tbuckley/cabot-search huggingface dataset:
Heroin injecting and the introduction of HIV/AIDS into a Scottish city
Authors: R. Robertson, A. Richardson
Journal: Journal of the Royal Society of Medicine (2007)

Although several accounts of the introduction of HIV infection into the drug-using population in the UK have been attempted by various contributors, the complete story remains somewhat opaque and surrounded in mystery, perhaps all the more interesting and intriguing for these reasons. Although this paper is unlikely to be the end of the story or even to present a totally clear revelation, it is worth adding some information in an attempt to increase the likelihood of us all learning from an unfortunate medical and public health disaster. Medical stories are common in the history of Edinburgh and infectious diseases contribute a significant number, including plague, cholera and tuberculosis, but the interest in HIV should go into history as being at least as important as these others.
A Validated Quantitative Assay to Detect Occult Micrometastases by Reverse Transcriptase-Polymerase Chain Reaction of Guanylyl Cyclase C in Patients with Colorectal Cancer
Authors: Stephanie Schulz, Terry Hyslop, Janis Haaf, Christine Bonaccorso, Karl Nielsen, Matthew E. Witek, Ruth Birbe, Juan Palazzo, David Weinberg, Scott A. Waldman
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Guanylyl cyclase C (GCC), a receptor for bacterial diarrheagenic enterotoxins, may be a prognostic and predictive marker to detect occult micrometastases in patients undergoing staging for colorectal cancer. However, quantification of GCC expression in tissues by the quantitative reverse transcription-PCR (qRT-PCR) has not undergone analytic and clinicopathologic validation. Experimental Design: A technique to quantify GCC mRNA in tissues employing RT-PCR was developed and validated employing external calibration standards of RNA complementary to GCC. Results: GCC qRT-PCR exhibited reaction efficiencies &amp;gt;92%, coefficients of variations &amp;lt;5%, linearity &amp;gt;6 orders of magnitude, and a limit of quantification of &amp;gt;25 copies of GCC cRNA. This assay confirmed that GCC mRNA was overexpressed by colorectal tumors from 41 patients, which correlated with increased GCC protein quantified by immunohistochemistry. Analyses obtained with 164 lymph nodes from patients free of cancer and 15 nodes harboring metastases established a threshold for metastatic disease of ∼200 GCC mRNA copies/μg total RNA, with a sensitivity of 93% and specificity of 97%. GCC mRNA above that threshold was detected in 76 of 367 (∼21%) nodes free of disease by histopathology from 6 of 23 (26%) patients, suggesting the presence of occult micrometastases. Conclusions: Quantifying GCC mRNA in tissues by RT-PCR employing external calibration standards is analytically robust and reproducible, with high clinicopathologic sensitivity and specificity. This validated assay is being applied to ∼10,000 lymph nodes in a prospective trial to define the sensitivity of GCC qRT-PCR for staging patients with colorectal cancer.
Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis.
Authors: H R Alexander, B C Sheppard, J C Jensen, H N Langstein, C M Buresh, D Venzon, E C Walker, D L Fraker, M C Stovroff, J A Norton
Journal: Journal of Clinical Investigation (1991)

Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily x 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 micrograms/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P less than 0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.
Diabetes- and Nondiabetes-Related Lower Extremity Amputation Incidence Before and After the Introduction of Better Organized Diabetes Foot Care
Authors: Ronan J. Canavan, Nigel C. Unwin, William F. Kelly, Vincent M. Connolly
Journal: Diabetes Care (2008)

There is a lack of continuous longitudinal population-based data on lower extremity amputation (LEA) in the U.K. We present here accurate data on trends in diabetes-related (DR) LEAs and non-DRLEAs in the South Tees area over a continuous 5-year period.All cases of LEA from 1 July 1995 to 30 June 2000 within the area were identified. Estimated ascertainment using capture-recapture analysis approached 100% for LEAs in the area. Data were collected longitudinally using the standard method of the Global Lower Extremity Amputation Study protocol.Over 5 years there were 454 LEAs (66.3% men) in the South Tees area, of which 223 were diabetes related (49.1%). Among individuals with diabetes, LEA rates went from 564.3 in the first year to 176.0 of 100,000 persons with diabetes in the fifth year. Over the same period, non-DRLEAs increased from 12.3 to 22.8 of 100,000 persons without diabetes. The relative risk of a person with diabetes undergoing an LEA went from being 46 times that of a person without diabetes to 7.7 at the end of the 5 years. The biggest improvement in LEA incidence was seen in the reduction of repeat major DRLEAs.Our data show that in the South Tees area at a time when major non-DRLEA rates increased, major DRLEA rates have fallen. These diverging trends mark a significant improvement in care for patients with diabetic foot disease as a result of better organized diabetes care.
HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability
Authors: Gi-Ae Kim, Young-Suk Lim, Jihyun An, Danbi Lee, Ju Hyun Shim, Kang Mo Kim, Han Chu Lee, Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh
Journal: Gut (2013)

