tbuckley/cabot-search huggingface dataset:
STUDIES ON THE MECHANISM OF IMMUNITY IN TYPHUS FEVER
Authors: M. Ruiz Castaneda
Journal: The Journal of Experimental Medicine (1936)

This study of the lesions produced in the skin of guinea pigs inoculated intracutaneously with Mexican typhus virus, shows that there is an early polymorphonuclear response at the point of inoculation. As early as 24 hours after the virus is given, a mononuclear phagocytic infiltration, which is more pronounced around the larger vessels of the corium, vascularis, and muscularis, replaces the polymorphonuclear infiltration. The endothelial cells of capillaries and small vessels swell up, thus partially occluding the lumina. Rickettsia bodies are found in the swollen cells, in numbers which remind one of the intracellular Rickettsiae of the tunica in typhus infected guinea pigs. The mature Mooser's cells are found in abundance on the 3rd to the 4th day after inoculation. They are found in various positions as follows: (a) in the endothelial cells of capillaries, particularly in places of little or no infiltration; (b) within the mononuclear nodules formed around the larger vessels and within the dense infiltration of the vascularis (the parasitized cells are usually traced to a capillary wall); and (c) less frequently the organisms are found within the swollen cells of arterioles and small veins. The organisms disappear gradually from the zones of increasing polymorphonuclear infiltrations, suggesting that the presence of such polymorphonuclears is due to the bursting of the infected cells. In the artificial lesions produced in the skin by the inoculation of considerable numbers of Rickettsiae, the tissue reactions are abnormally enhanced. One can see in the same slide different stages of the development of the lesions and their relationship to the infecting agent. The early perivascular infiltration by mononuclear phagocytes does not seem to be related to an actual infection of the endothelial lining by the inoculated virus, but seems rather, when properly controlled, to be primarily due to a nonspecific type of response. The capillaries or small vessels within these infiltrated zones may become parasitized and call forth a polymorphonuclear reaction which may thus transform the cytological picture of the nodule. The subsequent migration of macrophages terminates the histological sequence. In capillaries apart from areas of cellular infiltrations, the polymorphonuclear reaction is first to appear, when the Rickettsiae are liberated from the cells. One cannot safely generalize from the results observed in an artificial typhus lesion, but in the light of these observations, it is probable that the Rickettsia bodies are difficult to find in typhus patients or infected animals because they disappear rapidly from the nodules, or perhaps because some nodules are not necessarily related to an infected endothelium. At any rate, a late typhus lesion is not likely to reveal Rickettsiae which most probably have been removed by the early polymorphonuclear invasion.
The Tuberin/mTOR Pathway Promotes Apoptosis of Tubular Epithelial Cells in Diabetes
Authors: Chakradhar Velagapudi, Basant S. Bhandari, Sherry Abboud-Werner, Simona Simone, Hanna E. Abboud, Samy L. Habib
Journal: Journal of the American Society of Nephrology (2011)

Apoptosis contributes to the development of diabetic nephropathy, but the mechanism by which high glucose (HG) induces apoptosis is not fully understood. Because the tuberin/mTOR pathway can modulate apoptosis, we studied the role of this pathway in apoptosis in type I diabetes and in cultured proximal tubular epithelial (PTE) cells exposed to HG. Compared with control rats, diabetic rats had more apoptotic cells in the kidney cortex. Induction of diabetes also increased phosphorylation of tuberin in association with mTOR activation (measured by p70S6K phosphorylation), inactivation of Bcl-2, increased cytosolic cytochrome c expression, activation of caspase 3, and cleavage of PARP; insulin treatment prevented these changes. In vitro, exposure of PTE cells to HG increased phosphorylation of tuberin and p70S6K, phosphorylation of Bcl-2, expression of cytosolic cytochrome c, and caspase 3 activity. High glucose induced translocation of the caspase substrate YY1 from the cytoplasm to the nucleus and enhanced cleavage of PARP. Pretreatment the cells with the mTOR inhibitor rapamycin reduced the number of apoptotic cells induced by HG and the downstream effects of mTOR activation noted above. Furthermore, gene silencing of tuberin with siRNA decreased cleavage of PARP. These data show that the tuberin/mTOR pathway promotes apoptosis of tubular epithelial cells in diabetes, mediated in part by cleavage of PARP by YY1.
Src Family Kinases as Novel Therapeutic Targets to Treat Breast Cancer Brain Metastases
Authors: Siyuan Zhang, Wen-Chien Huang, Lin Zhang, Chenyu Zhang, Frank J. Lowery, Zhaoxi Ding, Hua Guo, Hai Wang, Suyun Huang, Aysegul A. Sahin, Kenneth D. Aldape, Patricia S. Steeg, Dihua Yu
Journal: Cancer Research (2013)

