tbuckley/cabot-search huggingface dataset:
Pneumococcal trafficking across the blood-brain barrier. Molecular analysis of a novel bidirectional pathway.
Authors: A Ring, J N Weiser, E I Tuomanen
Journal: Journal of Clinical Investigation (1998)

Although Streptococcus pneumoniae is a major cause of meningitis in humans, the mechanisms underlying its traversal from the circulation across the blood-brain barrier (BBB) into the subarachnoid space are poorly understood. One mechanism might involve transcytosis through microvascular endothelial cells. In this study we investigated the ability of pneumococci to invade and transmigrate through monolayers of rat and human brain microvascular endothelial cells (BMEC). Significant variability was found in the invasive capacity of clinical isolates. Phase variation to the transparent phenotype increased invasion as much as 6-fold and loss of capsule approximately 200-fold. Invasion of transparent pneumococci required choline in the pneumococcal cell wall, and invasion was partially inhibited by antagonists of the platelet-activating factor (PAF) receptor on the BMEC. Pneumococci that gained access to an intracellular vesicle from the apical side of the monolayer subsequently were subject to three fates. Most opaque variants were killed. In contrast, the transparent phase variants were able to transcytose to the basal surface of rat and human BMEC in a manner dependent on the PAF receptor and the presence of pneumococcal choline-binding protein A. The remaining transparent bacteria entering the cell underwent a previously unrecognized recycling to the apical surface. Transcytosis eventually becomes a dominating process accounting for up to 80% of intracellular bacteria. Our data suggest that interaction of pneumococci with the PAF receptor results in sorting so as to transcytose bacteria across the cell while non-PAF receptor entry shunts bacteria for exit and reentry on the apical surface in a novel recycling pathway.
Ultrastructure of the cardiac myxoma and the papillary tumour of heart valves
Authors: P. G. I. Stovin, D. Heath, S. U. Khaliq
Journal: Thorax (1973)

The ultrastructure of a cardiac myxoma has been studied and compared with that of a `papillary tumour of heart9. The histochemistry of the myxoma was studied at the same time. The predominant myxoma cell contains intracytoplasmic fibrils similar to those occurring in cells (`myofibroblasts9) found in granulation tissue, deep within thrombi, and in the subendocardial layer of the heart. It also contains numerous secretory granules which appear to discharge their contents into the pericellular matrix. The material adjacent to the myxoma cell is shown by histochemistry to contain hyaluronic acid and chondroitin sulphate acidic mucins while the surrounding stroma contains sialomucins. The ultrastructure and histochemistry of the cardiac myxoma are very similar to those of the `papillary tumour of heart9 which is widely regarded as non-neoplastic and formed by growth of a Lambl9s excrescence. Hence these findings do not resolve the classical controversy as to whether the cardiac myxoma is neoplastic or thrombotic in origin.
Bax Expression Decreases Significantly From Primary Tumor to Metastasis in Colorectal Cancer
Authors: A. Jansson
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Bax is a proapoptotic member of the bcl-2 family. Previous studies about Bax have shown that the expression increases from normal to tumor tissue, but the clinical significance is contradictory. Our aims were to analyze the expression of Bax from normal mucosa to primary tumor and to metastases in colorectal cancer patient. We further investigated whether low Bax expression in the primary tumor or changed expression from normal mucosa to primary tumor and to metastases had biologic and clinical significance. PATIENTS AND METHODS: The study included 135 patients with primary colorectal adenocarcinoma, of whom 31 had metastases in the lymph nodes and 75 had normal mucosa. Immunohistochemistry, DNA sequencing, and microsatellite analysis were used to detect Bax expression, mutations, and microsatellite instability. RESULTS: The protein was observed in 132 of 135 tumors, all normal epithelial cells and metastases. The frequencies of weak expression were greater from well/moderately to poorly differentiated and to mucinous carcinomas. Bax expression was stronger from normal to tumor tissue, but subsequently decreased in metastases. The matched cases with lower expression in the metastases than in the primary tumor showed a more infiltrative growth pattern and more distal metastases. CONCLUSION: The association of Bax expression with tumor differentiation/histologic types and a decreased expression in the metastases, suggests that Bax expression may be involved in tumor differentiation/histologic types and metastatic progression. We also propose the novel notion that changed Bax expression in the metastases compared with the primary tumors might provide information to determine the clinicopathologic characteristics of the tumor.
THE PRODUCTION OF A PERSISTENT ALTERATION IN INFLUENZA VIRUS BY LANTHANUM OR ULTRAVIOLET IRRADIATION
Authors: Sven E. Björkman, Frank L. Horsfall
Journal: The Journal of Experimental Medicine (1948)

