tbuckley/cabot-search huggingface dataset:
Correction of Murine PKU Following AAV-mediated Intramuscular Expression of a Complete Phenylalanine Hydroxylating System
Authors: Zhaobing Ding, Cary O Harding, Alexandre Rebuffat, Lina Elzaouk, Jon A Wolff, Beat Thöny
Journal: Molecular Therapy (2008)

Phenylketonuria (PKU) caused by phenylalanine hydroxylase (PAH) deficiency leads to toxic accumulation of phenylalanine (Phe). PAH is predominantly expressed in liver and its activity requires a supply of tetrahydrobiopterin (BH4) cofactor, but we propose that expression of a complete Phe hydroxylating system (PAH plus BH4 synthetic enzymes) in skeletal muscle will lead to therapeutic reduction of blood Phe levels in Pahenu2 mice, a model of human PKU. In order to test this hypothesis, we first developed transgenic Pahenu2 mice that lack liver PAH activity but coexpress, in their skeletal muscle, PAH and guanosine triphosphate cyclohydrolase I (GTPCH). The latter is responsible for the committing enzymatic step in BH4 biosynthesis. Despite sufficient muscle enzyme expression, these mice remained hyperphenylalaninemic, thereby suggesting that expression of additional BH4 synthetic enzymes would be necessary. A recombinant triple-cistronic adeno-associated virus-2 (AAV2) pseudotype 1 vector expressing PAH along with GTPCH and 6-pyruvoyltetrahydrobiopterin synthase (PTPS), the next step in BH4 synthesis, was generated. Injection of this vector into the gastrocnemius muscles of Pahenu2 mice led to stable and long-term reduction of blood Phe and reversal of PKU-associated coat hypopigmentation. We propose that muscle-directed gene therapy will be a viable alternative treatment approach to PKU and other inborn errors of metabolism. Phenylketonuria (PKU) caused by phenylalanine hydroxylase (PAH) deficiency leads to toxic accumulation of phenylalanine (Phe). PAH is predominantly expressed in liver and its activity requires a supply of tetrahydrobiopterin (BH4) cofactor, but we propose that expression of a complete Phe hydroxylating system (PAH plus BH4 synthetic enzymes) in skeletal muscle will lead to therapeutic reduction of blood Phe levels in Pahenu2 mice, a model of human PKU. In order to test this hypothesis, we first developed transgenic Pahenu2 mice that lack liver PAH activity but coexpress, in their skeletal muscle, PAH and guanosine triphosphate cyclohydrolase I (GTPCH). The latter is responsible for the committing enzymatic step in BH4 biosynthesis. Despite sufficient muscle enzyme expression, these mice remained hyperphenylalaninemic, thereby suggesting that expression of additional BH4 synthetic enzymes would be necessary. A recombinant triple-cistronic adeno-associated virus-2 (AAV2) pseudotype 1 vector expressing PAH along with GTPCH and 6-pyruvoyltetrahydrobiopterin synthase (PTPS), the next step in BH4 synthesis, was generated. Injection of this vector into the gastrocnemius muscles of Pahenu2 mice led to stable and long-term reduction of blood Phe and reversal of PKU-associated coat hypopigmentation. We propose that muscle-directed gene therapy will be a viable alternative treatment approach to PKU and other inborn errors of metabolism.
Moc Hoa: A Vietnam Medical-Military Adventure
Authors: Norig Ellison
Journal: JAMA (1992)

<i>Moe Hoa</i>describes the experiences of the author, an Army physician assigned to the Military-Provincial Hospital Assistance Program (MILPHAP), during a 12-month tour of duty in South Vietnam in 1966-1967. Moe Hoa is the name of a provincial capital in the Mekong Delta region where the author was stationed. I had a similar assignment the preceding year at the Pleiku Provincial Hospital in the Central Highlands of South Vietnam, and I particularly enjoyed the liberal use of pictures with the narrative. Over 150 photos, most in color, and 14 pen sketches by combat artist Theodore William Gostas liberally illustrate the events described by the author and will bring back memories to anyone who served in Vietnam in any capacity, not just MILPHAP physicians. For those who were on MILPHAP teams, mention of such interesting practices as a noon to 2:30 PM siesta, when the hospital literally shut down and patients
Haematoma complicating arterial Doppler studies
Authors: J.E. Gach, R. Charles-Holmes
Journal: British Journal of Dermatology (2002)

