tbuckley/cabot-search huggingface dataset:
Correction: Stable and Unstable Malaria Hotspots in Longitudinal Cohort Studies in Kenya
Authors: Philip Bejon, Thomas N. Williams, Anne Liljander, Abdisalan M. Noor, Juliana Wambua, Edna Ogada, Ally Olotu, Faith H. A. Osier, Simon I. Hay, Anna FÃ¤rnert, Kevin Marsh
Journal: PLoS Medicine (2011)

Background: Infectious diseases often demonstrate heterogeneity of transmission among host populations.This heterogeneity reduces the efficacy of control strategies, but also implies that focusing control strategies on ''hotspots'' of transmission could be highly effective. Methods and Findings:In order to identify hotspots of malaria transmission, we analysed longitudinal data on febrile malaria episodes, asymptomatic parasitaemia, and antibody titres over 12 y from 256 homesteads in three study areas in Kilifi District on the Kenyan coast.We examined heterogeneity by homestead, and identified groups of homesteads that formed hotspots using a spatial scan statistic.Two types of statistically significant hotspots were detected; stable hotspots of asymptomatic parasitaemia and unstable hotspots of febrile malaria.The stable hotspots were associated with higher average AMA-1 antibody titres than the unstable clusters (optical density [OD] = 1.24, 95% confidence interval [CI] 1.02-1.47versus OD = 1.1, 95% CI 0.88-1.33)and lower mean ages of febrile malaria episodes (5.8 y, 95% CI 5.6-6.0 versus 5.91 y, 95% CI 5.7-6.1).A falling gradient of febrile malaria incidence was identified in the penumbrae of both hotspots.Hotspots were associated with AMA-1 titres, but not seroconversion rates.In order to target control measures, homesteads at risk of febrile malaria could be predicted by identifying the 20% of homesteads that experienced an episode of febrile malaria during one month in the dry season.That 20% subsequently experienced 65% of all febrile malaria episodes during the following year.A definition based on remote sensing data was 81% sensitive and 63% specific for the stable hotspots of asymptomatic malaria.Conclusions: Hotspots of asymptomatic parasitaemia are stable over time, but hotspots of febrile malaria are unstable.This finding may be because immunity offsets the high rate of febrile malaria that might otherwise result in stable hotspots, whereas unstable hotspots necessarily affect a population with less prior exposure to malaria.
The Interaction of the Beta-Haloethyl Benzylamines, Xylamine, and DSP-4 with Catecholaminergic Neurons
Authors: M W Dudley, B D Howard, A K Cho
Journal: The Annual Review of Pharmacology and Toxicology (1990)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Sequential use of biologics in moderate-to-severe plaque psoriasis: case studies illustrating an individualized approach
Authors: M. Goodfield
Journal: British Journal of Dermatology (2012)

Biologics have added great value to the treatment of psoriasis; however, there is currently little guidance on which biologic to use and at what stage of disease, and even less guidance on how to switch therapy in the event of treatment failure or the occurrence of side-effects. Furthermore, drug switching may not always be essential in cases of biologic failure, and adding conventional systemics has a role in some patients. It is clear that we have limited data to support any particular policy in initiating and switching biologics in psoriasis, but a pragmatic approach to therapy is supported by the case reports described within this article. Specifically, the case studies include patients who were initiated on different biologics and subsequently switched to alternatives for a variety of reasons, such as unresponsiveness or a concomitant disease. As more evidence emerges from long-term studies and registry data, a clearer picture should emerge on how best to use biologics in different situations to aid successful treatment outcomes. Comparative studies are necessary before firm recommendations about sequential use can be made.
Population-Based Estimate of the Contribution of <i>TP53</i> Mutations to Subgroups of Early-Onset Breast Cancer: Australian Breast Cancer Family Study
Authors: Judy Mouchawar, Christopher Korch, Tim Byers, Todd M. Pitts, Efang Li, Margaret R.E. McCredie, Graham G. Giles, John L. Hopper, Melissa C. Southey
Journal: Cancer Research (2010)

