA conditions are used. Conclusions: Na+ current density/function does not recover to Con values in cAF. Further these enhanced Ca2+-dependent inactivation processes contribute significantly to the reduction of ICaL density observed in nAF cells while reduction of Ca2+ currents in cAF atria is probably by another mechanism
αv Integrin-Targeted Immunoconjugates Regress Established Human Tumors in Xenograft Models
Authors: Qiming Chen, Hillary J. Millar, Francis L. McCabe, Carol D. Manning, Rita Steeves, Kate Lai, Brenda Kellogg, Robert J. Lutz, Mohit Trikha, Marian T. Nakada, G. Mark Anderson
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Targeted delivery of cytotoxic agents to solid tumors through cell surface antigens can potentially reduce systemic toxicity and increase the efficacy of the targeted compounds. The purpose of this study was to show the feasibility of treating solid tumors by targeting αv integrins with antibody-maytansinoid conjugates and to test the relative in vivo activities of several linker-maytansinoid chemistries. Experimental Design: CNTO 364, CNTO 365, and CNTO 366 are targeted cytotoxic agents created by conjugating the CNTO 95 anti-αv integrin antibody with three distinct maytansinoid-linker structures. These structures were designed to have varying degrees of chemical substitution surrounding the disulfide bond linking the cytotoxic agent to the antibody. A model conjugate was shown to be specifically cytotoxic in vitro and highly active against established human tumor xenografts in immunocompromised rats. The in vivo antitumor activities of CNTO 364, CNTO 365, and CNTO 366 were compared in rat xenograft models. Results: CNTO 365, with a linker chemistry of expected intermediate stability, was shown to be substantially more active than the other two conjugates with lesser or greater substitution around the disulfide linkage. Conclusion: CNTO 95–maytansinoid immunoconjugates are potent antitumor agents against αv integrin–expressing human carcinomas. These studies show for the first time the feasibility of targeting αv integrins on solid tumors with tumor-activated prodrugs. The DM4 linker-maytansinoid configuration of CNTO 365 was substantially more active in the models tested here when compared with alternative configurations with greater or lesser chemical substitution surrounding the linker.
Slow Fitness Recovery in a Codon-Modified Viral Genome
Authors: J.J. Bull, I.J. Molineux, C.O. Wilke
Journal: Molecular Biology and Evolution (2012)

Extensive synonymous codon modification of viral genomes appears to be an effective way of attenuating strains for use as live vaccines. An assumption of this method is that codon changes have individually small effects, such that codon-attenuated viruses will be slow to evolve back to high fitness (and thus to high virulence). The major capsid gene of the bacterial virus T7 was modified to have varying levels of suboptimal synonymous codons in different constructs, and fitnesses declined linearly with the number of changes. Adaptation of the most extreme design, with 182 codon changes, resulted in a slow fitness recovery by standards of previous experimental evolution with this virus, although fitness effects of substitutions were higher than expected from the average effect of an engineered codon modification. Molecular evolution during recovery was modest, and changes evolved both within the modified gene and outside it. Some changes within the modified gene evolved in parallel across replicates, but with no obvious explanation. Overall, the study supports the premise that codon-modified viruses recover fitness slowly, although the evolution is substantially more rapid than expected from the design principle.
Studies on steroid fever
Authors: Phyllis Bodel, Morris Dillard
Journal: Journal of Clinical Investigation (1968)

When a serum-buffer solution of etiocholanolone is incubated with human blood leukocytes in vitro, a pyrogen is released. Like endogenous pyrogen of leukocyte origin, this pyrogen produces prompt monophasic fevers in rabbits, does not induce fever tolerance when given daily, and is inactivated by trypsin. In many respects, the characteristics of the in vitro reaction resemble experimental steroid-induced fever. For example, release of pyrogen varies directly with the concentration of steroid. 4-8 hr of contact between steroid and leukocyte is required for activation of the cell. Rabbit leukocytes are not activated by etiocholanolone. Finally, androsterone, the 5α-isomer of etiocholanolone, does not induce pyrogen release in vitro. These studies suggest that experimental steroid fever in man may be mediated by an endogenous pyrogen released from leukocytes.
Injury Biomechanics and Child Abuse
Authors: Mary Clyde Pierce, Gina Bertocci
Journal: Annual Review of Biomedical Engineering (2008)

Child abuse is a leading cause of morbidity and mortality in young children and infants in the United States. Medical care providers, social services, and legal systems make critical decisions regarding injury and history plausibility daily. Injury plausibility judgments rely on evidence-based medicine, individualized experiences, and empirical data. A poor outcome may result if abuse is missed or an innocent family is accused, therefore evidence and science-based injury assessments are required. Although research in biomechanics has improved clinical understanding of injuries in children, much work is still required to develop a more scientific, rigorous approach to assessing injury causation. This article reviews key issues in child abuse and how injury biomechanics research may help improve accuracy in differentiating abuse from accidental events. Case-based biomechanical investigations, human surrogate, and computer modeling biomechanics research applied to child abuse injury are discussed. The goal of this paper is to provide an overview of key research studies rather than on review or commentary articles. Limitations and future research needs are also reviewed.
Radiofrequency Heat-Enhanced Chemotherapy for Breast Cancer: Towards Interventional Molecular Image-Guided Chemotherapy
Authors: Yurong Zhou, Guocan Han, Yue Wang, Xi Hu, Zhiming Li, Lumin Chen, Weixian Bai, Jingfeng Luo, Yajing Zhang, Jihong Sun, Xiaoming Yang
Journal: Theranostics (2014)