Sir, Arterial Doppler studies are an established procedure in the assessment of lower limb ulceration. The test is simple to perform, cheap and noninvasive but lacks the accuracy of angiography, which is regarded as the ‘gold standard’ in assessing atherosclerotic occlusive disease. Angiography is an invasive procedure with a risk of complications often requiring hospital admission. While arterial Doppler flow studies are regarded as noninvasive we report a patient where these were followed by the development of a large haematoma. A 93‐year‐old woman was admitted to hospital with a history of multiple falls and chronic leg oedema. Her medical history included asthma, diverticular disease and congestive cardiac failure with atrial fibrillation. She was taking 125 µg of digoxin, 2·5 mg of bendrofluazide and 5 tablets of coamilofruse 5/40 (amiloride hydrochloride 5 mg/frusemide 40 mg) daily. Her asthma was controlled with inhaled beclomethasone dipropionate (Becodisks®) 400 µg twice daily and salbutamol (Ventodisks®) 400 µg when needed which she had been taking for the last 10 years. She had had no systemic steroids in the past. There was no history of deep vein thrombosis or varicose veins. On examination of her lower limbs she had marked oedema extending to her thighs. There was a 5‐cm ulcer on the medial aspect of the left lower leg with a central 1‐cm necrotic area. Clinical assessment of the arterial flow to the legs was impeded by her marked oedema. It seemed likely that the ulceration on the gaiter area of the left leg resulted from trauma sustained during a recent fall. The ulcer had been treated with simple, nonadhesive dressings and crepe bandages applied by district nurses in the community.
Biologic monitoring of exposure to organophosphorus pesticides in 195 Italian children.
Authors: C Aprea, M Strambi, M T Novelli, L Lunghini, N Bozzi
Journal: Environmental Health Perspectives (2000)

One hundred ninety-five 6- to 7-year-old children who lived in the municipality of Siena (Tuscany, Italy), underwent biologic monitoring to evaluate urinary excretion of several alkylphosphates that are metabolites of organophosphorus pesticides. We evaluated dimethylphosphate (DMP), dimethylthiophosphate (DMTP), dimethyldithiophosphate (DMDTP), diethylphosphate (DEP), diethylthiophosphate (DETP), and diethyldithiophosphate (DEDTP). We obtained urine samples taken in the children's schools, and each sample was accompanied by a questionnaire about lifestyle and dietary habits. We found DMP and DMTP in detectable concentrations in the greatest number of samples (96 and 94%, respectively). The DMP values were geometric mean (GM) 116.7, [geometric standard deviation (GSD) 2.5], and a range of 7.4-1,471.5 nmol/g creatinine. The corresponding DMTP values were GM 104.3 (GSD 2.8) and a range of 4.0-1,526.0 nmol/g creatinine. DMDTP, DEP, DETP, and DEDTP concentrations were GM 14.1, (GSD 3.0), and a range of 3.3-754.6 nmol/g creatinine in 34% of the children; GM 33.2, (GSD 2.4), and a range of 5.1-360.1 nmol/g creatinine in 75% of the children; GM 16.0, (GSD 2.9), and a range of 3.1-284.7 in 48% of the children; and GM 7.7, (GSD 2.1), and a range of 2.3-140.1 in 12% of the children, respectively. The significant variable for urinary excretion of these metabolites in children was pest control operations performed inside or outside the house in the preceding month; however, the presence of a vegetable garden near the house rarely emerged. The urinary excretion of alkylphosphates in children was significantly higher than in a group of the adult population resident in the same province.
Treatment of Emphysema
Authors: George C. Risman
Journal: JAMA (1964)

<h3>To the Editor:—</h3> Dr. Hurley L. Motley's recent answer (Questions and Answers,<i>JAMA</i><b>188</b>:1024 [June 15] 1964) regarding the diagnosis and treatment of emphysema reemphasizes the problem of evaluating applications for disability insurance benefits under private and governmental programs. In answering an inquiry on the treatment of emphysema, Dr. Motley stated, "... more information on the pulmonary function status would be desirable...." and "If pulmonary function tests reveal severe emphysema and hypoxia, a climate change... would be desirable." These comments were made, even though the inquirer presented full clinical data and chest x-ray and electrocardiographic findings. We agree fully with Dr. Motley, but we wish to focus further attention on the importance and usefulness of pulmonary function tests in the diagnosis and treatment of clinical problems as well as in the evaluation and measurement of disability due to pulmonary disease. The diagnosis of emphysema is being made
THE RELATION OF THE MEDICAL AND LEGAL DEPARTMENTS OF RAILWAYS.
Authors: L. E. LEMEN
Journal: JAMA (1898)

