tbuckley/cabot-search huggingface dataset:
Has child protection become a form of madness? Yes
Authors: A. Gregoire, S. Agnello Hornby
Journal: BMJ (2011)

During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to CNS insults, positioning these cells to have profound impact on the function of nearby neurons. We and others recently showed that microglial attributes differ significantly across brain regions in young adult mice. However, the degree to which microglial properties vary during aging is largely unexplored. Here, we analyze and manipulate microglial aging within the basal ganglia, brain circuits that exhibit prominent regional microglial heterogeneity and where neurons are vulnerable to functional decline and neurodegenerative disease. In male and female mice, we demonstrate that VTA and SNc microglia exhibit unique and premature responses to aging, compared with cortex and NAc microglia. This is associated with localized VTA/SNc neuroinflammation that may compromise synaptic function as early as middle age. Surprisingly, systemic inflammation, local neuron death, and astrocyte aging do not appear to underlie these early aging responses of VTA and SNc microglia. Instead, we found that microglial lysosome status was tightly linked to early aging of VTA microglia. Microglial ablation/repopulation normalized VTA microglial lysosome swelling and suppressed increases in VTA microglial density during aging. In contrast, CX3CR1 receptor KO exacerbated VTA microglial lysosome rearrangements and VTA microglial proliferation during aging. Our findings reveal a previously unappreciated regional variation in onset and magnitude of microglial proliferation and inflammatory factor production during aging and highlight critical links between microglial lysosome status and local microglial responses to aging. <b>SIGNIFICANCE STATEMENT</b> Microglia are CNS cells that are equipped to regulate neuronal health and function throughout the lifespan. We reveal that microglia in select brain regions begin to proliferate and produce inflammatory factors in late middle age, months before microglia in other brain regions. These findings demonstrate that CNS neuroinflammation during aging is not uniform. Moreover, they raise the possibility that local microglial responses to aging play a critical role in determining which populations of neurons are most vulnerable to functional decline and neurodegenerative disease.
Cardiac resynchronization therapy increases plasma levels of the endogenous inotrope apelin
Authors: Pietro Francia, Adriano Salvati, Cristina Balla, Paola De Paolis, Erika Pagannone, Marina Borro, Giovanna Gentile, Maurizio Simmaco, Luciano De Biase, Massimo Volpe
Journal: European Journal of Heart Failure (2006)
IMMUNE DONORS CAN PROTECT MARROW-TRANSPLANT RECIPIENTS FROM SEVERE CYTOMEGALOVIRUS INFECTIONS
Authors: J.P. Grob, H.G. Prentice, A.V. Hoffbrand, T. Tate, J.E. Grundy, P.D. Griffiths, M.D. Hughes, J.Z. Wimperis, M.K. Brenner
Journal: The Lancet (1987)
Hopping around the Tumor Genome: Transposons for Cancer Gene Discovery
Authors: Lara S. Collier, David A. Largaespada
Journal: Cancer Research (2005)

Abstract Retroviruses are powerful insertional somatic mutagens that have been used for many landmark discoveries of cancer genes in model organisms. However, their use as a cancer gene discovery tool has been limited to only a few tissues, mainly the hematopoietic system and mammary gland. Recently, the Sleeping Beauty (SB) transposon system was shown to be useful for random somatic cell mutagenesis in mice, allowing the induction or acceleration of tumor formation both in the hematopoietic system and in sarcomas. In these tumors, SB transposons repeatedly “tagged” specific genes, both known and new cancer genes. These results indicate that the SB system has great potential both for generating specific mouse models of human cancer and for cancer gene discovery in a wide variety of tissues.
Capsule endoscopy for abdominal pain - is it of value or just another test for doctors to do?
Authors: S. Pasha, D. Fleischer
Journal: Endoscopy (2007)

