tbuckley/cabot-search huggingface dataset:
High Capsid–Genome Correlation Facilitates Creation of AAV Libraries for Directed Evolution
Authors: Mathieu Nonnenmacher, Harm van Bakel, Roger J Hajjar, Thomas Weber
Journal: Molecular Therapy (2015)

Directed evolution of adeno-associated virus (AAV) through successive rounds of phenotypic selection is a powerful method to isolate variants with improved properties from large libraries of capsid mutants. Importantly, AAV libraries used for directed evolution are based on the "natural" AAV genome organization where the capsid proteins are encoded in cis from replicating genomes. This is necessary to allow the recovery of the capsid DNA after each step of phenotypic selection. For directed evolution to be used successfully, it is essential to minimize the random mixing of capsomers and the encapsidation of nonmatching viral genomes during the production of the viral libraries. Here, we demonstrate that multiple AAV capsid variants expressed from Rep/Cap containing viral genomes result in near-homogeneous capsids that display an unexpectedly high capsid-DNA correlation. Next-generation sequencing of AAV progeny generated by bulk transfection of a semi-random peptide library showed a strong counter-selection of capsid variants encoding premature stop codons, which further supports a strong capsid-genome identity correlation. Overall, our observations demonstrate that production of "natural" AAVs results in low capsid mosaicism and high capsid-genome correlation. These unique properties allow the production of highly diverse AAV libraries in a one-step procedure with a minimal loss in phenotype-genotype correlation.
Contraindications to Long-Term Fasting-Reply
Authors: Ernest J. Drenick
Journal: JAMA (1964)

The experience of Dr. Norbury is new to us. We have not noticed any impairment of renal function in prolonged starvation, with the exception of diminution of uric acid clearance. However, we have not treated anyone with known renal disease and have in fact rejected some obese patients because they were known to have a history of pyelonephritis and glomerulonephritis. We cannot offer a good explanation of the course of events in Dr. Norbury's patient. One may speculate that in a previously damaged kidney the accumulation of ketones may impair clearance of other metabolites and not just of uric acid. I agree with the suggestion that a creatinine clearance should be carried out either before, or perhaps 48 hours after, onset of starvation when ketosis has developed. The comments of Dr. Farber are well taken. In our report, we intended to emphasize metabolic changes during starvation. The psychological aspects of
EFFECT OF POSTPRANDIAL HYPERGLYCEMIA ON CLINICAL OUTCOMES IN NONDIABETIC PATIENTS WITH STABLE ANGINA
Authors: Shoichi Kuramitsu, Hiroyoshi Yokoi, Takenori Domei, Kyohei Yamaji, Yoshimitsu Soga, Takeshi Arita, Shinichi Shirai, Kenji Ando, Koyu Sakai, Masashi Iwabuchi, Hideyuki Nosaka, Masakiyo Nobuyoshi
Journal: Journal of the American College of Cardiology (2010)
Turkey surprised by extent of aid
Authors: J. Ciment
Journal: BMJ (1999)

As rescue operations come to a halt, caring for the survivors and tending to their immediate health needs has become the major priority in Turkey The earthquake that struck the country's northwestern corridor on 17 August has exposed major shortcomings in many aspects of Turkey's infrastructure, including its ability to coordinate a major medical relief effort for the survivors of the earthquake.

The death count itself …
Pericardiocentesis in myocarditis: the protective role of the pericardium in severe heart failure.
Authors: A D Timmis, K Daly, M Monaghan, D E Jewitt
Journal: BMJ (1983)

Une observation rare de myocardite compliquee d'epanchement pericardique massif avec tamponade. La pericardiocentese est suivie d'une dilatation cardiaque amenant rapidement la mort
Pulmonary disease after amitriptyline overdosage.
Authors: A Marshall, K Moore
Journal: BMJ (1973)