Abstract Although germline TP53 mutations have been identified in women with breast cancer from families meeting Li-Fraumeni criteria, their contribution to breast cancer per se is not well known, but is thought to be minimal. We aimed to determine the prevalence of germline TP53 mutations in subgroups of early-onset breast cancer. Germline TP53 mutation status was assessed by DNA sequencing, screening for heterozygous single-nucleotide polymorphisms, and Multiplex Ligation-Dependent Probe Amplification analyses. From an Australian population-based series of invasive breast cancers, we studied (a) 52 women diagnosed before age 30 years unselected for family history [very early-onset (VEO)] and (b) 42 women diagnosed in their 30s with two or more first- or second-degree relatives with breast or ovarian cancer [early-onset family history (EO-FH)]. Of the VEO group, two (4%) had a mutation: G13203A (exon 6 missense) in a 24-year-old and a large 5,338-bp genomic deletion in a 26-year-old. Neither had a family cancer history that met Li-Fraumeni criteria. Of the EO-FH group, three (7%) had a mutation: T13240G (a known intron 5 splicing mutation) in a 36-year-old from a classic Li-Fraumeni family; G12299A (exon 4 missense) in a 33-year-old from a Li-Fraumeni–like family; and 14058delG (exon 7 frame-shift) in a 39-year-old with a family cancer history that did not meet Li-Fraumeni criteria. Germline TP53 mutations play a larger role in early-onset breast cancer than previously thought, and in this context, can be evident outside clinically defined Li-Fraumeni families. Cancer Res; 70(12); 4795–800. ©2010 AACR.
Effect of Dimethylmyleran on Cell-Mediated Immunity to a Tumor Allograft2
Authors: Albert B. Einstein, Alexander Fefer
Journal: JNCI Journal of the National Cancer Institute (1975)

C57BL/6 mice (H-2b) were inoculated on day 0 with killed Moloney lymphoma cells (LSTRA) of BALB/c origin (H-2d), and their spleen cells were tested for reactivity against LSTRA by the 51Cr-release cytotoxicity assay. Cytotoxic reactivity of cells from ice not treated with drug was maximal by day 6 and disappeared by day 10. Cells from mice given dimethylmyleran (DDM) (12 or 16 mg/kg) on day -1 showed higher levels of cytotoxicity, whereas DMM administered on day +1 had little effect. The effect of DMM on the secondary response was tested and compared with that of cyclophosphamide (CY), 180 mg/kg. Cytotoxicity of cells from mice immunized on days 0 and 10 was maximal on day 15 and then declined. CY administered on day 11 prevented the development of any cytotoxicity and, when given on day 14 in the presence of a detectably strong secondary cytotoxic response, abolished the established response. In contrast, DMM given on day 11 delayed the onset and moderately decreased the peaks of secondary reactivity but had no effect when administered on day 14. These results showed that DMM enhanced a primary response, interfered somewhat with the development of a secondary response, and had no effect on an established secondary cell-mediated response to a tumor allograft. DMM thus was one of the rare agents with antitumor activity and little immunosuppressive action.
THE CARE OF RHEUMATIC CHILDREN
Authors: A. D. Fordyce
Journal: BMJ (1929)

MEDTCLL JOURNAl CASE VII.-Type V-Bacteriaemia with Recorcry.This case belonged to Type V; the blood culture was positive on the eighth day, though the temperature was below 1020.This patient either sterilized his own blood, or there was sufficient protection for Type V associated with the Type II serum.There were probably only 400 units of Type V protection given in the serum, (See Chart 3.) CASE VIII.-TypeV Bacteriaemia mistaken for Type Il: Fatal.This patient was a married woman who, on the third day of her illness, had a positive blood culture and sputum; the organism was reported from another laboratory.as Type II.On the fourth day she had a miscarriage at eight months.She received large doses of Type I and Type II serum.On the fifth day there was ample antibody for Types I and II.Her blood cuilture continued positive; the serum was unavailing.The original blood culture, which had been reported Type II, was then re-typed, as well as a blood culture after ample antibody for Type t and Type II had been administered and was demonstrable in the blood, and was found to be actually Type V.CASE IX.-Type II Bacteriaemia: Fatat-"Inftuenzal Pneumonia."This patient came in on the influenza service of the hospital.When a consolidation was discovered on the sixth day a blood culture was taken.He was given 15,000 units of Type II serum,
Alterations of Na <sup>+</sup> Currents in Myocytes From Epicardial Border Zone of the Infarcted Heart
Authors: Jielin Pu, Penelope A. Boyden
Journal: Circulation Research (1997)