The rates of elution from RBC of the Lee and PR8 strains of influenza virus were studied by means of a step-wise elution technique. By means of a single treatment with lanthanum acetate or irradiation with ultraviolet and subsequent passage in chick embryos, it was possible to alter the elution rate of the Lee strain so that it was similar to that of the PR8 strain. This alteration proved to be persistent on serial passage in the absence of the agent which caused it. As far as was determined, the elution rate of the virus appeared to be the only property which was altered. The phenomenon can be most readily understood on the assumption that the difference in elution rates of the two strains is due to a heterogeneous population of virus particles in the Lee strain with respect to elution rate.
Photosensitive Smith-Lemli-Opitz syndrome is not caused by a single gene mutation: analysis of the gene encoding 7-dehydrocholesterol reductase in five U.K. families
Authors: A.V. Anstey, R.M. Azurdia, L.E. Rhodes, A.D. Pearse, P.E. Bowden
Journal: British Journal of Dermatology (2005)

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive malformation syndrome characterized by a disorder in cholesterol metabolism. SLOS is caused by mutations in the DHCR7 gene which encodes 7-dehydrocholesterol reductase, an enzyme that catalyses the final step in cholesterol biosynthesis. We have previously established the clinical and photobiological features of the photosensitivity that is frequently a feature of SLOS.In this study, we have performed mutational analysis of the DHCR7 gene in individuals from five families with SLOS. In each family, one member was affected by severe photosensitivity as a manifestation of SLOS.Fifteen samples (including family controls) were screened using polymerase chain reaction amplification and direct automated sequencing.Six different DHCR7 mutations were identified of which five were single point mutations that caused missense amino acid substitutions (P51H, T93M, L99P, E448K and R450L). The other was a splice site mutation (G-->C in splice acceptor site) affecting the intron 8-exon 9 splice junction (IVS8-1 G-->C). This splice site mutation and four of the five missense mutations have been previously published as causal in SLOS but the P51H is a novel mutation which has not previously been reported.This is the first study in which DHCR7 gene mutational analysis has been performed on SLOS subjects with severe photosensitivity and indicates that no single mutation is responsible for the photosensitivity which characterizes this disorder.
ARE WE DEGENERATING? IF SO, WHY?
Authors: E. STUVER
Journal: JAMA (1900)

This is a question which is being seriously discussed by sages, philosophers, statesmen, physicians and all persons interested in the welfare of the race; but to the physician, who is brought into such intimate contact with its causes and manifestations, and who by his training and opportunities is well prepared to throw a flood of light on it, to illumine its dark recesses and banish misconceptions, it should be a subject of absorbing interest. Before we can formulate a definite opinion one way or another in this matter, we must have some standard or ideal by which to be governed in arriving at conclusions. This standard should be a broad and a comprehensive one, and should embrace not merely certain parts or phases of human progress, but should include all those elements which are necessary for the symmetric development and uplifting of the human race. Men and women should not
Abstract LB-92: Loss of a single Hic1 allele accelerates polyp formation in Apc mice
Authors: Helai Mohammad, Wei Zhang, Helen Selonick, Benjamin Leadem, Minsi Zhang, Craig Hooker, David N. Watkins, Baktiar Karim, David Huso, James G. Herman, Stephen B. Baylin
Journal: Cancer Research (2010)

