tbuckley/cabot-search huggingface dataset:
881. Safety, Efficacy and Biodistribution of Recombinant AAV2-RPE65 Vector Delivered by Ocular Subretinal Injection
Authors: Samuel G. Jacobson, Gregory M. Acland, Gustavo D. Aguirre, Tomas S. Aleman, Sanford L. Boye, Sharon B. Schwartz, Artur V. Cideciyan, Caroline J. Zeiss, Andras M. Komaromy, Alejandro J. Roman, Elizabeth A.M. Windsor, Alexander Sumaroka, Susan E. Pearce-Kelling, Thomas J. Conlon, Quihong Li, Vincent A. Chiodo, Terence R. Flotte, Albert M. Maguire, Jean Bennett, William W. Hauswirth
Journal: Molecular Therapy (2006)

Top of pageAbstract
Introduction: AAV2 delivery of the RPE65 cDNA to the retina of blind RPE65-deficient dogs or rd12 mice restores vision as determined electrophysiologically and behaviorally. This strategy is being considered for human trials in RPE65-associated Leber congenital amaurosis, but safety and dose-efficacy within a non-toxic range with this vector have not been defined. Here we report the results of toxicology and biodistribution studies in two mammalian species, dogs and rats. Methods: Vector related pathology and spread after subretinal delivery of AAV2-CBA-RPE65 was studied in RPE65-mutant dogs and normal Spague-Dawley rats. Doses of vector delivered bracketed those intended for the clinical study. Results: There was no systemic toxicity at any vector dose in either species. In dogs ocular examinations showed mild or moderate inflammation that resolved over an initial 3-month period. Retinal histopathology indicated that traumatic lesions from the injection were common, but retinal thinning within the injection region only occurred at the highest vector doses. Biodistribution studies were also performed in RPE65-mutant dogs at various times after vector injection and in normal rats at about 2 weeks and 2 months post-injection. Vector DNA was not widespread outside the injected eye with blood and gonadal tissue consistently negative. Concomitant dose-response results in the RPE65-mutant dogs indicated that the highest 1.5 log unit range of vector doses was efficacious. Conclusions: Given the efficacy and toxicity limits defined in this study, a range for safe vector dose escalation of subretinal AAV2-CBA-RPE65 is suggested for initial human trials.
Paternalism, Family Duties, and My Aunt Maude-Reply
Authors: Steven H. Miles
Journal: JAMA (1988)

In Reply.—  Cataract surgery, usually a brief, outpatient procedure, is neither minor nor trivial in the skill it requires, the dedication of its practitioners, its benefits, its psychological immediacy to patients, the potential morbidity of its thankfully rare complications, or its costs. Nevertheless, I suspect that physicians and the most ardent proponents of respect for a patient's perceptions could probably agree that Maude's equation of the risks and burdens of cataract extraction with those of an emergency cholecystectomy in 1940 was irrational. Five years ago, the Food and Drug Administration found that a large majority of the 3.5% to 8% rate of sight-threatening (not life-threatening) complications of this procedure could be treated with excellent recovery of vision, even in persons more than 80 years old. 1 By contrast, a recent study 2 found that cholecystectomy in persons more than 70 years of age carries a 44% rate of major complications
Simultaneous measurement of gastric emptying, small bowel residence and colonic filling of a solid meal by the use of the gamma camera.
Authors: N W Read, M N Al-Janabi, A M Holgate, D C Barber, C A Edwards
Journal: Gut (1986)

A method for determining the profiles of gastric emptying, small intestinal residence, and colonic filling of a solid test meal, labelled with 250 microCi 99mTechnetium sulphur colloid has been evaluated in nine healthy volunteers and six patients with a disturbance in bowel habit. Mean small bowel transit time was determined by deconvolving the rate of colonic filling with the rate of gastric emptying. In normal subjects, the stomach appeared to empty exponentially with a half time of 1.2 +/- 0.3 hours (mean +/- SD). Food reached the colon by 2.8 +/- 1.5 hours. The mean small bowel transit time was 4.0 +/- 1.4 hours. In most normal subjects, the colon appeared to fill in a linear fashion with approximately 16% food residues entering every hour, and the profile of colonic filling in normal subjects was similar to the profile of ileal emptying observed after feeding a similar radiolabelled solid meal to 14 patients equipped with terminal ileostomies. There was a highly significant correlation between the onset of breath hydrogen excretion and the appearance of radioactivity over the caecum (r = 0.88, p less than 0.01), though in one third of subjects the increase in caecal radioactivity preceded the rise in breath hydrogen concentration by more than 20 minutes. There was also a highly significant correlation between the mean transit time and values for colonic filling but not values for gastric emptying. Patients with irritable bowel syndrome who had diarrhoea tended towards short small bowel transit and early colonic filling, whereas patients who have constipation tended towards long small bowel transit and delayed colonic filling. This method offers a novel means of assessing small bowel transit time, small bowel residence and the profile of colonic filling in man.
The Surgeon at 2 A.M.
Authors: H. Byrne
Journal: BMJ (2008)

