tbuckley/cabot-search huggingface dataset:
Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma
Authors: M Reis-Sobreiro, G Roué, A Moros, C Gajate, J de la Iglesia-Vicente, D Colomer, F Mollinedo
Journal: Blood Cancer Journal (2013)

Recent evidence shows that lipid raft membrane domains modulate both cell survival and death. Here, we have found that the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is present in the lipid rafts of mantle cell lymphoma (MCL) cells, and this location seems to be critical for full activation and MCL cell survival. The antitumor lipids (ATLs) edelfosine and perifosine target rafts, and we found that ATLs exerted in vitro and in vivo antitumor activity against MCL cells by displacing Akt as well as key regulatory kinases p-PDK1 (phosphatidylinositol-dependent protein kinase 1), PI3K and mTOR (mammalian TOR) from lipid rafts. This raft reorganization led to Akt dephosphorylation, while proapoptotic Fas/CD95 death receptor was recruited into rafts. Raft integrity was critical for Ser473 Akt phosphorylation. ATL-induced apoptosis appeared to correlate with the basal Akt phosphorylation status in MCL cell lines and primary cultures, and could be potentiated by the PI3K inhibitor wortmannin, or inhibited by the Akt activator pervanadate. Classical Akt inhibitors induced apoptosis in MCL cells. Microenvironmental stimuli, such as CD40 ligation or stromal cell contact, did not prevent ATL-induced apoptosis in MCL cell lines and patient-derived cells. These results highlight the role of raft-mediated PI3K/Akt signaling in MCL cell survival and chemotherapy, thus becoming a new target for MCL treatment.
Arthrogryposis Syndrome (Kuskokwim Disease) in the Eskimo
Authors: Jack H. Petajan
Journal: JAMA (1969)

A new syndrome of congenital skeletal abnormalities has been found in the Alaskan Eskimo. The condition is characterized by multiple joint contractures predominantly affecting the knees and ankles, with atrophy or compensatory hypertrophy of associated muscle groups. Intellectual functioning is not impaired, and, aside from the skeletal system and possibly the skin, there are no other consistent physical anomalies. General laboratory studies disclosed no abnormality, extensive electromyographic investigation showed no basic defect of the motor unit, and results of muscle biopsies were normal. Treatment to date has been entirely orthopedic, with use of surgery, casting and bracing, and passive manipulation. This condition can be separated from the heterogeneous category of arthrogryposis multiplex congenita by its distinctive clinical features and by the familial pattern of distribution, which suggests an autosomal recessive mode of inheritance.
201 CORTICOSTEROIDS IMPROVE 28-DAY SURVIVAL IN PATIENTS WITH SEVERE ALCOHOLIC HEPATITIS: INDIVIDUAL DATA ANALYSIS OF THE LAST 5 RANDOMIZED CONTROLLED TRIALS
Authors: P. Mathurin, J. O'Grady, R.L. Carithers, M. Phillips, M.-J. Ramond, A. Louvet, H. Castel, S. Naveau, T. Morgan, W.C. Maddrey, C.L. Mendenhall
Journal: Journal of Hepatology (2009)
Lessons from the end of a life
Authors: Ros Levenson
Journal: BMJ (2004)

T his is the story of the final chapter of my mother's journey through dementia up to her death just after her 83rd birthday. The story includes extreme kindness and sensitivity from some doctors, nurses, and other health professionals, alongside crass, ill judged defensiveness from others.

After almost two years in a care home, which followed several years of gradually worsening dementia, my mother became unwell and much less responsive than usual. She was admitted to a hospital medical assessment ward for investigations. No specific ailment was diagnosed, though she was having trouble swallowing.

The speech and language therapists declared her “nil by mouth”—unsurprisingly, as she was asleep most of the time. A few days later a nurse told me they had been unsuccessful in putting in a nasogastric tube and intended to try again later; after that my mother would need a “PEG.” I don't recall any explanations of what a PEG (percutaneous gastrostomy tube) was, but I knew what it was from my work. I also knew that my mother wouldn't want this. She had made it clear that she hated being “messed around with.” In recent months she had resisted even having her nails cut, hair washed, or dressings changed.