<h3>CONNECTION BETWEEN LAW AND MEDICINE.</h3> Law and medicine, like "knowledge and wisdom," are "far from being one," but here Cowper's distinction ceases to apply, for the connection between the two professions is close and intimate, and each new discovery in this age of rapid, scientific progress unites more closely these great branches of learning. Medical jurisprudence has widened far beyond testamentary capacity, commissions in lunacy and expectation of life. The toxicologist and the chemist are quite commonly assistants of both commonwealth and accused in capital trials; the surgeon, the bacteriologist and the biologist are hand in hand with attorney and counsellor in civil and criminal causes. Where the<i>Green Bag</i>or the<i>London Lancet</i>was once filed alone, the<i>Medico-Legal Journal</i>now shares shelf space and attention, and the journals of both professions devote much printed space to medical jurisprudence and medico-legal surgery. The Medico-Legal Society, from an insignificant local
Early Microvascular Dysfunction in Healthy Normal-Weight Males With Heredity for Type 2 Diabetes
Authors: Gun Jörneskog, Majid Kalani, Jeanette Kuhl, Peter Båvenholm, Abram Katz, Gustaf Allerstrand, Michael Alvarsson, Suad Efendic, Claes-Göran Östenson, John Pernow, John Wahren, Kerstin Brismar
Journal: Diabetes Care (2005)

The pathogenesis behind diabetic microangiopathy is complex; both genetic (1–3) and metabolic factors (4–6) are clearly of importance. Recently, it has been demonstrated that not only patients with diabetes but also healthy individuals at risk for diabetes have functional vascular disturbances (7). These findings suggest that factors other than hyperglycemia are of importance for microvascular dysfunction. The aim of the present study was to investigate whether genetic factors (heredity for type 2 diabetes) are associated with disturbances in nutritive skin capillary circulation, nonnutritive skin microcirculation, and/or brachial macrocirculation.

Subjects were from the Stockholm Diabetes Prevention Program, a population-based study (8). Normal-weight men who were free of medication, who were nonsmokers, and who had normal oral glucose tolerance tests and insulin sensitivity as assessed by a hyperinsulinemic-euglycemic clamp (9) were investigated. Ten men with heredity for type 2 diabetes were matched for age and BMI with 10 men without heredity. Heredity for type 2 diabetes was defined as known diabetes in at least two second-degree relatives (grandparent, uncle, or aunt) or in at least one first-degree relative in the generation of the proband (sister or brother) or the parents (8).

The investigations were performed in the …
Abstract 3770: ER-α36-mediated non-genomic estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells .
Authors: Hao Deng, Xintian Zhang, Molin Wang, Mingxi Guo, Lijiang Liu, Zhaoyi Wang
Journal: Cancer Research (2013)

