tbuckley/cabot-search huggingface dataset:
Comparative Vertebrate Evolutionary Analyses of Type I Collagen: Potential of COL1a1 Gene Structure and Intron Variation for Common Bone-Related Diseases
Authors: D. A. Stover, B. C. Verrelli
Journal: Molecular Biology and Evolution (2010)

Collagen type I alpha 1 (COL1a1), which encodes the primary subunit of type I collagen, the main structural and most abundant protein in vertebrates, harbors hundreds of mutations linked to human diseases like osteoporosis and osteogenesis imperfecta. Previous studies have attempted to predict the phenotypic severity associated with type I collagen mutations, yet an evolutionary analysis that compares historical and recent selective pressures, including across noncoding regions, has never been conducted. Here, we use a comparative genomic and species evolutionary analysis representing ∼450 My of vertebrate history to investigate functional constraints associated with both exons and introns of the >17-kb COL1a1 gene. We find that although the COL1a1 amino acid sequence is highly conserved, there are both spatial and temporal signatures of varying selective constraint across protein domains. Furthermore, sites of high evolutionary constraint significantly correlate with the location of disease-associated mutations, the latter of which also cluster with respect to specific severity classes typically categorized in clinical studies. Finally, we find that COL1a1 introns are significantly short in length with high GC content, patterns that are shared across highly diverged vertebrates, and which may be a signature of strong stabilizing selection for high COL1a1 gene expression. In conclusion, although previous studies focused on COL1a1 coding regions, the current results implicate introns as areas of high selective constraint and targets of bone-related phenotypic variation. From a broader perspective, our comparative evolutionary approach provides further resolution to models predicting mutations associated with bone-related function and disease severity.
Cellular and genetic control of antibody responses. V. Helper T-cell recognition of H-2 determinants on accessory cells but not B cells.
Authors: A Singer, K S Hathcock, R J Hodes
Journal: The Journal of Experimental Medicine (1979)

Requirements for helper T-cell recognition of H-2 determinants expressed on adherent accessory cells and on B cells was individually assessed in the anti-hapten PFC responses to TNP-KLH. Complicating allogeneic effects were minimized or avoided by the use of helper T cells from normal F1 hybrids, parent leads to F1 chimeras, and F1 leads to parent chimeras. The results of both in vitro and in vivo experiments demonstrated that: (a) helper T cells are not required to recognize the identical H-2 determinants on both accessory cells and B cells; (b) helper T cells are required to recognize K or I-A region-encoded determinants expressed on accessory cells; (c) no requirement was observed in vitro or in vivo for helper T-cell recognition of B-cell-expressed H-2 determinants; and (d) no requirement was observed for H-2 homology between accessory cells and B cells. The absence of required helper T-cell recognition of the identical H-2 determinants on both accessory cells and B cells was demonstrated in two ways: (a) naive of KLH-primed (A x B)F1 hybrid helper T cells collaborated equally well with B cells from either parentA or parentB in the presence of accessory cells from either parent; (b) A leads to (A x B)F1 chimeric spleen cells depleted of accessory cells collaborated equally well with accessory cells from either parentA or parentB, even though the B cells only expressed the H-2 determinants of parentA. A requirement for helper T-cell recognition of K or I-A region-encoded H-2 determinants on accessory cells was also demonstrated in two ways: (a) (A x B)F1 leads to parentA chimeric spleen cells depleted of accessory cells collaborated with accessory cells from parentA but not parentB; and (b) (A x B)F1 leads to parentA chimeric helper T cells collaborated with normal F1 B cells only in the presence of parental or recombinant accessory cells that expressed the K or I-A region-encoded determinants of parentA. Although restricted in their ability to recognize H-2 determinants on accessory cells, it was demonstrated both in vitro and in vivo that (A x B)F1 leads to parentA chimeric helper T cells were able to collaborate with B cells from either parentA or parentB. In vitro in the presence of accessory cells from parentA, (A x B)F1 leads to parentA chimeric helper T cells collaborated equally well with B cells from either parent. In addition, the inability of (A x B)F1 leads to parentA chimeric helper T cells to collaborate with (B + accessory) cells from parentB was successfully reversed by the addition of parentA SAC as added accessory cells. In vivo, upon the addition of parentA accessory cells, (A x B)F1 leads to parentA chimeric helper T cells collaborated with parentB B cells in short-term adoptive transfer experiments.
Diagnosis of asthma in children
Authors: J Townshend, S Hails, M Mckean
Journal: BMJ (2007)