Breast cancer is the most common malignancy in women worldwide. Recent developments in minimally invasive interventional radiology techniques have significantly improved breast cancer treatment. This study aimed to develop a novel technique for the local management of breast cancers using radiofrequency heat (RFH). We performed both in vitro experiments using human breast cancer cells and in vivo validation in xenograft animal models with magnetic resonance imaging (MRI) and pathological correlation to investigate the feasibility of our approach. Four treatment groups, including (1) no treatment (control), (2) RFH-only, (3) chemo (doxorubicin)-only, and (4) combination therapy with both doxorubicin and RFH, were conducted in each experiment. In vitro combination therapy significantly decreased breast cancer cell proliferation while increased their apoptosis index compared to the other three groups. MRI demonstrated a significant tumor size reduction in animals treated with combination therapy compared to those receiving other treatments in vivo. Such result was further confirmed by pathological examination. In conclusion, our findings suggests that RFH can enhance the therapeutic efficiency of doxorubicin on breast cancers, thus establishing the basis for future development of interventional molecular image-guided local chemotherapy for breast malignancies.
Vaccination of Patients with Small-Cell Lung Cancer with Synthetic Fucosyl GM-1 Conjugated to Keyhole Limpet Hemocyanin
Authors: Lee M. Krug, Govind Ragupathi, Chandra Hood, Mark G. Kris, Vincent A. Miller, Jennifer R. Allen, Stacy J. Keding, Samuel J. Danishefsky, Jorge Gomez, Leslie Tyson, Barbara Pizzo, Valerie Baez, Philip O. Livingston
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Immunotherapy directed toward cell surface antigens may provide a novel approach to the eradication of chemoresistant micrometastatic disease in patients with small-cell lung cancer (SCLC). Studies in SCLC cell lines and human tissues suggest that the ganglioside fucosyl GM1 is an abundant yet specific target. A prior clinical study demonstrated the potent immunogenicity of fucosyl GM-1 derived from bovine thyroid gland, conjugated to keyhole limpet hemocyanin (KLH) and administered with QS-21 adjuvant. Experimental Design: We tested the immunogenicity of three different doses of a synthetic version of fucosyl-GM1 in patients with SCLC after a major response to initial therapy. The primary end point was to establish the lowest effective dose capable of inducing antibody production. Results: Five of six patients at the 30-μg dose and three of five patients at the 10-μg dose mounted IgM responses of 1:80 or greater. These antibodies were confirmed by flow cytometry in seven of eight cases. None of the patients at the 3-μg dose had titers above 1:80. One patient at the 30-μg dose had an IgG response with a titer of 1:80. The sera from six of the eight responders induced potent complement-mediated cytotoxicity of tumor cells. Conclusions: Vaccination with the synthetic fucosyl GM1-KLH conjugate induces an IgM antibody response against fucosyl GM1 and tumor cells expressing fucosyl GM1, comparable with the response induced by the bovine derivative. We plan to combine synthetic fucosyl GM1 vaccine at a dose of 30 μg with vaccines against three other antigens—GM2, Globo H, and polysialic acid—to test in patients with SCLC after initial chemotherapy.
Impaired vascular function in small resistance arteries of LOX-1 overexpressing mice on high-fat diet
Authors: Birgit Eichhorn, Gregor Muller, Anja Leuner, Tatsuya Sawamura, Ursula Ravens, Henning Morawietz
Journal: Cardiovascular Research (2009)

LOX-1 is a major vascular receptor for oxidized low-density lipoprotein (oxLDL). In this study, we analysed the impact of LOX-1 overexpression and high dietary fat intake on vascular function in small resistance arteries.Relaxation of mesenteric arteries was measured using a wire myograph. Compared with the control group, mice overexpressing LOX-1 on a high-fat diet (FD) had preserved vascular smooth muscle relaxation, but impaired endothelium-dependent relaxation via NO. Vascular NO availability was decreased by exaggerated formation of reactive oxygen species and decreased endothelial NO synthase expression. Endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation via cytochrome P450 metabolites was increased in LOX-1 + FD animals, but did not completely compensate for the loss of NO. Currents of calcium-activated potassium channels with large conductance (BKCa channels) were measured by the voltage-clamp method. The BKCa current amplitudes were not altered in endothelial cells, but highly increased in vascular smooth muscle cells from resistance arteries of LOX-1-overexpressing mice on FD. BK(Ca) currents were activated by low-dose H2O2 and cytochrome P450 metabolites 11,12-EET and 14,15-EET as EDHF in control mice.LOX-1 overexpression and FD caused functional changes in endothelial and vascular smooth muscle cells of small resistance arteries.