Chronic abdominal pain represents a true diagnostic challenge to both gastroenterologists and primary care physicians. The underlying etiologies are diverse, including but not limited to inflammatory bowel disease, gastrointestinal infections, ischemic diseases, malabsorption syndromes, malignancies, and functional disorders. Irritable bowel syndrome (IBS), functional abdominal pain and functional dyspepsia account for up to 50 % of referrals for the gastroenterological evaluation of abdominal pain and associated gastrointestinal symptoms [1]. The positive yield of diagnostic testing in patients with IBS is only 2 %, which is equivalent to the yield in the general healthy population [2]. According to a systematic review, the pretest probability of organic diseases, including inflammatory bowel disease, infectious diarrhea and colorectal cancer was found to be less than 1 % in patients with suspected IBS [3]. The only exception was celiac sprue, which was associated with a pretest probability of 5 %, compared with < 1 % in healthy controls. The presence of alarm features of age greater than 50 years, gastrointestinal bleed, weight loss, and anemia have been reported as independent predictors of organic disease in patients with suspected functional disorders [4]. There is a huge financial burden related to chronic abdominal pain, with an estimated $ 8 billion spent annually in the US on patients with IBS alone [5]. Better stratification of patients with chronic abdominal pain would lead to a more appropriate and cost-effective use of resources.
Evolution: The Grand Synthesis
Authors: Michael T. McGuire
Journal: JAMA (1987)

The vision that lies behind this book is disturbing: we live in a period of major discontinuity in world history, a period marked by an explosion of world population, the loss of traditional values, social destabilization, unemployment, obsolescence of institutions and political systems, and the disappearance of traditional ideologies that in the past have given our behavior its bearings. The author, Ervin Laszlo, is a member of the Club of Rome, which, in recent years, has been a meeting place of intellectuals interested in the "world problematique." Laszlo's strategy for dealing with our dilemma is to understand the natural forces that direct physical processes, biology, and social behavior and, through that understanding, master our destiny. His intention is noble, the task itself may be another matter. This is where evolution enters the picture. In the author's view, an expanded evolutionary theory is the best theory available to organize and synthesize
Insulin stimulates volume absorption in the rabbit proximal convoluted tubule.
Authors: M Baum
Journal: Journal of Clinical Investigation (1987)

The present in vitro microperfusion study examined whether insulin affects volume absorption (Jv) in the proximal convoluted tubule (PCT). PCT were perfused with an ultrafiltrate-like solution and were bathed in a serum-like albumin solution. Addition of a physiologic concentration of 10(-10) M insulin to the bathing solution resulted in a stimulation of Jv and a more negative transepithelial potential difference (PD). There was a progressive stimulation of the lumen negative PD and Jv with higher insulin concentrations. Maximal stimulation occurred at 10(-8) M bath insulin. The insulin-induced stimulation of volume reabsorption was also observed when glucose and amino acids were removed from the luminal perfusate. Direct examination of the effect of insulin on glucose, chloride, and bicarbonate absorption demonstrated that the transport of all these solutes was stimulated by insulin. Addition of insulin to the luminal perfusate had no affect on Jv. These data show that insulin has a direct effect to stimulate Jv in the proximal tubule.
DEFORMITY OF THE AIR BUBBLE OF THE STOMACH IN CARCINOMA
Authors: Jacob Buckstein
Journal: JAMA (1926)

In a fluoroscopic survey of the abdomen, an important factor that may be overlooked is the appearance of the magenblase, or air bubble of the stomach. The normal air bubble (fig. 1) has. a wide variation as to size and shape, but all agree in the absence of any irregularity in contour. By a careful inspection of this region, irregularities due to the projection within it of an infiltrative mass may be noted, and a diagnosis of carcinoma of this region made, even prior to the administration of a barium meal. The barium, however, by coating the mass, may bring it into clearer relief. In order to emphasize the significance of the deformed bubble, I am including the roentgenograms of three cases of operatively demonstrated carcinoma of the cardiac zone of the stomach. These cases represent various degrees in deformity, from the crescentic deformity of the base, due to the
Management of an Inherited Predisposition to Breast Cancer
Authors: Mark Robson, Kenneth Offit
Journal: New England Journal of Medicine (2007)