Children presenting with wheeze are likely to have either atopic asthma or episodic viral wheeze; distinguishing between these has important implications for management If it's wheeze it must be asthma, and if it's asthma it must mean bronchodilators and inhaled corticosteroids-simple enough.Indeed, as asthma is so common this paradigm might seem to be logical.The large scale international study of asthma and allergy in childhood (ISAAC) found that the United Kingdom, Australia, and New Zealand had among the highest prevalences, with 15% of children affected. 1Asthma is more complicated, however, especially in children.We are often uncertain whether children who wheeze do have asthma, and some people say that diagnosing asthma in very young children is not possible.An increasing body of evidence suggests that asthma is a complex disorder and that different patterns of illness have different underlying pathogenesis.Many studies have investigated various treatments in older children with classic allergic asthma, yet relatively few have considered the many young children who have recurrent wheeze.Many common treatments now have a good evidence base, but gaps still exist, such as treatments for the most difficult and severe childhood asthma.Therapeutic advances include both new drugs and new licences for older drugs.For example, the new drug omalizumab and montelukast are now licensed down to 6 months of age.Yet despite an increasing number of therapeutic options, children still die from asthma (23 recorded deaths in 2002 2 ).With this in mind, this first of two articles will review the features of the two most common patterns of childhood wheezing illnesses: atopic asthma and episodic viral wheeze.The second review will focus on management. How do patients present?If one feature consistently points to a diagnosis of asthma, it is wheeze.Wheeze is the end result of narrowing of small airways due to processes that include oedema of the airway wall, contraction of smooth muscle, and mucus plugging.A study of parents of wheezing children found that some thought that wheeze was a sound such as whistling, squeaking, or gasping, whereas others defined it as a different rate,
House of Lords rejects attempts to stop passage of health bill
Authors: A. O'Dowd
Journal: BMJ (2011)

The government’s controversial reforms of the NHS have passed their first substantial hurdle in the House of Lords as peers this week rejected attempts to stall the process and prevent the Health and Social Care Bill from becoming law next year.

Two amendments that would have either killed the bill or led to delays while parts of it were scrutinised by a special committee were both defeated in a vote on 12 October.

In a marathon two day debate some 100 peers spoke on the bill. The bill had led to an “unprecedented” level of concern from clinicians and the public, said peers.

Two crossbench peers—Lord Owen and Lord Hennessey—tabled an amendment calling for part of the bill to be sent to a special select committee to allow for closer scrutiny on issues such as the role of the health secretary in overseeing the NHS ( BMJ 2011;343:d6391, doi:10.1136/bmj.d6391). This amendment was rejected by 330 to 262 votes. 

Only two Liberal Democrat peers supported this amendment (Baroness Nicholson of Winterbourne and Baroness Tonge), while 80 Lib Dems opposed it. Baroness Shirley Williams, who has been outspoken in her opposition to the bill ( BMJ 2011;343:d6359, …
Brief Report: Number of Circulating Follicular Helper 2 T Cells Correlates With IgG4 and Interleukin‐4 Levels and Plasmablast Numbers in IgG4‐Related Disease
Authors: Mitsuhiro Akiyama, Katsuya Suzuki, Kunihiro Yamaoka, Hidekata Yasuoka, Masaru Takeshita, Yuko Kaneko, Harumi Kondo, Yoshiaki Kassai, Takahiro Miyazaki, Rimpei Morita, Akihiko Yoshimura, Tsutomu Takeuchi
Journal: Arthritis & Rheumatology (2015)