Abstract Previously, we have shown abnormalities in V̇ max and in the recovery of V̇ max in myocytes dispersed from the epicardial border zone (EBZ) of the 5-day infarcted canine heart (myocytes from the EBZ [IZs]). Thus, we sought to determine the characteristics of the whole-cell Na + current ( I Na ) in IZs and compare them with the I Na of cells from noninfarcted hearts (myocytes from noninfarcted epicardium [NZs]). I Na was recorded using patch-clamp techniques under conditions that eliminated contaminating currents and controlled I Na for measurement (19°C, 5 mmol/L [Na + ] o ). Peak I Na density (at −25 mV) was significantly reduced in IZs (4.9±0.44 pA/pF, n=36) versus NZs (12.8±0.55 pA/pF, n=54; P &lt;.001), yet the half-maximal activation voltage (V 0.5 ), time course of decay, and time to peak I Na were no different. However, in IZs, V 0.5 of the availability curve ( I / I max curve) was shifted significantly in the hyperpolarizing direction (−80.2±0.48 mV in NZs [n=45] versus −83.9±0.59 mV in IZs [n=27], P &lt;.01). Inactivation of I Na directly from a depolarized prepotential (−60 mV) was significantly accelerated in IZs versus NZs (fast and slow time constants [τ 1 and τ 2 , respectively] were as follows: NZs [n=28], τ 1 =71.5±5.6 ms and τ 2 =243.7±17.1 ms; IZs [n=21], τ 1 =36.3±2.4 ms and τ 2 =153±11.3 ms; P &lt;.001). Recovery of I Na from inactivation was dependent on the holding potential (V H ) in both cell types but was significantly slower in IZs. At V H =−90 mV, I Na recovery had a lag in 18 (82%) of 22 IZs (with a 17.6±1.5-ms lag) versus 2 (9%) of 22 NZs (with 5.9- and 8.7-ms lags); at V H =−100 mV, τ 1 =60.9±2.6 ms and τ 2 =352.8±28.1 ms in NZs (n=41) versus τ 1 =76.3±4.8 ms and τ 2 =464.4±47.2 ms in IZs (n=26) ( P &lt;.002 and P &lt;.03, respectively); at V H =−110 mV, τ 1 =33.4±1.8 ms and τ 2 =293.5±33.6 ms in NZs (n=21) versus τ 1 =44.3±2.9 ms and τ 2 =388.4±38 ms in IZs (n=18) ( P &lt;.002 and P &lt;.07, respectively). In sum, I Na is reduced, and its kinetics are altered in IZs. These changes may underlie the altered excitability and postrepolarization refractoriness of the ventricular fibers of the EBZ, thus contributing to reentrant arrhythmias in the infarcted heart.
Effects of Intracarotid Injections of Hypertonic Solutions on Arterial Pressure in the Rabbit
Authors: ROBERT C. HOLLAND, JOHN W. SUNDSTEN, CHARLES H. SAWYER
Journal: Circulation Research (1959)

The intracarotid injection of hypertonic saline in the rabbit induces a brief drop in arterial pressure followed by a somewhat longer pressor phase. The "osmoreceptors" activating these changes are related to the hindbrain and are not the elements responsible for releasing neurohypophysial hormones. The pressure changes are not prevented by vagotomy, deafferentation of the carotid body and sinus, adrenalectomy, or parasympathetic blockade. The blood pressure effects are interpreted as resulting from sequential inhibition and stimulation of medullary vasomotor centers by the hypertonic solutions.
Detection of rearrangement of immunoglobulin heavy chain and T‐cell receptor beta chain in leukemic cells by restricted polymerase chain reaction
Authors: V. Stole, J. Uhrmacher, J. R. Krause
Journal: American Journal of Hematology (1991)