Abstract Mutations in the Adenomatous Polyposis Colt (APC) gene have been implicated both in familial as well as sporadic gastrointestinal (GI) cancers. APC mutations are associated with autosomal dominant inheritance of disease in humans. Similarly, mice that contain a single mutant APC gene encoding a protein truncated at aa 716 (Ape716) develop multiple polyps throughout the GI tract as early as 4 weeks after birth. Inactivation of another tumor suppressor gene, Hypermethylated in Cancer 1 (HIC1) often occurs in human cancers, including GI, via CpG island hypermethylation. Homozygous deletion of Hic1 in mice results in major developmental defects and embryonic lethality. Hic1 heterozygotes have previously been shown to develop age dependent tumors of a variety of tissue types. We now report that loss of a single Hic1 allele can promote crypt dysplasia of the small intestine and further potentiate polyp formation in Apc716 mice. Hic1+/−, Apc716 double heterozygous mice develop increased numbers of polyps throughout the GI tract by 60 days. Hic1 expression is lost in polyps with a selective increase in DNA hypermethylation of this gene only in polyps from double-heterozygous mice. Immunohistochemical analyses of polyps show increases in markers such as -catenin, SIRT1, and Sox9, indicating aberrant Wnt and Hic1 signaling. Together, our data suggest that loss of a gene frequently silenced via epigenetic mechanisms, Hic1, can cooperate with loss of a gene often mutated in GI cancer, Apc, to promote tumorigenesis in an in-vivo model of multiple intestinal neoplasia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-92.
Somatic Manifestations of Psychoneurosis
Authors: I. Douglas-Wilson
Journal: BMJ (1944)

Uncertainties persist about management and prognosis of mammary cancers that occur during and after pregnancy and during lactation. Pathological features of mammary cancers occurring during pregnancy are the same as those in non-pregnant women and survival rates are comparable. Management should be the same as in non-pregnant patients. Termination of pregnancy does not improve survival but it should be advised if the prognosis is poor. Mastectomy apparently presents little danger to the fetus, though treatment such as chemotherapy and irradiation should be avoided. Women who have received treatment for mammary cancer need not be advised against subsequent pregnancy. Routine ovarian radiation in non-pregnant premenopausal women is not generally to be recommended, since it does not prolong survival and would deprive some of the chance of further pregnancy. In lactating women who develop mammary cancers survival is apparently not adversely affected. Lactation should be suppressed initially and followed by mastectomy. Regimens of immunotherapy, chemotherapy, or radiotherapy may then be begun. Until results of current trials of combined treatments of mammary cancers associated with pregnancy are available, management should be neither aggressive nor tentative. It should be based on a well-balanced concept of applying all available treatments, as in non-pregnant patients.
Psychogenic Urinary Retention (‘Paruresis’): Diagnosis and Epidemiology in a Representative Male Sample
Authors: Philipp Hammelstein, Reinhard Pietrowsky, Martin Merbach, Elmar Braehler
Journal: Psychotherapy and Psychosomatics (2005)

&lt;i&gt;Background:&lt;/i&gt; Although research interest in social phobias has expanded during the last decade, a special subtype of social phobia known as paruresis, which manifests in the inability to urinate in public rest rooms, is rarely mentioned. The aim of the present study was to achieve for the first time an estimation of point prevalence in a representative male sample (n = 1,105). &lt;i&gt;Method:&lt;/i&gt; Due to the lack of well-established screening instruments for paruresis, the Paruresis Checklist (PCL) must be tested for reliability and validity. An empirically based cutoff score must be determined by using the subjective interference with everyday life as an external criterion. &lt;i&gt;Results:&lt;/i&gt; Reliability of the PCL seemed to be sufficient, and adequate evidence for validity was found. Using the empirically based cutoff score of the PCL, 2.8% of the sample was diagnosed as suffering from paruresis. In contrast to other forms of social phobia, paruresis is not associated with a lower educational or occupational level.
Height, Fibroplasia, and Renovascular Hypertension
Authors: James C. Stanley, William J. Fry
Journal: JAMA (1973)