To elucidate the pathologic role of follicular helper T (Tfh) cells and their subsets in active, untreated IgG4-related disease.Fifteen patients with active, untreated, biopsy-proven IgG4-related disease, 24 patients with primary Sjögren's syndrome (SS), 12 patients with allergic rhinitis, and 23 healthy controls were evaluated. Tfh cells were defined as CD3+CD4+CXCR5+CD45RA- cells. Circulating Tfh cell subsets among CXCR5+CD45RA-CD4+ T cells were defined as Tfh17 cells (CXCR3-CCR6+), Tfh1 cells (CXCR3+CCR6-), or Tfh2 cells (CXCR3-CCR6-). CD19+CD20-CD27+CD38+ cells were defined as plasmablasts. Serum cytokine levels (interleukin-4 [IL-4], IL-10, IL-21, and IL-33) were measured by cytometric bead array or enzyme-linked immunosorbent assay.Patients with IgG4-related disease had significantly increased levels of Tfh2 cells compared to healthy controls or patients with primary SS or allergic rhinitis. Increased Tfh2 levels were strongly associated with increased serum IgG4 levels and the IgG4:IgG ratio in IgG4-related disease. A positive correlation was observed between Tfh2 counts, plasmablast counts, and serum IL-4 levels. Interestingly, levels of plasmablasts and serum IL-4 and IgG4 decreased after treatment with glucocorticoids, whereas no obvious change was observed in Tfh2 cell counts.The Tfh2 cell count was specifically increased in IgG4-related disease and was correlated with elevated serum levels of IgG4 and IL-4 and plasmablast counts. Tfh2 cells were the only component that was not affected by glucocorticoid treatment, suggesting that Tfh2 cells are the cell type implicated in IgG4-related disease.
Comprehensive Standardized Report of Complications of Retropubic and Laparoscopic Radical Prostatectomy
Authors: Farhang Rabbani, Luis Herran Yunis, Rodrigo Pinochet, Lucas Nogueira, Kinjal C. Vora, James A. Eastham, Bertrand Guillonneau, Vincent Laudone, Peter T. Scardino, Karim Touijer
Journal: European Urology (2009)
Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall
Authors: Marie Billaud, Alexander W. Lohman, Scott R. Johnstone, Lauren A. Biwer, Stephanie Mutchler, Brant E. Isakson
Journal: Pharmacological Reviews (2014)

It has become increasingly clear that the accumulation of proteins in specific regions of the plasma membrane can facilitate cellular communication. These regions, termed signaling microdomains, are found throughout the blood vessel wall where cellular communication, both within and between cell types, must be tightly regulated to maintain proper vascular function. We will define a cellular signaling microdomain and apply this definition to the plethora of means by which cellular communication has been hypothesized to occur in the blood vessel wall. To that end, we make a case for three broad areas of cellular communication where signaling microdomains could play an important role: 1) paracrine release of free radicals and gaseous molecules such as nitric oxide and reactive oxygen species; 2) role of ion channels including gap junctions and potassium channels, especially those associated with the endothelium-derived hyperpolarization mediated signaling, and lastly, 3) mechanism of exocytosis that has considerable oversight by signaling microdomains, especially those associated with the release of von Willebrand factor. When summed, we believe that it is clear that the organization and regulation of signaling microdomains is an essential component to vessel wall function.
Non-fatal injuries sustained by back seat passengers.
Authors: M S Christian
Journal: BMJ (1975)

Stimulation of myocardial <i>β</i><sub>1</sub>-adrenoceptors (AR) is a major mechanism that increases cardiac function. We investigated the functional consequences of genetic <i>β</i><sub>1</sub>-AR knockdown in three-dimensional engineered heart tissue (EHT). For <i>β</i><sub>1</sub>-AR knockdown, short interfering RNA (siRNA) sequences targeting specifically the <i>β</i><sub>1</sub>-AR (shB1) and a scrambled control (shCTR) were subcloned into a recombinant adeno-associated virus (AAV)–short hairpin RNA (shRNA) expression system. Transduction efficiency was ∼100%, and radioligand binding revealed 70% lower <i>β</i><sub>1</sub>-AR density in AAV6-shB1–transduced EHTs. Force measurements, performed over the culture period of 14 days, showed paradoxically higher force generation in AAV6-shB1 compared with shCTR under basal (0.19 ± 0.01 versus 0.13 ± 0.01 mN) and after <i>β</i>-AR-stimulated conditions with isoprenaline (Δfractional shortening: 72 ± 5% versus 34 ± 4%). Large scale gene expression analysis revealed that AAV6-shCTR compared with nontransduced EHTs showed only few differentially regulated genes (&lt;20), whereas AAV6-shB1 induced marked changes in gene expression (&gt;250 genes), indicating that <i>β</i><sub>1</sub>-AR knockdown itself determines the outcome. None of the regulated genes pointed to obvious off-target effects to explain higher force generation. Moreover, compensational regulation of <i>β</i><sub>2</sub>-AR signaling or changes in prominent <i>β</i><sub>1</sub>-AR downstream targets could be ruled out. In summary, we show paradoxically higher force generation and isoprenaline responses after efficient <i>β</i><sub>1</sub>-AR knockdown in EHTs. Our findings 1) reveal an unexpected layer of complexity in gene regulation after specific <i>β</i><sub>1</sub>-AR knockdown rather than unspecific dysregulations through transcriptional interference, 2) challenge classic assumptions on the role of cardiac <i>β</i><sub>1</sub>-AR, and 3) may open up new avenues for <i>β</i>-AR loss-of-function research in vivo.
"Elastic globes" in human skin.
Authors: P. J. Hare
Journal: British Journal of Dermatology (1966)