Rearrangement of the immunoglobulin heavy chain and of the T-cell receptor beta subunit was analyzed by using restricted polymerase chain reaction (PCR). To differentiate between the germline configuration and the rearranged genome in a DNA sample extracted from lymphocytes, we compared the ratio of the amplified products. The intensity of amplification of the intron region (JHF) upstream of the first joining region was compared to the intensity of joining region 6 of the immunoglobulin heavy chain. The number of the amplification cycles in the PCR was designated in such a way that the ratio of JHF/JH6 was less than one in the rearranged configuration. As the concentration of clonal B-lymphocytes with the rearranged genome in the sample increased the amplification of the JHF intron proportionally decreased. We used the same approach for the two constant regions of the T-cell receptor beta chain. As one of the intron regions of the constant sequence became depleted by rearrangement so the amplification of the particular region decreased. Therefore, the absence or decreased concentration of a particular product of amplification indicated deletion and thus rearrangement of the genome in the leukemic B- or T-lymphocytes. The threshold of detection of cells with the rearranged genome on a photograph of agarose gel loaded with the particular amplified regions and staining with the ethidium bromide is less than 10% by densitometric tracing and 25-50% by visual evaluation. This novel approach allows the detection of the rearranged DNA sequences in a 2 day span. Hence, it can serve as a diagnostic tool for the identification of clonal expansion of lymphocytes in acute leukemias and lymphomas in particular and for the detection of deleted genomic regions in general.
Distribution and functional impact of DNA copy number variation in the rat
Authors: Victor Guryev, Kathrin Saar, Tatjana Adamovic, Mark Verheul, Sebastiaan A A C van Heesch, Stuart Cook, Michal Pravenec, Timothy Aitman, Howard Jacob, James D Shull, Norbert Hubner, Edwin Cuppen
Journal: Nature Genetics (2008)
Persistence of Cytogenetic Abnormalities at Complete Remission After Induction in Patients With Acute Myeloid Leukemia: Prognostic Significance and the Potential Role of Allogeneic Stem-Cell Transplantation
Authors: Yiming Chen, Jorge Cortes, Zeev Estrov, Stefan Faderl, Wei Qiao, Lynne Abruzzo, Guillermo Garcia-Manero, Sherry Pierce, Xuelin Huang, Partow Kebriaei, Tapan Kadia, Marcos De Lima, Hagop Kantarjian, Farhad Ravandi
Journal: Journal of Clinical Oncology (2011)

Purpose To determine the prognostic impact of persistent cytogenetic abnormalities at complete remission (CR) on relapse-free survival (RFS) and overall survival (OS) in patients with acute myeloid leukemia (AML) and to examine the potential role of allogeneic stem-cell transplantation (SCT) in this setting. Patients and Methods Data from 254 adult patients with AML (excluding acute promyelocytic leukemia) who achieved CR after induction chemotherapy on various first-line protocols were examined. Results Median follow-up for surviving patients was 43 months. Patients with cytogenetic abnormalities at CR (n = 71) had significantly shorter RFS (P = .001) and OS (P &lt; .001) compared with patients with normal cytogenetics at CR (n = 183); 3-year RFS was 15% and 45%, and 3-year OS was 15% and 56%, respectively. Among the patients with persistent cytogenetic abnormalities at CR, those who underwent SCT in first CR (CR1; n = 15) had better RFS and OS compared to those without SCT (n = 56; P = .04 and .06, respectively). In multivariate analysis, persistent cytogenetic abnormalities at CR was an independent predictor for RFS (P &lt; .001) and OS (P = .001), but among patients with persistent cytogenetic abnormalities at CR, no significant differences in OS (P = .25) was observed between those who did or did not receive SCT with a trend favoring SCT for RFS (P = .08). Conclusion Persistent cytogenetically abnormal cells at CR predict a significantly shorter RFS and OS. SCT in CR1 may improve the clinical outcome of patients lacking cytogenetic remission after induction although this depends on patient selection.
THE EFFECT OF X-RADIATION ON THE MULTIPLICATION OF INFLUENZA A VIRUS IN EMBRYONATE EGGS
Authors: Herman T. Blumenthal, Donald Greiff, Masahiro Chiga, Henry Pinkerton
Journal: The Journal of Experimental Medicine (1953)

Groups of embryonate eggs were given 250, 500, 750, and 1000 r of x-radiation. 18 hours later, these 4 groups, together with a control group, were injected intra-allantoically with influenza A virus. Radiation at all dosage levels caused significant changes in the infectivity titre curves during the next 90 hours. The most striking alterations were the prolonged incubation period and the uniformly low infectivity titre in the group of eggs given 750 r.
Massive oesophagostomiasis of the colon
Authors: J. E. Jacques, J. B. Lynch
Journal: Gut (1964)

EDITORIAL SYNOPSiS Findings and treatment are described in a case of massive infestation of the colon with Oesophagostomum apiostomum.This is the seventh recorded human case, and the first from the Sudan.Problems of diagnosis are discussed briefly.Awareness of the condition, the real incidence of which is not known, could lead to a diagnosis.It is evident that good results may be obtained by radical surgery, even with massive involvement.Alimentary helminthiasis is not generally associated with severe intramural bowel lesions.We recently encountered a young man with extensive involve- ment of the wall of the colon by the worm oeso- phagostomum.Six human cases have been reported previously, but this was unique in its extent, the patient presenting with acute-on-chronic obstruction.
Inhibition of Ca2+ Signaling by <i>Mycobacterium tuberculosis</i>Is Associated with Reduced Phagosome–Lysosome Fusion and Increased Survival within Human Macrophages
Authors: Zulfiqar A. Malik, Gerene M. Denning, David J. Kusner
Journal: The Journal of Experimental Medicine (2000)