A rapidly fatal diffuse pulmonary consolidation after ingestion of amitriptyline is reported.-Thedisease process was ac- companied by noticeable loss of lung compliance, and a gross diffusion defect at alveolar level.It seems unlikely that the course was that of an aspiration or bronchopneumonia, and clinically and pathologically it re- sembled the changes seen in surfactant deficiency.It is sug- gested that amitriptyline in overdosage may interfere with the production of surfactant.Case Report A 26-year-old housewife was admitted to an intensive care unit three hours after ingesting an unknown quantity of amitriptyline tablets.She was unconscious but responded to painful stimuli.Tendon reflexes were brisk and the plantar responses were extensor.An electrocardiogram showed a heart rate of 100 beats per minute in sinus rhythm, T-wave flattening in V5 and V6, but no bundle-branch block or ectopic beats.There were no abnormal respiratory signs and laryngeal reflexes were present.There was no history of previous chest disease.After 24 hours she was responding to all stimuli, and became agitated on tactile stimulation.She was still drowsy and irritable at 48 hours but was able to answer simple questions.At this time, however, her temperature rose to 101°F (38'3°C) and a few rales were audible at both lung bases.Routine chest physiotherapy was unproductive.Cloxacillin and ampicillin were started intramuscu- larly but during the third hospital day the rales became more ex- tensive and a chest x-ray picture showed patchy areas of consoli- dation in both lunz fields.The temperature varied between 990 and 103'F (37'2°-39 4°C).During the fourth hospital day she became dyspnoeic over a period of four hours.Her level of consciousness had not deterior- ated and all reflexes were now normal.Respiratory rate increased to 60 a minute.There was no evidence of bronchospasm.A chest x-ray picture showed diffuse consolidation throughout both lung fields (Fig. 1).In view of the deterioration and unproductive physio- therapy she was intubated, 30%/O humidified oxygen in air was given, and bronchial suction was performed.Very little secretion was aspirated and bacteriological culture grew no pathogens.She was attached to a Bennett ventilator which was patient triggered.The inspired oxygen was continued at 30%.The antibiotics were chang- ed to penicillin and streptomycin.On day six she became increasingly distressed and cyanosed while triggering the ventilator.Blood gases showed Pao, 42 mg Hg and Paco, 70 mm Hu (Fig. 2).Rales were audible throu-rhout the lungs, a chest radiograph confirmed generalized consolidation, and bronchial suction remained unproductive.Positive pressure respiration was started with a Barnet III ventilator using a high tidal volume and a minute volume of 15 litres.Intramuscular
Prognostic Value of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) and TRAIL Receptors in Renal Cell Cancer
Authors: Stephan Macher-Goeppinger, Sebastian Aulmann, Katrin E. Tagscherer, Nina Wagener, Axel Haferkamp, Roland Penzel, Antje Brauckhoff, Markus Hohenfellner, Jaromir Sykora, Henning Walczak, Bin T. Teh, Frank Autschbach, Esther Herpel, Peter Schirmacher, Wilfried Roth
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The death ligand tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-R) are involved in immune surveillance and tumor development. Here, we studied a possible association between the expression of TRAIL/TRAIL-Rs and the prognosis in patients with renal cell carcinomas (RCC). Experimental Design: A tissue microarray containing RCC tumor tissue samples and corresponding normal tissue samples from 838 patients was generated. Expression of TRAIL and TRAIL-Rs was examined by immunohistochemistry and the effect of TRAIL and TRAIL-R expression on disease-specific survival was assessed. Results: High TRAIL-R2 expression levels were associated with high-grade RCCs (P &amp;lt; 0.001) and correlated negatively with disease-specific survival (P = 0.01). Similarly, high TRAIL expression was associated with a shorter disease-specific survival (P = 0.01). In contrast, low TRAIL-R4 expression was associated with high-stage RCCs (P &amp;lt; 0.001) as well as with the incidence of distant metastasis (P = 0.03) and correlated negatively with disease-specific survival (P = 0.02). In patients without distant metastasis, multivariate Cox regression analyses revealed that TRAIL-R2 and TRAIL are independent prognostic factors for cancer-specific survival (in addition to tumor extent, regional lymph node metastasis, grade of malignancy, and type of surgery). Conclusion: High TRAIL-R2, high TRAIL, and low TRAIL-R4 expression levels are associated with a worse disease-specific survival in patients with RCCs. Therefore, the assessment of TRAIL/TRAIL-R expression offers valuable prognostic information that could be used to select patients for adjuvant therapy studies. Moreover, our findings are of relevance for a potential experimental therapeutic administration of TRAIL-R agonists in patients with RCCs.
The Changing American Health Scene
Authors: David E. Rogers
Journal: JAMA (1977)