She had been frail and desperately miserable for a long time and had declined steeply since my father's death nine months earlier. If she expressed emotion, it was to …
Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin
Authors: David Sancho, Diego Mourão-Sá, Olivier P. Joffre, Oliver Schulz, Neil C. Rogers, Daniel J. Pennington, James R. Carlyle, Caetano Reis e Sousa
Journal: Journal of Clinical Investigation (2008)

The mouse CD8alpha+ DC subset excels at cross-presentation of antigen, which can elicit robust CTL responses. A receptor allowing specific antigen targeting to this subset and its equivalent in humans would therefore be useful for the induction of antitumor CTLs. Here, we have characterized a C-type lectin of the NK cell receptor group that we named DC, NK lectin group receptor-1 (DNGR-1). DNGR-1 was found to be expressed in mice at high levels by CD8+ DCs and at low levels by plasmacytoid DCs but not by other hematopoietic cells. Human DNGR-1 was also restricted in expression to a small subset of blood DCs that bear similarities to mouse CD8alpha+ DCs. The selective expression pattern and observed endocytic activity of DNGR-1 suggested that it could be used for antigen targeting to DCs. Consistent with this notion, antigen epitopes covalently coupled to an antibody specific for mouse DNGR-1 were selectively cross-presented by CD8alpha+ DCs in vivo and, when given with adjuvants, induced potent CTL responses. When the antigens corresponded to tumor-expressed peptides, treatment with the antibody conjugate and adjuvant could prevent development or mediate eradication of B16 melanoma lung pseudometastases. We conclude that DNGR-1 is a novel, highly specific marker of mouse and human DC subsets that can be exploited for CTL cross-priming and tumor therapy.
Efficacy and Safety of Exenatide Once Weekly Versus Metformin, Pioglitazone, and Sitagliptin Used as Monotherapy in Drug-Naive Patients With Type 2 Diabetes (DURATION-4)
Authors: David Russell-Jones, Robert M. Cuddihy, Markolf Hanefeld, Ajay Kumar, Jose G. González, Melanie Chan, Anne M. Wolka, Marilyn K. Boardman
Journal: Diabetes Care (2011)

To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes.Patients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n = 246), PIO 45 mg/day + SC placebo (n = 163), or SITA 100 mg/day + SC placebo (n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily.Baseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA(1c) 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes duration 2.7 years. HbA(1c) reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were -1.53 vs. -1.48 (P = 0.620), -1.63 (P = 0.328), and -1.15 (P < 0.001), respectively. Weight changes (kg) were -2.0 vs. -2.0 (P = 0.892), +1.5 (P < 0.001), and -0.8 (P < 0.001), respectively. Common adverse events were as follows: EQW, nausea (11.3%) and diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred.EQW was noninferior to MET but not PIO and superior to SITA with regard to HbA(1c) reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia.
Apolipoprotein E Status as a Predictor of the Development of Alzheimer's Disease in Memory-Impaired Individuals
Authors: Ronald C. Petersen
Journal: JAMA (1995)