A healthy 33-year-old woman comes to establish care. She has no breast symptoms, her age at menarche was 14 years, and she has no children. She notes a family history of early-onset breast cancer in her sister, mother, and maternal aunt. Her maternal grandfather died of prostate cancer. What screening and risk-reduction strategies would you advise?
Chronic ethanol ingestion impairs alveolar type II cell glutathione homeostasis and function and predisposes to endotoxin-mediated acute edematous lung injury in rats.
Authors: F Holguin, I Moss, L A Brown, D M Guidot
Journal: Journal of Clinical Investigation (1998)

Chronic alcohol abuse increases the incidence and mortality of the acute respiratory distress syndrome (ARDS) in septic patients. To examine a potential mechanism, we hypothesized that ethanol ingestion predisposes to sepsis-mediated acute lung injury by decreasing alveolar type II cell glutathione homeostasis and function. Lungs isolated from rats fed ethanol (20% in water for >/= 3 wk), compared with lungs from control-fed rats, had greater (P < 0. 05) edematous injury (reflected by nonhydrostatic weight gain) after endotoxin (2 mg/kg intraperitoneally) and subsequent perfusion ex vivo with n-formylmethionylleucylphenylalanine (fMLP, 10(-7) M). Ethanol ingestion decreased (P < 0.05) glutathione levels in the plasma, lung tissue, and lung lavage fluid, and increased (P < 0.05) oxidized glutathione levels in the lung lavage fluid. Furthermore, ethanol ingestion decreased type II cell glutathione content by 95% (P < 0.05), decreased (P < 0.05) type II cell surfactant synthesis and secretion, and decreased (P < 0.05) type II cell viability, in vitro. Finally, treatment with the glutathione precursors S-adenosyl-L-methionine and N-acetylcysteine in the final week of ethanol ingestion significantly reduced lung edema during perfusion ex vivo. We conclude that ethanol ingestion in rats alters alveolar type II cell glutathione levels and function, thereby predisposing the lung to acute edematous injury after endotoxemia. We speculate that chronic alcohol abuse in humans predisposes to ARDS through similar mechanisms.
Genetic Abnormalities of the <i>EGFR</i> Pathway in African American Patients With Non–Small-Cell Lung Cancer
Authors: Rom S. Leidner, Pingfu Fu, Bradley Clifford, Ayad Hamdan, Cheng Jin, Rosana Eisenberg, Titus J. Boggon, Margaret Skokan, Wilbur A. Franklin, Federico Cappuzzo, Fred R. Hirsch, Marileila Varella-Garcia, Balazs Halmos
Journal: Journal of Clinical Oncology (2009)

Purpose Previous studies in non–small-cell lung cancer (NSCLC) have demonstrated a wide variation in responsiveness to epidermal growth factor receptor (EGFR) –targeting agents and in genetic aberrancies of the EGFR pathway according to ethnic background, most notably a higher frequency of activating EGFR mutations among East-Asian patients. We investigated the frequency of EGFR pathway aberrancies among African American patients with NSCLC, for whom limited information presently exists. Patients and Methods EGFR fluorescent in situ hybridization (FISH) was performed on archived tissues from 53 African American patients. Extracted DNA was sequenced for mutational analysis of EGFR exons 18 to 21 and KRAS exon 2. Results were compared by multivariate analysis to an historical control cohort of 102 white patients with NSCLC. Results African Americans were significantly less likely to harbor activating mutations of EGFR than white patients (2% v 17%; P = .022). Only one EGFR mutation was identified, a novel S768N substitution. EGFR FISH assay was more frequently positive for African Americans than for white patients (51% v 32%; P = .018). KRAS mutational frequency did not differ between the groups (23% v 21%; P = .409). Conclusion African American patients with NSCLC are significantly less likely than white counterparts to harbor activating mutations of EGFR, which suggests that EGFR tyrosine kinase inhibitors (TKIs) are unlikely to yield major remissions in this population. Our findings add to a growing body of evidence that points to genetic heterogeneity of the EGFR pathway in NSCLC among different ethnic groups and that underscores the need for consideration of these differences in the design of future trials of agents that target the EGFR pathway.
Importance of Murine Study Design for Testing Toxicity of Retroviral Vectors in Support of Phase I Trials
Authors: Elke Will, Jeff Bailey, Todd Schuesler, Ute Modlich, Brenden Balcik, Ben Burzynski, David Witte, Gerlinde Layh-Schmitt, Cornelia Rudolph, Brigitte Schlegelberger, Christof von Kalle, Christopher Baum, Brian P Sorrentino, Lars M Wagner, Patrick Kelly, Lilith Reeves, David A Williams
Journal: Molecular Therapy (2007)