Since the increased efforts to improve medical care for Americans were initiated 15 years ago, it is generally believed they had little impact on the problems addressed. Review of national data suggests otherwise. American medical care and health status are getting better. We have improved the availability of physician services and largely eliminated the gap between visits made by rich and poor, or white and black citizens. We have greatly expanded the number of health professionals who provide medical care. Better organized programs to provide care to groups with special health problems have reduced both mortality and morbidity. Age-adjusted death rates, infant and maternal mortality, and death rates from coronary artery disease have fallen. While there remains an important agenda for the future, there seems room for cautious optimism about the abilities of American society to make forward progress.
Desensitization to dapsone in HIV-positive patients
Authors: C. E. Metroka
Journal: JAMA (1992)

<h3>To the Editor.</h3> —In a prospective randomized double-blind study reported by Medina et al<sup>1</sup>in<i>The New England Journal of Medicine</i>, dapsone in combination with trimethoprim was as effective as a combination of trimethoprim and sulfamethoxazole (TMP/ SMX) for<i>Pneumocystis carinii</i>pneumonia (PCP) treatment and significantly better tolerated (<i>P</i>=.025). Neutropenia and elevated transaminase levels were five times less frequent in the dapsone group, but cutaneous reactions and nausea and vomiting occurred in equal numbers of patients. For prophylaxis, we reported that oral dapsone (25 mg, four times daily) was equally effective as daily TMP/SMX in preventing PCP with adverse reactions in 10% of those receiving dapsone vs 38% of those receiving TMP/SMX.<sup>2</sup>These findings and the appearance of other reports of dapsone efficacy in PCP prophylaxis<sup>3,4</sup>prompted us to explore desensitization of patients with the acquired immunodeficiency syndrome (AIDS) demonstrating a clear sensitivity reaction to dapsone.
Will the lead clinician please stand up?
Authors: Maurice Conlon
Journal: BMJ (2005)

Managing chronic diseases Palliative care spectrum starts early onEditor-Palliative care does not start when a patient is dying. 1 A whole spectrum of palliation begins from the day of diagnosis of a potentially terminal disease, such as soft tissue sarcoma.Palliation, in the sense of needing to absorb what this means for the patient, becomes even then a medical imperative.The "How long have I got, Doc?" question may not be articulated, but it will be there and needs an empathetic response.Curative treatment is sought, but-with sarcoma-lung metastases signal the end of that phase and the beginning of palliative treatment.The doctor and the patient know the dragon can be disabled but never slain.Palliation is then partnership, working to decide what may be gained at what cost.(This may apply during curative treatment: to take chemotherapy drugs now "just in case," or to keep them for later?)Palliative treatment can be long (in sarcoma up to 20 years or more), or it can be brief.Its ending is not solely a medical judgment.Doctors may decide they can do no more, but active patients use online support groups, seeking new treatment options across the world.Patients may decide to end palliative treatment.Grown weary of painful chemotherapy offering diminishing returns, they may prefer a shorter but better life.Making that choice together is an aspect of palliation.When death is near, palliative care becomes terminal care.If throughout doctors and patients have aligned their understanding of the disease, and have taken decisions jointly, have explored the holistic meaning of disease in life and death, the palliative spectrum may offer healing if not cure.If, however, being palliative begins only when the patient is dying doctors cannot then meet patients, where they are most needed, in the ground of their being and their not being.
Television drug advert causes upset in New Zealand
Authors: C Essex
Journal: BMJ (1994)

The advertising of a prescription only medicine on television in New Zealand for the first time has upset the Ministry of Health, the Consumers' Institute, the New Zealand Medical Association, and the pharmaceuticals regulatory body, Pharmac. All have expressed concerns about the advertising, by Merck Sharp and Dohme, of Proscar (finasteride, a 5a- reductase inhibitor), a treatment for benign prostatic hypertrophy.

Advertising prescription only drugs to the public is not illegal, but none of the pharmaceutical companies in New Zealand has done this until now. Although section 58 of …
Palmoplantar keratoderma ("tripe palms") associated with primary pulmonary adenocarcinoma
Authors: A Patel
Journal: Thorax (2005)