The outcome of patients with mild cognitive impairment is not known, yet these patients present a difficult dilemma for the clinician. This study was designed to characterize the outcome of a group of patients with mild cognitive impairment and to determine whether the presence of the epsilon 4 allele on the apolipoprotein E gene (APOE) is a predictor of that outcome.A prospective, longitudinal inception cohort.General community clinic.A consecutive sample of 66 patients who met criteria for a diagnosis of a mild cognitive impairment and who had at least one clinical reevaluation was identified from the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry.We evaluated patients initially and at 12- to 18-month intervals up to 54 months using standard neurological and neuropsychological measures such as the Mini-Mental State Examination, the Dementia Rating Scale, the Wechsler Adult Intelligence Scale--Revised, the Wechsler Memory Scale--Revised, and the Free and Cued Selective Reminding Test. The APOE status of study patients was determined.The development of dementia as determined by the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria.Sixty-six individuals had been reevaluated once (mean of 18 months), 36 individuals twice (mean of 36 months), and 22 individuals on three occasions (mean of 54 months), with conversion rates to dementia at these intervals of 24%, 44%, and 55%, respectively. A multivariate Cox regression model demonstrated that possession of an APOE epsilon 4 allele was the strongest predictor of clinical outcome.These data suggest the following: (1) patients with mild cognitive impairment can be clinically defined, (2) many members of this group progress to Alzheimer's disease, and (3) APOE epsilon 4 allele status appears to be a strong predictor of clinical progression.
The effect of lightly crosslinked poly(carboxybetaine) hydrogel coating on the performance of sensors in whole blood
Authors: Wei Yang, Tao Bai, Louisa R. Carr, Andrew J. Keefe, Jiajie Xu, Hong Xue, Colleen A. Irvin, Shengfu Chen, Joseph Wang, Shaoyi Jiang
Journal: Biomaterials (2012)
Improvement of health-related quality of life and work productivity in chronic hepatitis C patients with early and advanced fibrosis treated with ledipasvir and sofosbuvir
Authors: Zobair M. Younossi, Maria Stepanova, Nezam Afdhal, Kris V. Kowdley, Stefan Zeuzem, Linda Henry, Sharon L. Hunt, Patrick Marcellin
Journal: Journal of Hepatology (2015)
Myocardial perfusion and fatty acid metabolism in patients with tako-tsubo-like left ventricular dysfunction
Authors: Satoshi Kurisu, Ichiro Inoue, Takuji Kawagoe, Masaharu Ishihara, Yuji Shimatani, Kenji Nishioka, Takashi Umemura, Suji Nakamura, Masashi Yoshida, Hikaru Sato
Journal: Journal of the American College of Cardiology (2003)
GRAYSCALE INTRAVASCULAR ULTRASOUND EVIDENCE OF IN-STENT NEOATHEROSCLEROSIS 3 YEARS AFTER DRUG-ELUTING STENT IMPLANTATION
Authors: Diaa El din Abd El Hakim, Gary S. Mintz, Reni Rusinova, Giora Weisz, Varinder P. Singh, Martin B. Leon, Gregg Stone, Jeffery Moses, Akiko Maehara
Journal: Journal of the American College of Cardiology (2011)
Cervical screening: a smear campaign
Authors: D. Spence
Journal: BMJ (2010)

I once worked in Norfolk; but when my wife fell pregnant she choked, “I want to go home.” Concrete tower blocks, Irish tricolours, Union Jacks, and red hair flashed through my mind. “To Glasgow!” I said. But Scotland has enduring qualities: humour, respectful irreverence, directness, pragmatism, swearing, and a national mantra, “Life is for living.” We may have some of the worst health statistics in the Western world, but we are a country of the unworried unwell. It is odd that there is a current anomaly in screening policy in the UK countries. Cervical …
GAPDH Gene Diversity in Spirochetes: A Paradigm for Genetic Promiscuity
Authors: Rainer Martin Figge, Rüdiger Cerff
Journal: Molecular Biology and Evolution (2001)

In this study we have determined gap sequences from nine different spirochetes. Phylogenetic analyses of these sequences in the context of all other available eubacterial and a selection of eukaryotic Gap sequences demonstrated that the eubacterial glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene diversity encompasses at least five highly distinct gene families. Within these gene families, spirochetes show an extreme degree of sequence divergence that is probably the result of several lateral gene transfer events between spirochetes and other eubacterial phyla, and early gene duplications in the eubacterial ancestor. A Gap1 sequence from the syphilis spirochete Treponema pallidum has recently been shown to be closely related to GapC sequences from Euglenozoa. Here we demonstrate that several other spirochetal species are part of this cluster, supporting the conclusion that an interkingdom gene transfer from spirochetes to Euglenozoa must have occurred. Furthermore, we provide evidence that the GAPDH genes present in the protists Parabasalia may also be of spirochetal descent.
GSK-3α is a central regulator of age-related pathologies in mice
Authors: Jibin Zhou, Theresa A. Freeman, Firdos Ahmad, Xiying Shang, Emily Mangano, Erhe Gao, John Farber, Yajing Wang, Xin-Liang Ma, James Woodgett, Ronald J. Vagnozzi, Hind Lal, Thomas Force
Journal: Journal of Clinical Investigation (2013)