Although retroviral vectors are one of the most widely used vehicles for gene transfer, there is no uniformly accepted pre-clinical model defined to assess their safety, in particular their risk related to insertional mutagenesis. In the murine pre-clinical study presented here, 40 test and 10 control mice were transplanted with ex vivo manipulated bone marrow cells to assess the long-term effects of the transduction of hematopoietic cells with the retroviral vector MSCV-MGMTP140Kwc. Test mice had significant gene marking 8–12 months post-transplantation with an average of 0.93 vector copies per cell and 41.5% of peripheral blood cells expressing the transgene MGMTP140K, thus confirming persistent vector expression. Unexpectedly, six test mice developed malignant lymphoma. No vector was detected in the tumor cells of five animals with malignancies, indicating that the malignancies were not caused by insertional mutagenesis or MGMTP140K expression. Mice from a concurrent study with a different transgene also revealed additional cases of vector-negative lymphomas of host origin. We conclude that the background tumor formation in this mouse model complicates safety determination of retroviral vectors and propose an improved study design that we predict will increase the relevance and accuracy of interpretation of pre-clinical mouse studies. Although retroviral vectors are one of the most widely used vehicles for gene transfer, there is no uniformly accepted pre-clinical model defined to assess their safety, in particular their risk related to insertional mutagenesis. In the murine pre-clinical study presented here, 40 test and 10 control mice were transplanted with ex vivo manipulated bone marrow cells to assess the long-term effects of the transduction of hematopoietic cells with the retroviral vector MSCV-MGMTP140Kwc. Test mice had significant gene marking 8–12 months post-transplantation with an average of 0.93 vector copies per cell and 41.5% of peripheral blood cells expressing the transgene MGMTP140K, thus confirming persistent vector expression. Unexpectedly, six test mice developed malignant lymphoma. No vector was detected in the tumor cells of five animals with malignancies, indicating that the malignancies were not caused by insertional mutagenesis or MGMTP140K expression. Mice from a concurrent study with a different transgene also revealed additional cases of vector-negative lymphomas of host origin. We conclude that the background tumor formation in this mouse model complicates safety determination of retroviral vectors and propose an improved study design that we predict will increase the relevance and accuracy of interpretation of pre-clinical mouse studies.
Indian Supreme Court tells government to act on illegal clinical trials
Authors: M. Kay
Journal: BMJ (2013)

The Supreme Court of India has said that the government failed to put in place proper mechanisms to stop “rackets” being committed by multinational companies that conduct illegal clinical trials and has asked it to deal with the problem urgently. 

The court told the health secretary in the Health and Family Welfare Ministry to directly monitor clinical trials of drugs on humans to ensure that statutory procedures were followed. The court order stated that “until further order by this Court, clinical trials …
Serum Lipoproteins in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications Cohort
Authors: Alicia J. Jenkins, Timothy J. Lyons, Deyi Zheng, James D. Otvos, Daniel T. Lackland, Daniel McGee, W. Timothy Garvey, Richard L. Klein
Journal: Diabetes Care (2003)