<h3>Objective</h3> Little is known about the long-term clinical outcome and durability of HBsAg seroclearance following nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). <h3>Design</h3> During a median follow-up period of 6 years (33 567 patient-years) of 5409 CHB patients who were initially treated with lamivudine or entecavir, a total of 110 achieved HBsAg seroclearance (0.33% annual seroclearance rate) and were included in this study. <h3>Results</h3> Baseline alanine aminotransferase (ALT) level &gt;5 times of upper limit of normal was associated with higher probability of HBsAg seroclearance (HR 1.80, p&lt;0.01), while HBeAg positivity (HR 0.46, p&lt;0.01), high HBV DNA level (log<sub>10</sub> IU/mL; HR 0.61, p&lt;0.01), and cirrhosis (HR 0.48, p&lt;0.01) were inversely associated with the probability of HBsAg seroclearance by multivariable analysis. During follow-up for 287 patient-years after HBsAg seroclearance, only two patients with baseline cirrhosis developed hepatocellular carcinoma (HCC) or died (0.7% annual risk), which was of a significantly lower rate compared with propensity score-matched patients without HBsAg seroclearance (HR 0.09, p&lt;0.01). HBsAg reversion and/or HBV DNA reversion occurred in 18 patients, most of which were transient with extremely low serum levels of HBsAg (0.05–1.00 IU/mL) and HBV DNA (17-1818 IU/mL). None required retreatment. The cumulative probability of anti-HBs seroconversion (detection of anti-HBs) at 4 years was 67.4% by Kaplan–Meier analysis. Selection for lamivudine-resistance HBV mutants during treatment was not associated with composite reversion (p=0.66). <h3>Conclusions</h3> HBsAg seroclearance achieved after NUC treatment was associated with favourable clinical outcomes and was durable in most cases during long-term follow-up.
GDF15 Triggers Homeostatic Proliferation of Acid-Secreting Collecting Duct Cells
Authors: Jean Paul Duong Van Huyen, Lydie Cheval, May Bloch-Faure, Marie France Belair, Didier Heudes, Patrick Bruneval, Alain Doucet
Journal: Journal of the American Society of Nephrology (2008)

Although adult kidney cells are quiescent, enlargement of specific populations of epithelial cells occurs during repair and adaptive processes. A prerequisite to the development of regenerative therapeutics is to identify the mechanisms and factors that control the size of specific populations of renal cells. Unfortunately, in most cases, it is unknown whether the growth of cell populations results from transdifferentiation or proliferation and whether proliferating cells derive from epithelial cells or from circulating or resident progenitors. In this study, the mechanisms underlying the enlargement of the acid-secreting cell population in the mouse kidney collecting duct in response to metabolic acidosis was investigated. Acidosis led to two phases of proliferation that preferentially affected the acid-secreting cells of the outer medullary collecting duct. All proliferating cells displayed polarized expression of functional markers. The first phase of proliferation, which started within 24 h and peaked at day 3, was dependent on the overexpression of growth differentiation factor 15 (GDF15) and cyclin D1 and was abolished when phosphatidylinositol-3 kinase and mammalian target of rapamycin were inhibited. During this phase, cells mostly divided along the tubular axis, contributing to tubule lengthening. The second phase of proliferation was independent of GDF15 but was associated with induction of cyclin D3. During this phase, cells divided transversely. In summary, acid-secreting cells proliferate as the collecting duct adapts to metabolic acidosis, and GDF15 seems to be an important determinant of collecting duct lengthening.
Cross-Species Annotation of Basic Leucine Zipper Factor Interactions: Insight into the Evolution of Closed Interaction Networks
Authors: Christopher D. Deppmann, Rebecca S. Alvania, Elizabeth J. Taparowsky
Journal: Molecular Biology and Evolution (2006)

Dimeric basic leucine zipper (bZIP) factors constitute one of the most important classes of enhancer-type transcription factors. In vertebrates, bZIP factors are involved in many cellular processes, including cell survival, learning and memory, cancer progression, lipid metabolism, and a variety of developmental processes. These factors have the ability to homodimerize and heterodimerize in a specific and predictable manner, resulting in hundreds of dimers with unique effects on transcription. In recent years, several studies have described dimerization preferences for bZIP factors from different species, including Homo sapiens, Drosophila melanogaster, Arabidopsis thaliana, and Saccharomyces cerevisiae. Here, these findings are summarized as novel, graphical representations of closed, interacting protein networks. These representations combine phylogenetic information, DNA-binding properties, and dimerization preference. Beyond summarizing bZIP dimerization preferences within selected species, we have included annotation for a solitary bZIP factor found in the primitive eukaryote, Giardia lamblia, a possible evolutionary precursor to the complex networks of bZIP factors encoded by other genomes. Finally, we discuss the fundamental similarities and differences between dimerization networks within the context of bZIP factor evolution.
Determinants of Sensitivity and Resistance to Rapamycin-Chemotherapy Drug Combinations <i>In vivo</i>
Authors: Hans-Guido Wendel, Abba Malina, Zhen Zhao, Lars Zender, Scott C. Kogan, Carlos Cordon-Cardo, Jerry Pelletier, Scott W. Lowe
Journal: Cancer Research (2006)