Journal Article “Elastic globes” in human skin. Get access P. J. Hare P. J. Hare University College Hospital London, W.C.l Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 78, Issue 2, 1 February 1966, Pages 123–125, https://doi.org/10.1111/j.1365-2133.1966.tb12186.x Published: 01 February 1966
Thirty years of the human immunodeficiency virus epidemic and beyond
Authors: Fariba S Younai
Journal: International Journal of Oral Science (2013)

After more than 30 years of battling a global epidemic, the prospect of eliminating human immunodeficiency virus (HIV) as the most challenging infectious disease of the modern era is within our reach. Major scientific discoveries about the virus responsible for this immunodeficiency disease state, including its pathogenesis, transmission patterns and clinical course, have led to the development of potent antiretroviral drugs that offer great hopes in HIV treatment and prevention. Although these agents and many others still in development and testing are capable of effectively suppressing viral replication and survival, the medical management of HIV infection at the individual and the population levels remains challenging. Timely initiation of antiretroviral drugs, adherence to the appropriate therapeutic regimens, effective use of these agents in the pre and post-exposure prophylaxis contexts, treatment of comorbid conditions and addressing social and psychological factors involved in the care of individuals continue to be important considerations. Expanded preventative and therapeutic efforts will be critical to maintaining the momentum in the fight against human immunodeficiency virus (HIV), concludes Fariba Younai of the University of California at Los Angeles, USA. Younai has reviewed the scientific and medical advances that help HIV patients in controlling their disease, as well as assist patients and health-care workers in containing the spread of this virus. She noted that existing treatments control but do not eliminate infection. Younai also listed causes for concern, including high disease burdens and mortality rates in the developing world. She explored the value of preventative strategies, such as drug prophylaxis to prevent HIV transmission by pregnant mothers to their children, and male circumcision. She also examined experimental efforts to eradicate latent viral reservoirs that might eventually give rise to AIDS.
SOCS2 regulates T helper type 2 differentiation and the generation of type 2 allergic responses
Authors: Camille A. Knosp, Helen P. Carroll, Joanne Elliott, Sean P. Saunders, Hendrik J. Nel, Sylvie Amu, Joanne C. Pratt, Shaun Spence, Emma Doran, Nicola Cooke, Ruaidhri Jackson, Jonathan Swift, Denise C. Fitzgerald, Liam G. Heaney, Padraic G. Fallon, Adrien Kissenpfennig, James A. Johnston
Journal: The Journal of Experimental Medicine (2011)

The incidence of allergy and asthma in developed countries is on the increase and this trend looks likely to continue. CD4+ T helper 2 (Th2) cells are major drivers of these diseases and their commitment is controlled by cytokines such as interleukin 4, which are in turn regulated by the suppressor of cytokine signaling (SOCS) proteins. We report that SOCS2−/− CD4+ T cells show markedly enhanced Th2 differentiation. SOCS2−/− mice, as well as RAG-1−/− mice transferred with SOCS2−/− CD4+ T cells, exhibit elevated type 2 responses after helminth antigen challenge. Moreover, in in vivo models of atopic dermatitis and allergen-induced airway inflammation, SOCS2−/− mice show significantly elevated IgE, eosinophilia, type 2 responses, and inflammatory pathology relative to wild-type mice. Finally, after T cell activation, markedly enhanced STAT6 and STAT5 phosphorylation is observed in SOCS2−/− T cells, whereas STAT3 phosphorylation is blunted. Thus, we provide the first evidence that SOCS2 plays an important role in regulating Th2 cell expansion and development of the type 2 allergic responses.
AAV-mediated Tyrosinase Gene Transfer Restores Melanogenesis and Retinal Function in a Model of Oculo-cutaneous Albinism Type I (OCA1)
Authors: Annagiusi Gargiulo, Ciro Bonetti, Sandro Montefusco, Simona Neglia, Umberto Di Vicino, Elena Marrocco, Michele Della Corte, Luciano Domenici, Alberto Auricchio, Enrico M Surace
Journal: Molecular Therapy (2009)