OBJECTIVE—To relate the nuclear magnetic resonance (NMR)-determined lipoprotein profile, conventional lipid and apolipoprotein measures, and in vitro oxidizibility of LDL with gender and glycemia in type 1 diabetes. RESEARCH DESIGN AND METHODS—In the 1997–1999 Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) cohort, serum from 428 women and 540 men were characterized by conventional lipids, NMR, apolipoprotein levels, and LDL susceptibility to in vitro oxidation. Simple and partial correlation coefficients were calculated for each lipoprotein-related parameter versus gender, with and without covariates (age, diabetes duration, concurrent HbA1c, DCCT randomization, hypertension, BMI, waist-to-hip ratio, and albuminuria). For concurrent HbA1c, data were analyzed as above, exchanging gender for HbA1c. Associations were significant if P &amp;lt; 0.05. RESULTS—Although men and women had similar total and LDL cholesterol and triglycerides, men exhibited the following significant percent differences in NMR profiles versus women: small VLDL 41; IDL −30; medium LDL 39; small LDL 21; large HDL −32; small HDL 35; LDL particle concentration 4; VLDL and HDL diameters −8 and −4, respectively. Small VLDL, small HDL, medium LDL (women only), small LDL (men only), and LDL particle concentration were positively correlated, and HDL size was inversely correlated, with concurrent HbA1c. NMR profile was unrelated to prior DCCT randomization. Susceptibility of LDL to oxidation was unrelated to gender and glycemia. CONCLUSIONS—Male gender and poor glycemia are associated with a potentially more atherogenic NMR lipoprotein profile. Neither gender nor glycemia influence LDL oxidation in vitro.
Electronic Journals and Duplicate Publication Is a Byte a Word?
Authors: Annette Flanagin
Journal: JAMA (1992)

More than 300 years ago, general medical journals were created to capture in print the proceedings of scientific meetings and discussions and to communicate these proceedings to medical society members.<sup>1,2</sup>Mostly during the last century, these informal collections evolved into today's scholarly, formally peer-reviewed journals, disseminating scientific reports to readers worldwide. We are now witnessing another information evolution—the electronic journal—spreading the scientific word in tiny, invisible bits and bytes. An "electronic journal" transmits information to readers through a computer network. This information, which includes text, tables, and figures, is produced and stored on computers, is read on a video screen, and subsequently can be printed on paper.<sup>3,4</sup>Since one of the goals of an electronic journal is to disseminate information (usually the work of an author) to readers (albeit faster than conventionally printed and mailed paper journals), an electronic journal is merely another medium of publication, and the
The Hills of Angheri
Authors: Sanjay A Pai
Journal: BMJ (2006)

K avery Nambisan is among the few Indian doctors who is also a published writer and novelist. Moreover, she is that rarity, a woman surgeon. The Hills of Angheri is based loosely on her own experiences (see also http://careerfocus.bmjjournals.com/cgi/content/full/324/7347/S158).

The protagonist of this novel, Nalli, is a girl in a male dominated village in southern India and wishes, …
Covered Expandable Metalic Stent Placement for Hemostasis of Colonic Bleeding Caused by Invasion of Gallbladder Carcinoma
Authors: N. Hasegawa, K. Kato, K. Morita, M. Kuroiwa, M. Shinkai, T. Hayashi, T. Kamioka, H. Otagiri, Y. Shindo, H. Goto
Journal: Endoscopy (2003)

A 72-year-old Japanese man was admitted to our hospital complaining of right upper-quadrant abdominal pain, blood in his stool, and symptoms of anemia. On physical examination a hard mass, about 6 cm in diameter, was palpable in the right upper quadrant of the abdomen. Computed tomography revealed a gallbladder carcinoma which had invaded the transverse colon, with liver metastasis. We diagnosed gallbladder carcinoma, stage IVB. Colonoscopy was performed for persistent blood in the stools. This revealed an elevated lesion which appeared to be an invasion of gallbladder carcinoma, with diffuse bleeding from the right-side of the transverse colon. It proved difficult to stop this bleeding by ordinary therapeutic endoscopy. In order to achieve hemostasis we therefore inserted a covered Ultraflex metallic stent to compress the tumor. After stent placement, blood was no longer seen in the patient's stools, he became able to eat soft food and was discharged. This treatment was uninvasive and effective. Covered stent placement appears to be a new and useful method in the management of bleeding from malignant gastrointestinal tumors.
Emergency Department Overuse
Authors: James G. Adams
Journal: JAMA (2013)

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