Abstract Despite better control of early-stage disease and improved overall survival of patients with breast cancer, the incidence of life-threatening brain metastases continues to increase in some of these patients. Unfortunately, other than palliative treatments there is no effective therapy for this condition. In this study, we reveal a critical role for Src activation in promoting brain metastasis in a preclinical model of breast cancer and we show how Src-targeting combinatorial regimens can treat HER2+ brain metastases in this model. We found that Src was hyperactivated in brain-seeking breast cancer cells derived from human cell lines or from patients' brain metastases. Mechanistically, Src activation promoted tumor cell extravasation into the brain parenchyma via permeabilization of the blood–brain barrier. When combined with the EGFR/HER2 dual-targeting drug lapatinib, an Src-targeting combinatorial regimen prevented outgrowth of disseminated breast cancer cells through the induction of cell-cycle arrest. More importantly, this combinatorial regimen inhibited the outgrowth of established experimental brain metastases, prolonging the survival of metastases-bearing mice. Our results provide a rationale for clinical evaluation of Src-targeting regimens to treat patients with breast cancer suffering from brain metastasis. Cancer Res; 73(18); 5764–74. ©2013 AACR.
Outcomes in Young Adulthood for Very-Low-Birth-Weight Infants
Authors: Maureen Hack, Daniel J. Flannery, Mark Schluchter, Lydia Cartar, Elaine Borawski, Nancy Klein
Journal: New England Journal of Medicine (2002)

Very-low-birth-weight infants (those weighing less than 1500 g) born during the initial years of neonatal intensive care have now reached young adulthood.We compared a cohort of 242 survivors among very-low-birth-weight infants born between 1977 and 1979 (mean birth weight, 1179 g; mean gestational age at birth, 29.7 weeks) with 233 controls from the same population in Cleveland who had normal birth weights. We assessed the level of education, cognitive and academic achievement, and rates of chronic illness and risk-taking behavior at 20 years of age. Outcomes were adjusted for sex and sociodemographic status.Fewer very-low-birth-weight young adults than normal-birth-weight young adults had graduated from high school (74 percent vs. 83 percent, P=0.04). Very-low-birth-weight men, but not women, were significantly less likely than normal-birth-weight controls to be enrolled in postsecondary study (30 percent vs. 53 percent, P=0.002). Very-low-birth-weight participants had a lower mean IQ (87 vs. 92) and lower academic achievement scores (P<0.001 for both comparisons). They had higher rates of neurosensory impairments (10 percent vs. <1 percent, P<0.001) and subnormal height (10 percent vs. 5 percent, P=0.04). The very-low-birth-weight group reported less alcohol and drug use and had lower rates of pregnancy than normal-birth-weight controls; these differences persisted when comparisons were restricted to the participants without neurosensory impairment.Educational disadvantage associated with very low birth weight persists into early adulthood.
β3-Adrenoceptors in the heart
Authors: C Conrath
Journal: Cardiovascular Research (2002)

See article by Bosch et al. [4] ( pages 393 -403) in thisprolongation over the whole range of repolarization as a issue.result.The existence of b -adrenoceptors has been demon-3 strated in the human ventricle [1].The therapeutic indica-1 .b -Adrenoceptor stimulation and membrane
Health secretary is to bring back target to reduce numbers waiting 18 weeks for treatment
Authors: A. O'Dowd
Journal: BMJ (2011)

So called “hidden” waiting times for treatment in hospitals in England are to be tackled in a new drive that the government is expected to announce next week.

Hospitals could face financial penalties if they fail to meet a new target that is due to be unveiled before the end of November, set by the government to tackle the rising numbers of people waiting longer than 18 weeks for treatment.

Critics and health experts have expressed surprise that the government is planning a new target, given that it has repeatedly said it disapproved of the last Labour government’s many NHS targets.