<h3>To the Editor.—</h3> The significance of observations by Goldman et al (221:378, 1972) regarding the occurrence of renovascular hypertension in unusually tall women, as noted by Straus and Choi (223:440, 1973), deserves further comment. The exact incidence and pathogenesis of renal artery fibromuscular dysplasia remains unknown, but lesions in which medial fibroplasia predominates are most common. Histologic study of these lesions reveals medial thinning and mural aneurysms alternating with constricting areas of fibrous tissue that are consistent with an end-stage nonspecific medial "injury." The apparent predilection of medial fibroplasia for renal arteries, the right renal artery in particular, has never been explained. It is a reasonable speculation that intermittent stretching of the renal arteries, when associated with ptotic kidneys, may alter the vessel wall directly or indirectly by disrupting the vasa vasorum. Renovascular hypertension is often associated with renal ptosis. In the past this has led to nephropexy in many
Therapeutic strategies in inflammasome mediated diseases of the liver
Authors: Rafaz Hoque, Yoram Vodovotz, Wajahat Mehal
Journal: Journal of Hepatology (2012)

Tissue stress and cell death result in inflammation even in the absence of pathogens. Such sterile inflammation is dependent on a cytosolic complex of proteins inside immune cells termed the inflammasome. This complex converts two groups of extracellular signals into an inflammatory response via activation of caspase-1 and secretion of IL-1β and IL-18. Group 1 signals are typically TOLL like receptor agonists and result in transcriptional upregulation of inflammasome components and pro-cytokines. Group 2 signals are diverse, ranging from uric acid to ATP, and lead to assembly and activation of the inflammasome complex. Inflammasome components are required for a wide range of acute and chronic pathologies, including experimental alcoholic and non-alcoholic steatohepatitis, and drug-induced liver injury. Collectively, group 1 and 2 signals, inflammasome components, and cytokine receptors provide a rich source of therapeutic targets. Many of the advances in the field have come from standard reductionist experiments. Progress in the understanding of complex human systems will, however, be dependent on novel strategies such as systems analysis, which analyze large data sets to provide new insights.
RISK FACTORS FOR LONG-TERM MORTALITY IN VERY ELDERLY AFTER POST-OPERATIVE MYOCARDIAL INFARCTION FOLLOWING HIP FRACTURE SURGERY
Authors: Bhanu P. Gupta, Lisa L. Kirkland, Jeanne M. Huddleston, Paul M. Huddleston, M Caroline Burton, Larson R. Dirk, Rachel E. Gullerud, Stephen S. Cha, Charanjit Rihal, R Scott Wright
Journal: Journal of the American College of Cardiology (2011)
Study of Proteins and Fibrinolysis in Patients with Glomerulonephritis
Authors: E. N. Wardle, I. S. Menon, S. P. Rastogi
Journal: BMJ (1970)

Plasma and urine fibrinolysis were studied in 36 patients with glomerulonephritis and proteinuria. In 40% of these plasma fibrinolytic activator activity was moderately reduced and fibrinolytic inhibitors were increased. Globulins with antiplasmin effect were raised, particularly in the earlier months. Both the serum cholesterol and the plasma fibrinogen were related to the level of serum albumin, and those patients with high fibrinogen levels were also those with poor plasma fibrinolytic activator and those showing a steady deterioration. Urinary fibrinolysis was greatly reduced in most patients and bore no relation to plasma fibrinolysis levels. Hence urokinase is not derived from circulating plasminogen activator.
Development of Novel Formulations That Enhance Adenoviral-Mediated Gene Expression in the Lung in Vitro and in Vivo
Authors: Maria A. Croyle, Xuan Cheng, Arbans Sandhu, James M. Wilson
Journal: Molecular Therapy (2001)

Despite remarkable progress in the development of both viral and non-viral gene delivery vec-tors for cystic fibrosis therapy, low efficiency of gene transfer to the airway epithelium is a major obstacle to clinical application. Here we develop formulations that enhance cellular absorption of adenoviral vectors. We selected excipients from a panel of pharmaceutically acceptable com-pounds known to enhance drug absorption. Transduction efficiency of the virus in the presence of each ingredient was assessed in vitro and in vivo. Mannitol and chitosan substantially enhanced transduction efficiency in vitro and augmented expression in vivo by 4 and 8 log units, respectively. The most successful formulation (a blend of sucrose, mannitol, and Pluronic F68) transduced 100% of an A549 cell population in vitro and produced areas of intense gene expression in both large and small airways in vivo with minimal toxicity. Dose response studies also indicate that when placed in this formulation, the viral dose can be lowered by 1/2 log while maintaining superior levels of transgene expression. This formulation also enhanced the physical stability of the virus. No significant loss in titer was detected from a lyophilized formulation after storage at 25°C for 30 days.
Rethinking diagnostic delay in cancer: how difficult is the diagnosis?
Authors: G. Lyratzopoulos, J. Wardle, G. Rubin
Journal: BMJ (2014)