Abstract Accumulating experimental and clinical evidence indicated that breast cancer may arise from mammary stem/progenitor cells that posses the features like the ability of self-renewal and tumor generation from very few cells, slow cell division, differentiation into different lineages, selective resistance to radio- and chemo-therapy, constitutive activation of anti-apoptotic pathways and induction of angiogenesis, the ability to migrate and spread in metastasis. Many signaling pathways involved in regulation of normal mammary stem cells including Hedgehog, Bmi-1, Wnt, NOTCH, HER-2, p53 and PTEN/Akt/β-catenin pathways have been identified to play roles in breast cancer stem/progenitor cells. However, the involvement of estrogen signaling, a major signaling pathway in breast cancer development, in regulation of breast cancer stem/progenitor cells has not been well established, mainly because expression of estrogen receptor-α (ER-α) in breast cancer stem/progenitor cells remains controversial. Previously, we have identified and cloned a novel variant of ER-α, ER-α36, that is mainly expressed near the plasma membrane and in the cytoplasm, and mediates non-genomic estrogen signaling such as activation of the MAPK/ERK and PI3K/AKT signaling pathways. In this study, we ivestigated the function of ER-α36 in regulation of breast cancer stem/progenitor cells. We found that ER-α36 was highly expressed on the plasma membrane of the breast cancer stem/progenitor cells while the original ER-α was expressed outside of the cell nuclei. We also found that the genomic estrogen signaling was down-regulated in ER-positive breast cancer stem/progenitor cells. ER-positive breast cancer cells with forced expression of recombinant ER-α36 exhibited increased populations of stem/progenitor cells and high tumor seeding efficiency. Estrogen treatment significantly increased the population of breast cancer stem/progenitor cells while failed to do so in ER-positive breast cancer cells with knocked-down expression levels of ER-α36. We further found that estrogen positively regulates breast cancer stem/progenitor cells through ER-α36-mediated non-genomic estrogen signaling pathways such as activation of the PI3K/AKT pathway. Thus, our results demonstrated that the novel variant of ER-α, ER-α36 plays an important role in estrogen regulation of ER-positive breast cancer stem/progenitor cells. Citation Format: Hao Deng, Xintian Zhang, Molin Wang, Mingxi Guo, Lijiang Liu, Zhaoyi Wang. ER-α36-mediated non-genomic estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3770. doi:10.1158/1538-7445.AM2013-3770
Buccal oxytocin after amniotomy for induction of labour.
Authors: J. M. Ritchie, J. M. Brudenell
Journal: BMJ (1967)

In a recent article (Ritchie and Brudenell, 1966) we reported the results from using buccal oxytocin as a routine after amniotomy for induction of labour. By use of a standard course with a maximum of 3,800 units of buccal oxytocin and measuring the results in terms of induction delivery interval and the proportion not delivered 24 hours after amniotomy, improvements were obtained of approximately 30% and 60% respectively over control figures. These results were obtained without any increase of undesirable side-effects ; in particular the incidence of uterine hyperactivity or foetal distress was not adversely affected. In the discussion of the results we commented that further work was in progress to see whether the dose of buccal oxy tocin could be reduced. This paper is an account of that work and the results obtained.
Abstract 15311: Efficacy of Encapsulated GLP-1 Eluting Mesenchymal Stem Cells (CellBead): Results From a Blinded, Randomized, Dose-Finding Study in a Porcine Model of Acute Myocardial Infarction
Authors: Renate de Jong, Jaco H Houtgraaf, Jeroen Huizingh, Imo Hoefer, Gerard Pasterkamp, Andrew L Lewis, Peter W Stratford, Christine Wallrapp, Henricus J Duckers
Journal: Circulation (2011)

Objective CellBeads are 170 μm alginate microspheres that contain mesenchymal stem cells (MSC) transfected to express glucagon-like peptide-1 (GLP-1), alongside the inherent paracrine factors. GLP-...
Expression of CCR9 β-chemokine receptor is modulated in thymocyte differentiation and is selectively maintained in CD8+ T cells from secondary lymphoid organs
Authors: Laura Carramolino, Ángel Zaballos, Leonor Kremer, Ricardo Villares, Pilar Martı́n, Carlos Ardavı́n, Carlos Martı́nez-A, Gabriel Márquez
Journal: Blood (2001)
Pharmacies and Prevention of Potentially Fatal Drug Interactions-Reply
Authors: Lucian L. Leape
Journal: JAMA (1996)

<h3>In Reply.</h3> —The study by Dr Cavuto and colleagues makes an important point—that computerized screening programs are not a panacea. Nonetheless, we believe that they can be an effective tool for preventing prescribing errors, particularly if they receive iterative evaluation and improvement. Moreover, the glass was more than half full in this instance: in 68% of the pharmacies, the error was intercepted. Of course, a 32% failure rate for an error with such serious consequences is unacceptable, but it might have been much higher had no systems to intercept such errors been in place. What went wrong in the instances in which the errors slipped through? It seems to us that at least three of the possibilities have important implications: (1) the drug interaction checking systems may not have been updated to include the new interaction; (2) the pharmacists may have been bombarded by so many interaction reports that they
206. Frequency and Analysis of Liver Tumors in AAV-Treated B6C3F1 Hybrid Mice
Authors: Peter L. Bell, A. David Moscioni, Robert J. McCarter, Di Wu, Guang-Ping Gao, Albert Hoang, Julio San Miguel, Xun Sun, Nelson Wivel, Steven E. Raper, Emma E. Furth, Mark L. Batshaw, James M. Wilson
Journal: Molecular Therapy (2006)