Sylvia Plath (1932-1963) was a prolific poet and wrote several poems with medical themes in which gore and the grotesque feature heavily, such as Thalidomide , Facelift , Two views of a cadaver room , and In plaster , as well as Three women , which is set in a women’s hospital. The surgeon at 2 A.M. was written in 1961 and was possibly heavily influenced by her recent miscarriage and a hospitalisation for appendicitis at the now defunct St Pancras Hospital in London. In this extract, she manages to capture the surreal beauty of the operating theatre at night as well as that of the internal organs: …
Health Care for Persons with Non-Insulin-dependent Diabetes Mellitus: The German Experience
Authors: Michael Berger
Journal: Annals of Internal Medicine (1996)

A structured treatment and education program for patients with non–insulin-dependent diabetes mellitus (NIDDM) who are not taking insulin was developed, evaluated, and implemented at the primary health care level throughout Germany. The program is based on the definition of individual and pragmatic therapeutic goals for each patient, primarily using nondrug treatment, which includes systematic glycosuria self-monitoring by the patients and four structured sessions of group education held in a general practitioner's office. After documentation of the program's efficacy in a randomized, controlled trial and several pilot projects, the program has been officially incorporated into the general German health care scheme and includes payment to practicing physicians for each patient treated. More than 12 500 primary health care physicians have participated in special 2-day postgraduate courses given by diabetologists; these courses are a precondition to participating in the program. As part of the primary health care scheme, the NIDDM program will be continuously monitored for quality control and efficiency. Currently, similar structured treatment and education programs targeted to primary health care physicians are being introduced for both insulin-treated NIDDM and arterial hypertension.
Adding Insulin Glargine Versus Rosiglitazone
Authors: Aaron I. Vinik, Quanwu Zhang
Journal: Diabetes Care (2007)

OBJECTIVE—We sought to assess health-related quality of life (HRQOL) in patients with type 2 diabetes treated with insulin glargine or rosiglitazone as add-on therapy to sulfonylurea plus metformin. RESEARCH DESIGN AND METHODS—HRQOL was evaluated in 217 subjects uncontrolled with sulfonylurea plus metformin, enrolled in a 24-week, multicenter, randomized, open-label, parallel-group trial of add-on insulin glargine versus rosiglitazone. A 40-item, self-administered questionnaire at baseline and at weeks 2, 6, 12, 18, and 24 was given, including the 34-item Diabetes Symptom Checklist-Revised (DSC-R), a 5-item mental health scale from the 36-item Short-Form Health Survey (SF-36), and a single-item health rating from the SF-36. These assessments do not specify route of therapy. RESULTS—Both treatment groups showed similar improvements in glycemic control from baseline to week 24 (change in A1C: −1.66% in the insulin glargine group, −1.51% in the rosiglitazone group, P = 0.1446). Both groups also showed improvement in HRQOL, although subjects treated with insulin glargine experienced significantly greater improvements compared with rosiglitazone in the DSC-R total symptom score (P = 0.005), total symptom distress score (P = 0.03), individual domain scores for mood symptoms (P = 0.007), ophthalmologic symptoms (P = 0.007), ophthalmologic distress (P = 0.013), fatigue distress (P = 0.033), and SF-36 perception of general health (P = 0.047). CONCLUSIONS—Although addition of insulin glargine and rosiglitazone achieved comparable improvements in glycemic control, insulin glargine was associated with greater improvements in HRQOL, indicating that other factors (e.g., safety profile and nonglycemic actions) may further enhance HRQOL in patients with type 2 diabetes.
Letter: Current practice in tetanus prophylaxis.
Authors: D Caro, E Shaw
Journal: BMJ (1974)