Palmoplantar keratoderma (''tripe palms'') associated with primary pulmonary adenocarcinoma A 61 year old woman was investigated for a 12 month history of progressive thickening of the skin of her palms and soles.She had also complained of diarrhoea, exertional breathlessness and cough, and weight loss.There was no relevant past medical history or family history, but she had a 45 pack year history of cigarette smoking.Physical examination revealed diffuse hyperkeratosis of the palms and soles (fig 1), digital clubbing, and right sided chest signs.Her chest radiograph and thoracic CT scan (fig 2) showed a mass in the right upper lobe.This was confirmed by percutaneous biopsy to be a primary adenocarcinoma of the lung.Additional imaging excluded metastatic disease and detailed gastrointestinal investigations were all normal or negative.The keratoderma was managed initially with 10% salicylic acid in Vaseline with some response.As the tumour was inoperable on the grounds of lung function, the patient received systemic chemotherapy.This resulted in a reduction in size of the primary tumour associated with a marked improvement in the cutaneous appearance.Acquired non-familial palmoplantar keratoderma-sometimes referred to as ''tripe palms''-is strongly associated with underlying neoplasia. 1 2At least 90% of cases occur in patients with an internal malignancy, most commonly of the gastrointestinal tract or lung.Pulmonary tumours are usually non-small cell, with squamous carcinomas described most frequently.
Purification and characterization of guinea-pig epidermal acid phosphatase
Authors: T. MIYAGAWA, M. ANAI, H. URABE
Journal: British Journal of Dermatology (1977)

Guinea-pig epidermal acid phosphatase has been purified approximately 120-fold by a procedure including acid treatment, CM-cellulose and DEAE-cellulose chromatography, and gel filtration on Sephadex G-100. The enzyme had a pH optimum at 5.0 and the optimal temperature for activity was approximately 50 C. The enzyme was not activated by divalent cations or 2-mercaptoethanol, but it was inhibited by p-chloromercuribenzoate and by fluoride. The km value for p-nitrophenyl phosphate was 1.31 × 10−4 M, the molecular weight was about 73,000 as determined by Sephadex G-100 gel filtration and the isoelectric point was 6.1 The enzyme hydrolyzed deoxyribonucleoside monophosphates to deoxyribonucleosides.
Treatment of Mycobacterium haemophilum infection with an antibiotic regimen including clarithromycin
Authors: T.N. DARLING, N. SIDHU-MALIK, G.R. COREY, N.B. ALLEN, H. KAMINO, J.C. MURRAY
Journal: British Journal of Dermatology (1994)

Journal Article Treatment of Mycobacterium haemophilum infection with an antibiotic regimen including clarithromycin Get access T.N. DARLING, T.N. DARLING Division of Dermatology, Duke University Medical Center, Durham, NC, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar N. SIDHU‐MALIK, N. SIDHU‐MALIK Division of Dermatology, Duke University Medical Center, Durham, NC, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar G.R. COREY, G.R. COREY Division of Infectious Diseases, Duke University Medical Center, Durham, NC, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar N.B. ALLEN, N.B. ALLEN Division of Rheumatology, Department of Medicine, Duke University Medical Center, Durham, NC, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar H. KAMINO, H. KAMINO Department of Department of Pathology, Duke University Medical Center, Durham, NC, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar J.C. MURRAY J.C. MURRAY Division of Dermatology, Duke University Medical Center, Durham, NC, U.S.A. John Murray, Division of Dermatology, Department of Medicine, Duke University Medical Center, Box 2907, Durham, NC 27710, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 131, Issue 3, 1 September 1994, Pages 376–379, https://doi.org/10.1111/j.1365-2133.1994.tb08528.x Published: 01 September 1994 Article history Accepted: 26 January 1994 Published: 01 September 1994
Target gene modulation in hepatocellular carcinomas by decreased DNA-binding of p53 mutations
Authors: S Kubicka, C Trautwein, M Niehof, M Manns
Journal: Hepatology (1997)