We report on the frequency of liver tumors observed in a gene therapy study with AAV vectors in male mice of the B6C3F1 hybrid background, which are known to have a high frequency of spontaneous tumor formation in the liver. Because of their increased susceptibility to develop tumors, these animals should serve as sensitive models to reveal any potential tumorigenic properties of AAV vectors. Male mice with mutations in their OTC gene (spf and spf-ash) and their wild-type siblings had received AAV vectors expressing either the murine OTC (mOTC) or LacZ gene. Untreated control animals were included in the study. All experimental groups including wild-type and mOTC-deficient animals not treated with vector developed liver nodules. In the majority of the animals, H&E-stained liver samples were available that allowed to score the observed nodules according to their likelihood to represent hepatocellular carcinomas. In the spf group no statistically significant risk differences were found between vector-treated and untreated animals. Likewise, in the spf-ash group the administration of vectors expressing mOTC did not increase the risk of tumor development. However, these mice showed increased risks of tumor formation when treated with LacZ-expressing vectors compared to untreated animals or animals that had received vectors with mOTC as transgene, suggesting that the transgene but not the vector might play a role in the formation of tumors. In general, both the overall risk of developing liver nodules and the histological appearance as hepatocellular carcinoma was more frequent in mice that had received AAV-LacZ compared to untreated controls or animals treated with AAVmOTC. Tumor tissue contained consistently lower amounts of vector DNA than healthy liver tissue, and only one out of 16 tumors was found to express the transgene as determined by histochemistry to detect OTC activity and immunostaining against beta-galactosidase. We therefore conclude that AAV vectors alone do not contribute to the formation of tumors, even in mouse strains with a heightened susceptibility to the development of those lesions. However, the expression of LacZ alone or in combination with vector may be problematic.
Spontaneous running increases aortic compliance in Wistar-Kyoto rats
Authors: Bronwyn A Kingwell, Pamela J Arnold, Garry L Jennings, Anthony M Dart
Journal: Cardiovascular Research (1997)

Previous studies in humans have found, using non-invasive methodology, that arterial compliance is elevated with exercise training. Forced exercise in animals has corroborated these findings, but the association of this type of exercise with psychological stressors limits its relevance to humans. We have investigated the effects of spontaneous running exercise from 4-20 weeks of age on aortic and mesenteric compliance and vascular reactivity in Wistar-Kyoto (WKY) rats.Animals were killed using CO2 asphyxia and the aorta, mesentery and heart rapidly removed. The heart was dissected and weighed. The aorta was separated into 3 4-mm rings which were mounted on wires in organ baths for determination of compliance and vascular reactivity to noradrenaline, acetylcholine and sodium nitroprusside. The slope of diameter-pressure relationship derived using Laplace's equation was used as an index of compliance.During the final 2 weeks of training WKY rats ran an average of 7.9 +/- 1.0 km/24 h. Body weight was not affected by training. Training significantly increased the weight of the atria, left and right ventricles as well as total heart weight and left ventricular/body weight ratio. Aortic compliance was increased from 12.3 +/- 0.4 to 14.2 +/- 0.5 microns/mmHg (P < 0.05) after training. There was no effect of training on aortic reactivity to noradrenaline, acetylcholine or sodium nitroprusside.Exercise training increased intrinsic aortic compliance in WKY rats which provides evidence for a structural basis for the elevated compliance reported previously with 4 weeks of aerobic exercise in man.
A picture says more than a thousand words: Structural insights into hepatitis C virus translation initiation
Authors: Pantxika Bellecave, Darius Moradpour
Journal: Hepatology (2006)

Abstract Protein synthesis in mammalian cells requires initiation factor eIF3, a ˜750-kilodalton complex that controls assembly of 40S ribosomal subunits on messenger RNAs (mRNAs) bearing either a 5′-cap or an internal ribosome entry site (IRES). Cryoelectron microscopy reconstructions show that eIF3, a five-lobed particle, interacts with the hepatitis C virus (HCV) IRES RNA and the 5′-cap binding complex eIF4F via the same domain. Detailed modeling of eIF3 and eIF4F onto the 40S ribosomal subunit reveals that eIF3 uses eIF4F or the HCV IRES in structurally similar ways to position the mRNA strand near the exit site of 40S, promoting initiation complex assembly.