Complement receptor (CR)-mediated phagocytosis of Mycobacterium tuberculosis by macrophages results in intracellular survival, suggesting that M. tuberculosis interferes with macrophage microbicidal mechanisms. As increases in cytosolic Ca2+ concentration ([Ca2+]c) promote phagocyte antimicrobial responses, we hypothesized that CR phagocytosis of M. tuberculosis is accompanied by altered Ca2+ signaling. Whereas the control complement (C)-opsonized particle zymosan (COZ) induced a 4.6-fold increase in [Ca2+]c in human macrophages, no change in [Ca2+]c occurred upon addition of live, C-opsonized virulent M. tuberculosis. Viability of M. tuberculosis and ingestion via CRs was required for infection of macrophages in the absence of increased [Ca2+]c, as killed M. tuberculosis or antibody (Ab)-opsonized, live M. tuberculosis induced elevations in [Ca2+]c similar to COZ. Increased [Ca2+]c induced by Ab-opsonized bacilli was associated with a 76% reduction in intracellular survival, compared with C-opsonized M. tuberculosis. Similarly, reversible elevation of macrophage [Ca2+]c with the ionophore A23187 reduced intracellular viability by 50%. Ionophore-mediated elevation of [Ca2+]c promoted the maturation of phagosomes containing live C-opsonized bacilli, as evidenced by acidification and accumulation of lysosomal protein markers. These data demonstrate that M. tuberculosis inhibits CR-mediated Ca2+ signaling and indicate that this alteration of macrophage activation contributes to inhibition of phagosome–lysosome fusion and promotion of intracellular mycobacterial survival.
Bee venom stirs up buzz in antigen presentation
Authors: Luc Van Kaer
Journal: The Journal of Experimental Medicine (2015)

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Insight from Luc Van Kaer



While most T cells recognize peptide antigens presented by major histocompatibility complex (MHC) class I and class II molecules, some T cells react with lipid antigens presented by MHC-related CD1 proteins. In this issue, [Bourgeois et al.][2]
Opening the door on vested interests
Authors: Rebecca Coombes
Journal: BMJ (2005)

Two young men had similar nonobstructive idiopathic pachymeningitis cervicalis hypertrophica, causing chronic (13 and 11 years respectively) C8-T1 radiculomyelopathy proved by surgical and pathological findings. The preoperative Queckenstedt tests and myelography showed no evidence of CSF obstruction. These unusual findings contrast with previous reports which all described complete or at least partial, block. The findings on metrizamide computed tomogram have not been described before. In the two patients it revealed diffuse cord atrophy from C7 to T2 and hemiatrophy with lateral beaking from C4 to C7. The patients benefited from multiple transverse durotomies. The main pathogenesis of the cord atrophy was the compromizing of feeding radicular arteries rather than direct compression.
The Ego has landed! The .05 level of statistical significance is soft (Fisher) rather than hard (Neyman/Pearson)
Authors: Lester E. Krueger
Journal: Behavioral and Brain Sciences (1998)

Chow pays lip service (but not much more!) to Type I errors and thus opts for a hard (all-or-none) .05 level of significance (Superego of Neyman/Pearson theory; Gigerenzer 1993). Most working scientists disregard Type I errors and thus utilize a soft .05 level (Ego of Fisher; Gigerenzer 1993), which lets them report gradations of significance (e.g., p &lt; .001).
Multiple Sclerosis: An Immune or Neurodegenerative Disorder?
Authors: Bruce D. Trapp, Klaus-Armin Nave
Journal: Annual Review of Neuroscience (2008)

Multiple sclerosis (MS) is an inflammatory-mediated demyelinating disease of the human central nervous system. The clinical disease course is variable, usually starts with reversible episodes of neurological disability in the third or fourth decade of life, and transforms into a disease of continuous and irreversible neurological decline by the sixth or seventh decade. We review data that support neurodegeneration as the major cause of irreversible neurological disability in MS patients. We question whether inflammatory demyelination is primary or secondary in the disease process and discuss the challenges of elucidating the cause of MS and developing therapies that will delay or prevent the irreversible and progressive neurological decline that most MS patients endure.