and the doctor's general assessmnen-t and opinion.Dr. Sanazaro is experienced enough to anticipate criticism of the scheme.The criteria could be restrictive; they could become rigid rules which are difficult to modify or change, they could limit judgement and retard innovation.His qualifyn comment that such things have not hap- pened after medical auditing is not entirely reassuring and the cynic might reasonably suggest that even more commiittees are needed to pronounce on this.In general, bureaucratic methods seldom encourage initiative and are prone to political ex- pediency.They tend to encourage mediocrity and overemphasize the imnportance of mis-
Iron overload diminishes atherosclerosis in apoE-deficient mice
Authors: Elizabeth A. Kirk, Jay W. Heinecke, Renée C. LeBoeuf
Journal: Journal of Clinical Investigation (2001)

It has been proposed that elevated levels of tissue iron increase the risk for atherosclerosis, perhaps by favoring the formation of pro-atherogenic oxidized LDL. Working with apoE-deficient (apoE–/–) mice, which do not require a high-fat diet to develop atherosclerosis, we compared the effects of standard diet (0.02% iron) or a 2% carbonyl iron diet. After 24 weeks, mice fed the 2% carbonyl iron diet had twice as much iron in their plasma, a ninefold increase in bleomycin-detectable free iron in their plasma, and ten times as much iron in their livers as control mice. Dietary iron overload caused a modest (30%) rise in plasma triglyceride and cholesterol. Nevertheless, this regimen did not exacerbate, but rather reduced the severity of atherosclerosis by 50%, and it failed to elevate hepatic levels of heme oxygenase mRNA, which is induced by many different oxidative insults in vitro. Moreover, hepatic levels of protein-bound dityrosine and ortho-tyrosine, two markers of metal-catalyzed oxidative damage in vitro, failed to rise in iron-overloaded animals. Our observations suggest that elevated serum and tissue levels of iron are not atherogenic in apoE–/– mice. Moreover, they call into question the hypothesis that elevated levels of tissue iron promote LDL oxidation and oxidative stress in vivo.
Medicine in China. Medicine and society.
Authors: A J Smith, E M Adey
Journal: BMJ (1974)

alcoholism, abnormal personality, chronic mental illness, hypo- chondriacal symptoms, and a history of suicidal behaviour in the past.Nevertheless, spouses with good outcome did suffer after the suicide.One spouse, now happy, said that though relieved she experienced waves of grief that completely over- came her, but their frequency slowly decreased.At the time of the first research inquiry the interviewer was pessimistic about her future.She found that visit so helpful she now thinks that interviewing spouses after suicide should be "an essential social service."The validity of the finding about the helpfulness of the first research interview could have implications for the counselling of bereaved spouses.The benefits of catharsis, reflection, and explanation suggest that the chances of a good outcome might be improved by giving such help soon after the death.Bereavement through suicide is accompanied by shock and distress, but the worst effects that might be expected, increased mortality, psychiatric ill health, social criticism, and social dysfunction were not observed.The spouses of suicides re- semble more the widowed from all causes, but may be polarized into those with good and bad outcome to a greater extent.We thank Mrs. Molly Knowles for her help in planning the project and sharing the interviewing; Mr. Peter Fayers, M.R.C. Statistical Research and Services Unit, who estimated the expected numbers of deaths and advised; and Mrs.
AXL Is a Potential Target for Therapeutic Intervention in Breast Cancer Progression
Authors: Yi-Xiang Zhang, Peter G. Knyazev, Yuri V. Cheburkin, Kirti Sharma, Yuri P. Knyazev, László Őrfi, István Szabadkai, Henrik Daub, György Kéri, Axel Ullrich
Journal: Cancer Research (2008)