The previous government introduced a waiting time target stipulating that 90% of inpatients and 95% of …
Side effects of high-dose interferon therapy for chronic hepatitis C
Authors: Takeshi Okanoue, Shinichi Sakamoto, Yoshito Itoh, Masahito Minami, Koichiro Yasui, Masafumi Sakamoto, Kenichi Nishioji, Tatsuo Katagishi, Yoshihiro Nakagawa, Hisashi Tada, Yoshihiko Sawa, Masayuki Mizuno, Keizo Kagawa, Kei Kashima
Journal: Journal of Hepatology (1996)
REGULATION OF MAMMALIAN ACETYL-COENZYME A CARBOXYLASE
Authors: Ki-Han Kim
Journal: Annual Review of Nutrition (1997)

Long-chain fatty acids are involved in all aspects of cellular structure and function. For controlling amounts of fatty acids, cells are endowed with two acetyl-coenzyme A carboxylase (ACC) systems. ACC-alpha is the rate-limiting enzyme in the biogenesis of long-chain fatty acids, and ACC-beta is believed to control mitochondrial fatty acid oxidation. These two isoforms of ACC control the amount of fatty acids in the cells. Phosphorylation and dephosphorylation of ACC-alpha cause enzyme inactivation and activation, respectively, and serve as the enzyme's short-term regulatory mechanism. Covalently modified enzymes become more sensitive toward cellular metabolites. In addition, many hormones and nutrients affect gene expression. The gene products formed are heterogeneous and tissue specific. The ACC-beta gene is located on human chromosome 12; the cDNA for this gene has just been cloned. The gene for the alpha-isoform is located on human chromosome 17. The catalytic core of the beta-isoform is homologous to that of the alpha-isoform, except for an additional peptide of about 150 amino acids at the N terminus. This extra peptide sequence makes the beta-form about 10,000 daltons larger, and it is thought to be involved in the unique role that has been assigned to this enzyme. The detailed control mechanisms for the beta-isoform are not known.
Ternary complexes of pDNA, polyethylenimine, and γ-polyglutamic acid for gene delivery systems
Authors: Tomoaki Kurosaki, Takashi Kitahara, Shintaro Fumoto, Koyo Nishida, Junzo Nakamura, Takuro Niidome, Yukinobu Kodama, Hiroo Nakagawa, Hideto To, Hitoshi Sasaki
Journal: Biomaterials (2009)
Is symbolic inheritance similar to genetic inheritance?
Authors: Luc Steels
Journal: Behavioral and Brain Sciences (2007)

Abstract Jablonka &amp; Lamb's (J&amp;L's) book is refreshing in that it debunks the exclusively gene-centered approach used these days to explain almost anything about life and human behavior. The book is very accessible and most convincing when the authors discuss biological theories of genetic and epigenetic inheritance, but it does not shy away from the more slippery terrain of behavioral and symbolic inheritance, and specifically the origins of language. But is the analogy appropriate?
Go gently, please
Authors: L. Farrell
Journal: BMJ (2002)

One of our most solemn duties is to confirm that life has fled away into the darkness and can no longer claim any pension entitlements. Sometimes this can be easy, like when there's no head, but sometimes it can be a tough call, and once I got it very wrong.

I had known Jimmy many years ago, so when I saw his widow I went over to pay my respects. I was embarrassed that I hadn't attended the wake (de rigueur …
Genetic Factors Influencing Irradiation Protection by Bone Marrow. III. Midlethal Irradiation of Inbred Mice
Authors: Delta E. Uphoff
Journal: JNCI Journal of the National Cancer Institute (1963)

Results from inoculation of allogeneic marrow after midlethal irradiation in various donor-host combinations of inbred strains and F1 hybrids can he classified as follows: 1) an early lethal effect; 2) no beneficial or deleterious effect; 3) initial protection followed by late deaths; 4) lasting protection. These results depend on the strain combinations used. The early lethal effect in certain host-donor combinations was alteredby: delayed marrow inoculation, use of substrain C3HeB as the irradiated host, and preimmunization of the irradiated host. Certain host-donor combinations without early mortality presented evidence of reversal to host phenotype. This reversal was demonstrated by transplantation of reticuloendothelial tumors arising in the treated mice and by transplantation of strain-specific transplantable neoplasms.
High-Resolution Electrophysiological Assessment of Human Embryonic Stem Cell-Derived Cardiomyocytes
Authors: Izhak Kehat, Amira Gepstein, Alon Spira, Joseph Itskovitz-Eldor, Lior Gepstein
Journal: Circulation Research (2002)