Aging is regulated by conserved signaling pathways. The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases regulates several of these pathways, but the role of GSK-3 in aging is unknown. Herein, we demonstrate premature death and acceleration of age-related pathologies in the Gsk3a global KO mouse. KO mice developed cardiac hypertrophy and contractile dysfunction as well as sarcomere disruption and striking sarcopenia in cardiac and skeletal muscle, a classical finding in aging. We also observed severe vacuolar degeneration of myofibers and large tubular aggregates in skeletal muscle, consistent with impaired clearance of insoluble cellular debris. Other organ systems, including gut, liver, and the skeletal system, also demonstrated age-related pathologies. Mechanistically, we found marked activation of mTORC1 and associated suppression of autophagy markers in KO mice. Loss of GSK-3α, either by pharmacologic inhibition or Gsk3a gene deletion, suppressed autophagy in fibroblasts. mTOR inhibition rescued this effect and reversed the established pathologies in the striated muscle of the KO mouse. Thus, GSK-3α is a critical regulator of mTORC1, autophagy, and aging. In its absence, aging/senescence is accelerated in multiple tissues. Strategies to maintain GSK-3α activity and/or inhibit mTOR in the elderly could retard the appearance of age-related pathologies.
Airway inflammation after removal from the causal agent in occupational asthma due to high and low molecular weight agents
Authors: LP Boulet, M Boutet, M Laviolette, M Dugas, J Milot, C Leblanc, L Paquette, J Cote, A Cartier, JL Malo
Journal: European Respiratory Journal (1994)

In order to determine 1) the features of airway inflammation after removal from exposure to high (HMW) and low (LMW) molecular weight agents 2) if there are any differences in the pattern of inflammation induced by these two types of agents, we studied 18 subjects with a recently confirmed diagnosis of occupational asthma (OA) due to HMW (n = 11) and LMW (n = 7) agents. The duration of asthma symptoms varied from 2 to 108 months (mean 33 months), and withdrawal from exposure to the sensitizing agent from 3 to 24 weeks (mean 10 weeks). All subjects underwent measurements of expiratory flow rates, methacholine inhalation tests, and a flexible bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsies. Endoscopic findings were compared with a group of 10 normal subjects. At the time of the bronchoscopy, asthma symptoms were minimal in most subjects. Although 15/18 subjects had normal forced expiratory volume in one second (FEV1 &gt; 80% pred), all subjects had increased airway responsiveness to methacholine (provocation concentration producing a 20% fall in FEV1 = 0.2-10.0 mg.ml-1). BAL analysis showed similar median percentages of the total number of cells and differentials in control subjects and those exposed to HMW and LMW agents. Bronchial biopsies showed that mean inflammatory cell count, both epithelial and sub-epithelial, was similarly raised in OA subjects exposed to either HMW or LMW agents, compared to controls, except for epithelial lymphocyte count. In contrast to the controls, bronchial biopsy of both groups with OA also showed other changes such as extensive epithelial desquamation, ciliary abnormalities of the epithelial cells, smooth muscle hyperplasia and subepithelial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Micropuncture Study of Diuretic Effects on Sodium and Calcium Reabsorption in the Dog Nephron
Authors: B. R. Edwards, P. G. Baer, R. A. L. Sutton, J. H. Dirks
Journal: Journal of Clinical Investigation (1973)