Abstract Protein kinases play important roles in tumor development and progression. A variety of members of this family of signal transduction enzymes serve as targets for therapeutic intervention in cancer. We have identified the receptor tyrosine kinase (RTK) AXL as a potential mediator of motility and invasivity of breast cancer cells. AXL is expressed in most highly invasive breast cancer cells, but not in breast cancer cells of low invasivity. Ectopic expression of AXL was sufficient to confer a highly invasive phenotype to weakly invasive MCF7 breast cancer cells. Experimental inhibition of AXL signaling by a dominant-negative AXL mutant, an antibody against the extracellular domain of AXL, or short hairpin RNA knockdown of AXL decreased motility and invasivity of highly invasive breast cancer cells. To selectively interfere with cancer cell properties defining the rate of disease progression, we identified 3-quinolinecarbonitrile compounds, which displayed potent inhibitory activity against AXL and showed strong interference with motility and invasivity of breast cancer cells. Our findings validated the RTK AXL as a critical element in the signaling network that governs motility and invasivity of breast cancer cells, and allowed the identification of experimental anti-AXL small molecular inhibitors that represent lead substances for the development of antimetastatic breast cancer therapy. [Cancer Res 2008;68(6):1905–15]
Renal Biopsy and Its Clinical Correlation in Toxemia of Pregnancy
Authors: ALBERT ALTCHEK
Journal: Circulation (1964)

Through the combination of a renal biopsy technique modified for pregnant women, electron microscopy, and knowledge of fine (ultramicroscopic) glomerular anatomy, the pathology of the renal glomerular lesion of toxemia of pregnancy (preeclampsia-eclampsia) has been defined. The lesion is pathognomonic and consists of swelling of the cytoplasm of the endothelial cell, deposits underneath the basement membrane and within the swollen endothelial cytoplasm, and an increase of intercapillary cells. The lesion reduces the glomerular capillary lumen. It is the most sensitive pathological lesion of toxemia in the body, and is present in all cases of toxemia. Once formed, the lesion persists until evacuation of the uterus, in spite of apparent clinical improvement with therapy. The lesion accounts for the characteristically decreased glomerular filtration rate in toxemia, and this may be a factor in the formation of edema. Demonstration of the lesion is the only laboratory method that can reliably differentiate toxemia from uncomplicated essential hypertension (preeclampsia may be superimposed on essential hypertension): the presence of the glomerular lesion indicates toxemia, while absence of the lesion indicates that the illness is not due to toxemia. A severe glomerular lesion indicates impending fetal death. Although renal biopsy is mainly of investigative use in obstetrics, it is a valid diagnostic tool for discovering or dismissing the possibility of chronic renal disease.
Hepatitis B and Down's syndrome.
Authors: J. Green
Journal: BMJ (1988)

rarely fatal and currently not routinely looked for: in future this and other anomalies may be part of general screening and will be relevant to decisions about termination of pregnancy.At present most laboratories can cope with the demand by mothers of 37 and over for antenatal diagnosis on grounds of their age, although prob- ably only half those who might do so actually request the investigation.'This may change with wider availability ofchorionic villus sampling since mothers who would not contemplate a termination at 19-20 weeks may accept one at 12 weeks.For correct counselling we need more knowledge of regional and ethnic variation in the incidence of chromosome anomalies.We also should know the risk of amniocentesis in our own units.It would be well if the indications for amniocentesis on grounds of maternal age were clarified to simplify the reappraisal required by the advent of chorionic villus sampling.Since this is likely to increase the number of requests for antenatal diagnosis it has implications for the overall costs of antenatal diagnosis as well as for the correct advice we should give.
Laparoscopic surgery for rectal cancer
Authors: Manish Chand, Jemma Bhoday, Gina Brown, Brendan Moran, Amjad Parvaiz
Journal: Journal of the Royal Society of Medicine (2012)

Laparoscopic surgery for colonic cancer is a safe and established alternative to traditional open colectomy. The potential advantages of shorter length of stay, faster recovery and fewer operative complications are well documented. The last 5 years has seen an increase in the number of laparoscopic colorectal operations as more surgeons learn this technique. Short and medium term results have been encouraging with respect to oncological outcomes. However, laparoscopic surgery for rectal cancer remains a contentious issue. The increased complexity of operating within the confines of the pelvis and the greater risk of oncological compromise, have led to some surgeons urging caution. We present the challenges associated with laparoscopic rectal cancer surgery and explain that appropriate patient selection, surgical planning and laparoscopic experience are the key to successful outcomes.
Systemic Cardiac Amyloidoses
Authors: Claudio Rapezzi, Giampaolo Merlini, Candida C. Quarta, Letizia Riva, Simone Longhi, Ornella Leone, Fabrizio Salvi, Paolo Ciliberti, Francesca Pastorelli, Elena Biagini, Fabio Coccolo, Robin M.T. Cooke, Letizia Bacchi-Reggiani, Diego Sangiorgi, Alessandra Ferlini, Michele Cavo, Elena Zamagni, Maria Luisa Fonte, Giovanni Palladini, Francesco Salinaro, Francesco Musca, Laura Obici, Angelo Branzi, Stefano Perlini
Journal: Circulation (2009)