Abstract The phosphatidylinositol-3-OH kinase [PI(3)K] pathway is frequently activated in human cancers and represents a rational target for therapeutic intervention. We have previously shown that enforced expression of Akt, which is a downstream effector of PI(3)K, could promote tumorigenesis and drug resistance in the Eμ-myc mouse lymphoma model, and that these tumors were particularly sensitive to inhibition of mammalian target of rapamycin (mTOR) with rapamycin when combined with conventional chemotherapy. We now show that reduced dosage of PTEN, a negative regulator of PI(3)K signaling, is sufficient to activate Akt, but has only a modest effect on lymphomagenesis in the same model. Nonetheless, loss of even one PTEN allele resulted in lymphomas that were resistant to conventional chemotherapy yet sensitive to rapamycin/chemotherapy combinations. These effects could be recapitulated by using RNA interference to suppress PTEN expression in lymphomas, which were previously established in the absence of PI(3)K lesions. Finally, the introduction of lesions that act downstream of mTOR (eIF4E) or disable apoptosis (Bcl-2 and loss of p53) into PTEN+/− lymphomas promoted resistance to rapamycin/chemotherapy combinations. Thus, whether activation of the PI(3)K pathway confers sensitivity or resistance to therapy depends on the therapy used as well as secondary genetic events. Understanding these genotype-response relationships in human tumors will be important for the effective use of rapamycin or other compounds targeting the PI(3)K pathway in the clinic. (Cancer Res 2006; 66(15): 7639-46)
Secondary <i>BRCA1</i> Mutations in <i>BRCA1</i>-Mutated Ovarian Carcinomas with Platinum Resistance
Authors: Elizabeth M. Swisher, Wataru Sakai, Beth Y. Karlan, Kaitlyn Wurz, Nicole Urban, Toshiyasu Taniguchi
Journal: Cancer Research (2008)

Abstract Although ovarian carcinomas with mutated BRCA1 or BRCA2 are sensitive to platinum compounds, such carcinomas eventually develop platinum resistance. Previously, we showed that acquired resistance to cisplatin in BRCA2-mutated tumors can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. Here, we show that secondary mutations of BRCA1 also occur in BRCA1-mutated ovarian cancer with platinum resistance. We evaluated nine recurrent BRCA1-mutated ovarian cancers previously treated with platinum compounds, including five with acquired platinum resistance, one with primary platinum resistance, and three with platinum sensitivity. Four of the six recurrent platinum-resistant tumors had developed secondary genetic changes in BRCA1 that restored the reading frame of the BRCA1 protein, whereas none of the three platinum-sensitive recurrent tumors developed BRCA1 sequence alterations. We immunohistochemically confirmed restored expression of BRCA1 protein in two cases with secondary mutations. Intriguingly, the case with primary platinum resistance showed back mutation of BRCA1 in the primary tumor and showed another secondary mutation in the recurrent tumor. Our results suggest that secondary mutations in BRCA1 can mediate resistance to platinum in BRCA1-mutated ovarian tumors. [Cancer Res 2008;68(8):2581–6]
The utility of transposon mutagenesis for cancer studies in the era of genome editing
Authors: Gina M. DeNicola, Florian A. Karreth, David J. Adams, Chi C. Wong
Journal: Genome biology (2015)

The use of transposons as insertional mutagens to identify cancer genes in mice has generated a wealth of information over the past decade. Here, we discuss recent major advances in transposon-mediated insertional mutagenesis screens and compare this technology with other screening strategies.
Parietal Attentional System Aberrations During Target Detection in Adolescents With Attention Deficit Hyperactivity Disorder: Event-Related fMRI Evidence
Authors: Leanne Tamm, Vinod Menon, Allan L. Reiss
Journal: American Journal of Psychiatry (2006)