Oculo-cutaneous albinism type 1 (OCA1) is characterized by congenital hypopigmentation and is due to mutations in the TYROSINASE gene (TYR). In this study, we have characterized the morpho-functional consequences of the lack of tyrosinase activity in the spontaneous null mouse model of OCA1 (Tyr(c-2j)). Here, we show that adult Tyr(c-2j) mice have several retinal functional anomalies associated with photoreceptor loss. To test whether these anomalies are reversible upon TYR complementation, we performed intraocular administration of an adeno-associated virus (AAV)-based vector, encoding the human TYR gene, in adult Tyr(c-2j) mice. This resulted in melanosome biogenesis and ex novo synthesis of melanin in both neuroectodermally derived retinal pigment epithelium (RPE) and in neural crest-derived choroid and iris melanocytes. Ocular melanin accumulation prevented progressive photoreceptor degeneration and resulted in restoration of retinal function. Our results reveal novel properties of pigment cells and show that the developmental anomalies of albino mice are associated with defects occurring in postnatal life, adding novel insights on OCA1 disease pathogenesis. In addition, we provide proof-of-principle of an effective gene-based strategy relevant for future application in albino patients.
Dietary Fat Influences on Murine Melanoma Growth and Lymphocyte-Mediated Cytotoxicity23
Authors: Kent L. Erickson
Journal: JNCI Journal of the National Cancer Institute (1984)

Journal Article Dietary Fat Influences on Murine Melanoma Growth and Lymphocyte-Mediated Cytotoxicity Get access Kent L. Erickson Kent L. Erickson Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 72, Issue 1, January 1984, Pages 115–120, https://doi.org/10.1093/jnci/72.1.115 Published: 01 January 1984 Article history Received: 28 September 1982 Revision received: 11 July 1983 Accepted: 26 July 1983 Published: 01 January 1984
HEAD OF RYE GRASS IN THE LUNG REMOVED FROM PLEURA
Authors: R. E. Smith
Journal: BMJ (1920)

INTRANASAL DACRYOCYSTOSTOMY.70T=1 BOt and opened his eyes, wlhich were turned to the ceiling.Pro- longed suffering illness, sepsis, and repeated haemorrhages must lhave rendered the case particularly vulnierable.andl it is doubtful under the circumstances if thie cerebrulm cotu]el ldave withstood a less protracted arrest of its circulationi.As there had been a good deal of muscular tremor prior to the operation, an investigation was made after death as to the presence of tetanus, but this was excluded.The operation had niot )been begun at the time of the catastrophe. CASE III.An elderly woman in a state of collapse was undergoinlg operation for strangulated femoral hernia wlhenl tihe heart stopped beating.Cardiac massagre was at onice performiied anid sponitaneous contractions recurred.As the al)blomeni was being closed the heart again stoppedhbeating, anid a seconid attemlpt with cardiac massage tlhein failedl.Although the patienit was a poor subject, this experience seems to inidicate that nmassage should be carried on until cointractionis are established at maxinal strenigtlh, the task not being considered comilplete merely upoIn their reappearanlce. CASE IV.TIn this case general adhesions were found in the upper abdomen, and it was nlot possible to insert tthe hand below the (liaplragm or below the liver.Pressure below the stomuach immediately forced gastric contetnts out of the mlouth.Metlhods, 2, 3, or 4 were indicated but not tried.CASE V.On Febrq4ry 7th, 1918, a case of perforated gastric ulcer in a mnan aged 38 years came under my care.The operation was
ASSOCIATION OF IgG RECEPTOR Fc gamma RIIIB POLYMORPHISMS WITH IDIOPATHIC PULMONARY FIBROSIS
Authors: S. Bournazos, J. Grinfeld, E. Cole, K. Hodgson, A. Wass, S. Maggs, A. Lee, I. Bournazou, K. Alexander, Ian Dransfield, P. McFarlane, Nikhil Hirani, John Simpson, S. P. Hart
Journal: Thorax (2008)
Three-Dimensional Transformations for Goal-Directed Action
Authors: J. Douglas Crawford, Denise Y.P. Henriques, W. Pieter Medendorp
Journal: Annual Review of Neuroscience (2011)

Much of the central nervous system is involved in visuomotor transformations for goal-directed gaze and reach movements. These transformations are often described in terms of stimulus location, gaze fixation, and reach endpoints, as viewed through the lens of translational geometry. Here, we argue that the intrinsic (primarily rotational) 3-D geometry of the eye-head-reach systems determines the spatial relationship between extrinsic goals and effector commands, and therefore the required transformations. This approach provides a common theoretical framework for understanding both gaze and reach control. Combined with an assessment of the behavioral, neurophysiological, imaging, and neuropsychological literature, this framework leads us to conclude that (a) the internal representation and updating of visual goals are dominated by gaze-centered mechanisms, but (b) these representations must then be transformed as a function of eye and head orientation signals into effector-specific 3-D movement commands.