Background— Most studies of amyloidotic cardiomyopathy consider as a single entity the 3 main systemic cardiac amyloidoses: acquired monoclonal immunoglobulin light-chain (AL); hereditary, mutated transthyretin-related (ATTRm); and wild-type transthyretin-related (ATTRwt). In this study, we compared the diagnostic/clinical profiles of these 3 types of systemic cardiac amyloidosis. Methods and Results— We conducted a longitudinal study of 233 patients with clear-cut diagnosis by type of cardiac amyloidosis (AL, n=157; ATTRm, n=61; ATTRwt, n=15) at 2 large Italian centers providing coordinated amyloidosis diagnosis/management facilities since 1990. Average age at diagnosis was higher in AL than in ATTRm patients; all ATTRwt patients except 1 were elderly men. At diagnosis, mean left ventricular wall thickness was higher in ATTRwt than in ATTRm and AL. Left ventricular ejection fraction was moderately depressed in ATTRwt but not in AL or ATTRm. ATTRm patients less often displayed low QRS voltage (25% versus 60% in AL; P &lt;0.0001) or low voltage-to-mass ratio (1.1±0.5 versus 0.9±0.5; P &lt;0.0001). AL patients appeared to have greater hemodynamic impairment. On multivariate analysis, ATTRm was a strongly favorable predictor of survival, and ATTRwt predicted freedom from major cardiac events. Conclusions— AL, ATTRm, and ATTRwt should be considered 3 different cardiac diseases, probably characterized by different pathophysiological substrates and courses. Awareness of the diversity underlying the cardiac amyloidosis label is important on several levels, ranging from disease classification to diagnosis and clinical management.
Abstract 5157: Functional and regulatory role of src kinase in podoplanin expressing glioma cancer stem cells
Authors: Ravesanker Ezhilarasan, Lindsey D. Goodman, Patrice N. Love, Kenneth D. Aldape, Erik P. Sulman
Journal: Cancer Research (2010)

Abstract The majority of patients with malignant gliomas, the most common and most lethal brain tumor, develop disease recurrence despite aggressive, multi-modality therapies. This treatment resistance has been attributed to a small population of tumor-initiating glioma cancer stem cells (GSCs). We recently described a new marker of GSCs, podoplanin (pdpn), based on analyses of gene expression profiling data and have found it to more accurately identify the stem cell population than other described markers, such as CD133, and to play a functional role stem cell phenotype. Pdpn expressing cells formed neurospheres at high rates in vitro, were more resistant to ionizing radiation, and initiated tumors in vivo. Pdpn belongs to a mesenchymal gene signature that is characteritic of poor patients survival from malignant gliomas. To identify the mechasism of pdpn within GSCs, we evaluated putuative binding partners to this transmembrane glycoprotein. One such partner, target of myb-like-1 (tom1l1) has been shown to regulate the Src oncogene pathway. The cytoplasmic tyrosine kinases of the Src family (SFK) play important roles in signal transduction induced by growth factors leading to DNA synthesis, cytoskeletal rearrangement, and receptor endocytosis. We therefore hypothesized that pdpn's role GSCs is due to its interaction with the Src pathway. Our aim for this study was to analyze downstream signaling events of Src in association with pdpn and its functional significance in glioma stem cell maintanence, invasion, and chemoradiation resistance. Using primary GSC and established glioma cell lines engineered to either overexpress or silence PDPN, we screened for SFK protein activation (phosphorylation) by immunblot. Changes in Src activation were correlated to in vitro invasion assays, in vivo tumor initiation, and radiation resistance. Preliminary data confirms binding of tom1l1 to pdpn and regulation of SFK activation. Engineered clones with shRNA targeting pdpn and/or tom1l1 were examined by expression profiling for downstream transcriptional changes. In summary, our data suggest a role of SFKs in the regulation of stemness by pdpn. These data integrate well with ongoing trials using Src-kinase inhibitors which may directly target the pdpn-expressing, GSC population in tumors and perhaps overcome the treatment resistance of these critical cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5157.