Objective: Directed attention, the ability to allocate and direct attention toward a salient stimulus, is impaired in attention deficit hyperactivity disorder (ADHD). This construct is often assessed with target detection or oddball tasks, and individuals with ADHD perform poorly on such tasks. However, to date, the specific brain structures or neural mechanisms underlying target detection dysfunction in individuals with ADHD have not been identified. The authors' goal was to investigate neural correlates of target detection dysfunction in ADHD using event-related fMRI. Method: Behavioral and brain activation data were collected while subjects performed a visual oddball task. Participants included 14 right-handed male adolescents with ADHD (combined type) and 12 typically developing age- and handedness-matched male comparison subjects. Results: Individuals with ADHD made significantly more errors of commission than comparison subjects. Further, relative to comparison subjects, individuals with ADHD showed significantly less activation in the bilateral parietal lobes (including the superior parietal gyrus and supramarginal and angular gyri of the inferior parietal lobe), right precuneus, and thalamus. Conclusions: Adolescents with ADHD demonstrated significant impairments in their ability to direct and allocate attentional resources. These difficulties were associated with significant aberrations in the parietal attentional system, which is known to play a significant role in attention shifting and detecting specific or salient targets. Thus, dysfunction in the parietal attentional system may play a significant role in the behavioral phenotype of ADHD.
High Incidence of Thromboembolic Events in Patients Treated With Cisplatin-Based Chemotherapy: A Large Retrospective Analysis
Authors: Russell A. Moore, Nelly Adel, Elyn Riedel, Manisha Bhutani, Darren R. Feldman, Nour Elise Tabbara, Gerald Soff, Rekha Parameswaran, Hani Hassoun
Journal: Journal of Clinical Oncology (2011)

This study was designed to determine the incidence of venous and arterial thromboembolic events (TEEs) in patients treated with cisplatin-based chemotherapy and to analyze the prognostic value of patients' baseline and treatment characteristics in predicting TEE occurrence.We performed a large retrospective analysis of all patients treated with cisplatin-based chemotherapy for any type of malignancy at Memorial Sloan-Kettering Cancer Center in 2008. A TEE was cisplatin-associated if it occurred between the time of the first dose of cisplatin and 4 weeks after the last dose.Among 932 patients, 169 (18.1%) experienced a TEE during treatment or within 4 weeks of the last dose. TEEs included deep vein thrombosis (DVT) alone in 49.7%, pulmonary embolus (PE) alone in 25.4%, DVT plus PE in 13.6%, arterial TEE alone in 8.3%, or DVT plus arterial TEE in 3.0%. TEEs occurred within 100 days of initiation of treatment in 88% of patients. By univariate analysis, sex, age, race, Karnofsky performance status (KPS), exposure to erythropoiesis-stimulating agents, presence of central venous catheter (CVC), site of cancer, stage of cancer, leukocyte and hemoglobin levels, and Khorana score were all identified as risk factors. However, by multivariate analysis, only age, KPS, presence of CVC, and Khorana score retained significance.This large retrospective analysis confirms the unacceptable incidence of TEEs in patients receiving cisplatin-based chemotherapy. In view of the controversy associated with prophylactic anticoagulation in patients with cancer treated with chemotherapy, randomized studies are urgently needed in this specific cancer population treated with cisplatin-based regimens.
Neural Representations for Object Perception: Structure, Category, and Adaptive Coding
Authors: Zoe Kourtzi, Charles E. Connor
Journal: Annual Review of Neuroscience (2011)

Object perception is one of the most remarkable capacities of the primate brain. Owing to the large and indeterminate dimensionality of object space, the neural basis of object perception has been difficult to study and remains controversial. Recent work has provided a more precise picture of how 2D and 3D object structure is encoded in intermediate and higher-level visual cortices. Yet, other studies suggest that higher-level visual cortex represents categorical identity rather than structure. Furthermore, object responses are surprisingly adaptive to changes in environmental statistics, implying that learning through evolution, development, and also shorter-term experience during adulthood may optimize the object code. Future progress in reconciling these findings will depend on more effective sampling of the object domain and direct comparison of these competing hypotheses.
Design of an intravenous diet of amino-acids and fat suitable for intensive patient-care.
Authors: M. J. Peaston
Journal: BMJ (1966)

In serious illnesses complicated by dysphagia, vomiting, gastro intestinal obstruction, or ileus it is not possible to maintain nutrition by means of an adequate diet given by mouth or naso-gastric tube. The metabolic needs must therefore be supplied intravenously. Water and electrolytes are readily given, but it has been difficult t? satisfy the calorie and nitrogen requirements. Failure to provide these may not adversely influence the course of an illness of moderate severity or short duration, but during severe or prolonged illnesses, especially those associated with trauma or sepsis, the demands for calories and nitrogen are increased. Unless these demands are satisfied the patient will show muscle-wasting, delayed tissue repair, and a negative nitrogen balance ; the latter precedes the clinical signs. Nitrogen may be given intravenously as amino-acids, and commercial preparations have been available in this country since 1958. A high intake of calories in a relatively small volume can be provided conveniently only by a fat-emulsion (Moore, 1959). Until recently the emulsions available have produced serious toxic effects, but one prepared from soya bean oil and egg-yolk phosphatides (Intralipid) has been exten sively tested and has caused few serious reactions (Wretlind, 1964).