The goal of the present report was to establish a new in vitro model for the study of impulse propagation in human cardiac tissue. By using the human embryonic stem cell differentiating system, spontaneously contracting areas were generated in three-dimensional differentiating cell aggregates (embryoid bodies). Morphological analysis revealed an isotropic tissue of early-stage cardiac phenotype. Gap junctions, assessed by immunostaining of connexin43 and connexin45, were distributed along the cell borders. High-resolution activation maps demonstrated the presence of a functional syncytium with stable focal activation and conduction properties. Conduction was significantly slower in narrow bands of contracting tissue compared with broad cardiomyocyte regions. Establishment of this unique in vitro human model may be used for the assessment of long-term structure-function relationships, for pharmacological studies, for tissue engineering, and may permit the study of genetically modified cardiomyocytes.
Monomicrobial nonneutrocytic bacterascites: A variant of spontaneous bacterial peritonitis
Authors: Bruce A. Runyon
Journal: Hepatology (1990)

Spontaneous bacterial peritonitis is diagnosed when (a) the ascitic fluid culture is positive, (b) the ascitic fluid neutrophil count is greater than or equal to 250 cells/mm3 and (c) there is no evident intraabdominal surgically treatable source for infection. Few details are available regarding the variant of ascitic fluid infection in which the culture grows bacteria (pure growth of a single type of organism), but the neutrophil count is less than 250 cells/mm3. In this prospective study of 138 episodes of culture-positive spontaneously infected ascites detected in 105 patients, 44 (31.9%) were episodes of "monomicrobial nonneutrocytic bacterascites" compared with 94 (68.1%) episodes of spontaneous bacterial peritonitis. Seventeen patients had both types of infection. The infection-related mortality and hospitalization mortality were similar between the two groups. Patients with bacterascites appeared to have less severe liver disease. In 62% of bacterascites episodes in which a second paracentesis was performed before any treatment the fluid spontaneously became sterile without development of ascitic fluid neutrocytosis. Thirty-eight percent of patients with bacterascites (who underwent a second paracentesis before treatment was started) progressed to spontaneous bacterial peritonitis--sometimes within a few hours. The concentration of the chemoattractant C5a was not decreased in the ascitic fluid of the bacterascites patients; this excludes ascitic fluid C5a deficiency as the explanation of the lack of neutrocytosis. Monomicrobial nonneutrocytic bacterascites is a common variant of ascitic fluid infection that may resolve without treatment or may progress to spontaneous bacterial peritonitis.
Low carbohydrate-high protein diet and incidence of cardiovascular diseases in Swedish women: prospective cohort study
Authors: P. Lagiou, S. Sandin, M. Lof, D. Trichopoulos, H.-O. Adami, E. Weiderpass
Journal: BMJ (2012)

<b>Objective</b> To study the long term consequences of low carbohydrate diets, generally characterised by concomitant increases in protein intake, on cardiovascular health. <b>Design</b> Prospective cohort study. <b>Setting</b> Uppsala, Sweden. <b>Participants</b> From a random population sample, 43 396 Swedish women, aged 30-49 years at baseline, completed an extensive dietary questionnaire and were followed-up for an average of 15.7 years. <b>Main outcome measures</b> Association of incident cardiovascular diseases (ascertained by linkage with nationwide registries), overall and by diagnostic category, with decreasing carbohydrate intake (in tenths), increasing protein intake (in tenths), and an additive combination of these variables (low carbohydrate-high protein score, from 2 to 20), adjusted for intake of energy, intake of saturated and unsaturated fat, and several non-dietary variables. <b>Results</b> A one tenth decrease in carbohydrate intake or increase in protein intake or a 2 unit increase in the low carbohydrate-high protein score were all statistically significantly associated with increasing incidence of cardiovascular disease overall (n=1270)—incidence rate ratio estimates 1.04 (95% confidence interval 1.00 to 1.08), 1.04 (1.02 to 1.06), and 1.05 (1.02 to 1.08). No heterogeneity existed in the association of any of these scores with the five studied cardiovascular outcomes: ischaemic heart disease (n=703), ischaemic stroke (n=294), haemorrhagic stroke (n=70), subarachnoid haemorrhage (n=121), and peripheral arterial disease (n=82). <b>Conclusions</b> Low carbohydrate-high protein diets, used on a regular basis and without consideration of the nature of carbohydrates or the source of proteins, are associated with increased risk of cardiovascular disease.
Junctional sequences influence the specificity of gamma/delta T cell receptors.
Authors: B L Rellahan, J A Bluestone, B A Houlden, M M Cotterman, L A Matis
Journal: The Journal of Experimental Medicine (1991)