<b>Georgios Lyratzopoulos</b>, <b>Jane Wardle</b>, and <b>Greg Rubin</b> argue that delays in referral for suspected cancer are unlikely to be caused by poor professional performance and explore other potential causes and strategies for improvement
Human leukocyte antigen-associated sequence polymorphisms in hepatitis C virus reveal reproducible immune responses and constraints on viral evolution
Authors: Joerg Timm, Bin Li, Marcus G. Daniels, Tanmoy Bhattacharya, Laura L. Reyor, Rachel Allgaier, Thomas Kuntzen, Will Fischer, Brian E. Nolan, Jared Duncan, Julian Schulze zur Wiesch, Arthur Y. Kim, Nicole Frahm, Christian Brander, Raymond T. Chung, Georg M. Lauer, Bette T. Korber, Todd M. Allen
Journal: Hepatology (2007)

CD8(+) T cell responses play a key role in governing the outcome of hepatitis C virus (HCV) infection, and viral evolution enabling escape from these responses may contribute to the inability to resolve infection. To more comprehensively examine the extent of CD8 escape and adaptation of HCV to human leukocyte antigen (HLA) class I restricted immune pressures on a population level, we sequenced all non-structural proteins in a cohort of 70 chronic HCV genotype 1a-infected subjects (28 subjects with HCV monoinfection and 42 with HCV/human immunodeficiency virus [HIV] coinfection). Linking of sequence polymorphisms with HLA allele expression revealed numerous HLA-associated polymorphisms across the HCV proteome. Multiple associations resided within relatively conserved regions, highlighting attractive targets for vaccination. Additional mutations provided evidence of HLA-driven fixation of sequence polymorphisms, suggesting potential loss of some CD8 targets from the population. In a subgroup analysis of mono- and co-infected subjects some associations lost significance partly due to reduced power of the utilized statistics. A phylogenetic analysis of the data revealed the substantial influence of founder effects upon viral evolution and HLA associations, cautioning against simple statistical approaches to examine the influence of host genetics upon sequence evolution of highly variable pathogens.These data provide insight into the frequency and reproducibility of viral escape from CD8(+) T cell responses in human HCV infection, and clarify the combined influence of multiple forces shaping the sequence diversity of HCV and other highly variable pathogens.
Is NICE delivering the goods?
Authors: Nick Freemantle
Journal: BMJ (2004)

The extent to which trusts are prepared for NICE guidance and have put in place structures and processes to manage their implementation was variable.The degree of active promotion by NICE is likely to have some impact on adoption, although probably not directly proportional to the effort invested.The greatest effect is likely when opinion leaders including the professional bodies and associations adopt and promote the guidance. ConclusionsImplementation of NICE guidance is likely to be improved if it is clear and based on an understanding of clinical practice, if the evidence is strong and relatively stable, if adequate funding is available, and if the guidance is supported and disseminated by professional bodies.Trusts should institute strong supportive internal systems for handling guidance and gathering data on implementation.We acknowledge the support and cooperation of the NHS trusts that provided data, the audit staff and clinicians who carried out the case note audits, and the clinicians and managers who responded to the survey and participated in interviews.We thank the British Pacing and Electrophysiology Group (BPEG) for anonymised access to their register of Implantable Cardioverter Defibrillators and to the Trent and Welsh Arthroplasty Audit Groups for access to their anonymised database (TWAAG).We thank David Gibbons for advice on aspects of wisdom tooth removal and related issues and staff from the MRC Institute for Hearing Research who provided advice on the survey of audiology departments.