A close relationship has been observed between the clearance rates of sodium and calcium under a variety of diuretic conditions. The thiazide diuretics act differently in dissociating the renal tubular reabsorption of sodium and calcium. This phenomenon has been further investigated using recollection micropuncture and clearance techniques in a group of 14 dogs subjected to three consecutive experimental phases: expansion to 3% of body weight (BWt) with Ringer's solution, chlorothiazide infusion at 20 mg/kg/h, and furosemide in a prime of 10 mg/kg/ and a 10 mg/kg/h infusion. Diuretic losses were balanced with infusion of equal volumes of Ringer's solution throughout the experiment. Chlorothiazide increased the fractional excretion (FE) of sodium almost threefold while FE(Ca) was not significantly altered. Furosemide increased FE(Na) and FE(Ca) to an approximately equal, and more marked, degree. This dissociation of sodium and calcium reabsorption after chlorothiazide was also evident in the superficial distal tubule, where (tubule fluid/plasma sodium) (TF/P(Na)) increased from 0.32 to 0.49 (P < 0.01) and TF/(ultrafiltrate)UF(Ca) was unchanged (0.35-0.31). Furosemide markedly reduced the transtubular concentration gradient for both sodium (0.86) and calcium (0.94). TF/P(Inul in) decreased progressively from 3.79 to 2.78 to 2.33 in three phases. In the late proximal tubule, chlorothiazide induced a fall of TF/P(Inul in) from 1.57 to 1.44 (P < 0.01), but the ratio TF/UF(Ca): TF/P(Na) was unchanged. Furosemide had no significant proximal effect. It is concluded that acute administration of chlorothiazide reduces sodium reabsorption in the distal hephron, presumably the cortical diluting segment, without affecting calcium reabsorption.
Drugs for obesity are last resort treatment
Authors: H. Bower
Journal: BMJ (1997)

Appetite suppressant drugs should be prescribed as a last resort and only to patients who are clinically obese and respond rapidly to them, say new guidelines designed to crack down on the inappropriate use of slimming drugs.

The report, compiled by an expert working party of the Royal College of Physicians of London, concludes that treatment with anti-obesity drugs is appropriate only for people with a body mass index greater than 30 who fail to reduce their weight by 10% after three months determined effort with diet, exercise, and behavioural change.



Drugs for obesity …
Increase in filtration coefficient from actions of melittin on neutrophils in isolated rabbit lungs.
Authors: M R Littner, F D Lott
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

Activation of neutrophils may contribute to lung injury in the adult respiratory distress syndrome. We added rabbit neutrophils to the pulmonary circulation of salt-perfused and ventilated isolated rabbit lungs. These neutrophils were activated by adding synthetically pure melittin to the perfusate. This led to lung injury as measured by filtration coefficient under no-flow conditions. We also activated neutrophils in vitro before addition to the pulmonary circulation. These preactivated neutrophils also produced lung injury, indicating a primary action of melittin on neutrophils rather than on lung. The injury was prevented by aristolochic acid, which is an inhibitor of phospholipase A2 (PLA2), and independently by catalase, which is scavenger of hydrogen peroxide (H2O2). Aristolochic acid also appeared to act primarily on neutrophils since addition to neutrophils in vitro prevented injury from in vitro activation by melittin. Aristolochic acid did not appear to act as a free radical scavenger since it did not prevent injury from neutrophils activated by phorbol myristate acetate (PMA). PMA is a direct activator of protein kinase C in neutrophils and leads to formation of H2O2 with consequent lung injury. We conclude that activation of neutrophils by melittin leads to oxidant lung injury possibly from activation of PLA2. Since PLA2 does not directly produce a second messenger, such as diacylglycerol or inositol triphosphate, it is likely that other actions of PLA2 produce an intermediary mediator. We previously showed that an inhibitor of eicosanoid synthesis prevents lung injury from exogenous PLA2. This suggests that the formation of leukotriene B4 (LTB4), a 5-lipoxygenase product of arachidonic acid, may contribute to the oxidant lung injury from melittin.(ABSTRACT TRUNCATED AT 250 WORDS)
FRACTURE OF THE NECK OF THE FEMUR IN A CHILD
Authors: Charles A. Parker
Journal: JAMA (1918)

On account of the rarity of fracture of the neck, of the femur in children, this case is reported. Oct. 5, 1917, a well developed boy, aged 9 years, was admitted to my service in the Cook County Hospital with the complaint of "interference with gait following trauma of the left hip." Two months before, he had fallen from a roof a distance of 15 feet, striking on his left side. After three weeks in bed he was allowed to walk. There was no pain after his period in bed, but he walked with an obvious limp. This was his condition when he came to the hospital. The examination disclosed about one-half inch of shortening and a relatively high trochanter with almost normal movement of the joint. The roentgen ray cleared up the diagnosis. A plaster-of-Paris spica was applied, and recumbency advised, as the character of the union was in