T lymphocytes bearing the gamma/delta T cell receptor (TCR-gamma/delta) express a limited number of germline variable gene segments, generating receptor sequence diversity primarily through junctional mechanisms. To examine the role of V(D)J junctional sequences in antigen recognition by TCR-gamma/delta, we derived an alloreactive murine TCR-gamma/delta+ T cell line, LKD1, specific for the I-Ad class II major histocompatibility complex (MHC) molecule, and compared its receptor with that expressed by a previously characterized class II MHC alloreactive T cell line, LBK5, specific for I-Ek,b,s Ia molecules. Both LKD1 and LBK5 express receptors encoded by rearranged V gamma 1.2J gamma 2 and V delta 5D delta 2J delta 1 gene elements, differing in sequence only in the V(D)J junctional regions of the gamma and delta genes. These results demonstrate that junctionally encoded sequences corresponding to the putative third complementarity determining region can influence the antigen specificity of TCR-gamma/delta.
Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly
Authors: Masami Yamada, Yuko Yoshida, Daisuke Mori, Takako Takitoh, Mineko Kengaku, Hiroki Umeshima, Keizo Takao, Tsuyoshi Miyakawa, Makoto Sato, Hiroyuki Sorimachi, Anthony Wynshaw-Boris, Shinji Hirotsune
Journal: Nature Medicine (2009)
Smoking, Clopidogrel, and Mortality in Patients With Established Cardiovascular Disease
Authors: Jeffrey S. Berger, Deepak L. Bhatt, Steven R. Steinhubl, Mingyuan Shao, P. Gabriel Steg, Gilles Montalescot, Werner Hacke, Keith A. Fox, A. Michael Lincoff, Eric J. Topol, Peter B. Berger
Journal: Circulation (2009)

Background— Smoking increases platelet aggregability and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown. Methods and Results— We evaluated the relationship between smoking status (current smoker, former smoker, or never-smoker) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12 152 participants from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial who had established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.85 to 3.60), cardiovascular (HR 2.26, 95% CI 1.48 to 3.45), and cancer (HR 3.56, 95% CI 1.96 to 6.46) mortality compared with never smoking. The impact of clopidogrel on mortality differed by smoking status ( P for interaction=0.018 for current smokers). Among current smokers, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, 95% CI 0.49 to 0.94); clopidogrel did not reduce all-cause mortality among former smokers (HR 0.95, 95% CI 0.75 to 1.19) or never-smokers (HR 1.14, 95% CI 0.83 to 1.58). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding appeared to differ according to smoking status; randomized clopidogrel was associated with a significantly increased risk of severe or moderate bleeding (HR 1.62, P =0.04) among current smokers but a smaller and nonsignificant increase among never-smokers (HR 1.31, P =0.15). Conclusions— Clopidogrel therapy may be more effective in current smokers, but it may also confer a greater bleeding risk than in nonsmokers. Further studies are needed to investigate this possibility.
Heart fatty acid binding protein and Aβ-associated Alzheimer’s neurodegeneration
Authors: Rahul S Desikan, Wesley K Thompson, Dominic Holland, Christopher P Hess, James B Brewer, Henrik Zetterberg, Kaj Blennow, Ole A Andreassen, Linda K McEvoy, Bradley T Hyman, Anders M Dale
Journal: Molecular Neurodegeneration (2013)

Epidemiological and molecular findings suggest a relationship between Alzheimer's disease (AD) and dyslipidemia, although the nature of this association is not well understood. Using linear mixed effects models, we investigated the relationship between CSF levels of heart fatty acid binding protein (HFABP), a lipid binding protein involved with fatty acid metabolism and lipid transport, amyloid-β (Aβ), phospho-tau, and longitudinal MRI-based measures of brain atrophy among 295 non-demented and demented older individuals. Across all participants, we found a significant association of CSF HFABP with longitudinal atrophy of the entorhinal cortex and other AD-vulnerable neuroanatomic regions. However, we found that the relationship between CSF HABP and brain atrophy was significant only among those with low CSF Aβ1–42 and occurred irrespective of phospho-tau181p status. Our findings indicate that Aβ-associated volume loss occurs in the presence of elevated HFABP irrespective of phospho-tau. This implicates a potentially important role for fatty acid binding proteins in Alzheimer's disease neurodegeneration.