The crystallographic structure of the p53 core domain showed that most of the p53 mutations found in human tumors are located in conserved regions of the p53 DNA-binding domain. The aim of our study was to investigate the effect on DNA-binding and transactivation of three p53 mutations frequently found in hepatocellular carcinomas (HCC). Two of these mutations are located near the DNA-binding surface and are induced by aflatoxin B1 (249ser) and oxiradicals (249met). In contrast, mutation 220cys is not associated with a specific carcinogen in HCCs and is located outside the DNA binding structures of p53. Cotransfection experiments in two HCC cell lines, with mutated or deleted P53 genes, showed that all three mutations did not enhance reporter gene activity (RGC-CAT), in contrast to wt p53. However, in hepatoma cell lines all three mutations did suppress the p53 wildtype (wt) transactivation in a dose-dependent fashion. DNA-binding was monitored by gel shift assays using the consensus-, Waf-, and RGC-p53 binding sites. All three p53 mutations did decrease DNA-binding versus all binding sites included. Interestingly although all mutations showed the same DNA-binding and transactivation properties, differences in the ectopic expression in different hepatoma cells were observed. Therefore our results indicate that p53 mutations in HCC found in the DNA-binding domain and outside the conserved DNA-binding structures modulate target gene expression by decreasing sequence specific DNA-binding in a dominant negative fashion. The cellular environment may contribute to an additional selection advantage of some mutations.
Erythrocyte Promotion of Platelet Reactivity Decreases the Effectiveness of Aspirin as an Antithrombotic Therapeutic Modality
Authors: Juana Valles, M. Teresa Santos, Justo Aznar, Ana Osa, Aida Lago, Juan Cosin, Elena Sanchez, M. Johan Broekman, Aaron J. Marcus
Journal: Circulation (1998)

Aspirin (acetylsalicylic acid, ASA) is widely used for secondary prevention of ischemic vascular events, although its protection only occurs in 25% of patients. We previously demonstrated that platelet reactivity is enhanced by a prothrombotic effect of erythrocytes in a thromboxane-independent manner. This diminishes the antithrombotic therapeutic potential of ASA. Recent data from our laboratory indicate that the prothrombotic effect of erythrocytes also contains an ASA-sensitive component. In accordance with this observation, intermittent treatment with high-dose ASA reduced the prothrombotic effects of erythrocytes ex vivo in healthy volunteers. In the present study, the effects of platelet-erythrocyte interactions were evaluated ex vivo in 82 patients with vascular disease: 62 patients with ischemic heart disease treated with 200 mg ASA/d and 20 patients with ischemic stroke treated with 300 mg ASA/d.Platelet activation (release reaction) and platelet recruitment (fluid-phase proaggregatory activity of cell-free releasates from activated platelets) were assessed after collagen stimulation (1 microg/mL) of platelets, platelet-erythrocyte mixtures, or whole blood. Platelet thromboxane A2 synthesis was inhibited by >94% by ASA administration in all patients. Importantly, platelet recruitment followed one of three distinct patterns. In group A (n=32; 39%), platelet recruitment was blocked by ASA both in the presence and absence of erythrocytes. In group B (n=37; 45%), recruitment was abolished when platelets were evaluated alone but continued in the presence of erythrocytes, indicating a suboptimal effect of ASA on erythrocytes of this patient group. In group C (n= 13; 16%), detectable recruitment in stimulated platelets alone persisted and was markedly enhanced by the presence of erythrocytes.In two thirds of a group of patients with vascular disease, 200 to 300 mg ASA was insufficient to block platelet reactivity in the presence of erythrocytes despite abolishing thromboxane A2 synthesis. Platelet activation in the presence of erythrocytes can induce the release reaction and generate biologically active products that recruit additional platelets into a developing thrombus. Insufficient blockade of this proaggregatory property of erythrocytes can lead to development of additional ischemic complications.
THE EFFECT OF SERUM UPON THE GERMICIDAL ACTION OF SOAPS
Authors: Arnold H. Eggerth
Journal: The Journal of Experimental Medicine (1927)

1. Far more information about the effect of serum or other substances upon the germicidal action of soaps can be obtained by determining the germicidal titers over a wide range of pH than by determining the titer at a single pH. In this way a characteristic curve for each test substance is obtained. 2. The curve for a particular concentration of serum bears a definite relationship to the curve for salt solution (buffer) alone. Wherever the titer in salt solution is high, very small amounts of serum greatly diminish that titer. Wherever the titer in salt solution is low, small amounts of serum leave the titer unchanged. Thus small additions of serum flatten the curves and make them more nearly horizontal. If further large amounts of serum are added, a further reduction in titer takes place at all reactions. 3. The calcium of serum has only a very slight effect upon the soap titer. 4. The protein of serum is probably inhibitory to soaps; but the curve for partially defatted serum, and the curves for other protein substances tested, do not run parallel to the serum-soap curves. 5. The various lipoids that are known to be present in serum are inhibitory to the action of soaps, both as emulsions and as clear solutions. 6. The action of serum upon soaps may be regarded as a complex reaction, in which lipoids, protein, and, to a lesser extent, calcium salts take part. Their effect is due to the fact that these substances, by combining with the soaps, remove them from the field of germicidal action.