tbuckley/cabot-search huggingface dataset:
Improved Retinal Transduction In Vivo and Photoreceptor-specific Transgene Expression Using Adenovirus Vectors With Modified Penton Base
Authors: Siobhan M Cashman, Laura McCullough, Rajendra Kumar-Singh
Journal: Molecular Therapy (2007)

Adenovirus (Ad) vectors can be injected into human ocular tissues without producing adverse events and are therefore a promising means of gene transfer to the retina. However, when administered subretinally, Ad vectors primarily transduce the retinal pigment epithelium (RPE), whereas the majority of mutant gene products that cause photoreceptor (PR) degeneration are expressed exclusively in the PR cells. While it has been shown previously that pseudotyping of Ad can partially overcome the limited PR transduction by Ad5, we found that pseudotyping of Ad is not necessary for transduction of PR cells. We determined that, in the context of Ad, the cytomegalovirus (CMV) promoter is not significantly active in PRs. We compared expression levels from CMV and chicken beta actin (CBA) promoters in neural retina and found that CBA has a 173-fold greater potency than CMV. We also investigated the nature of the Ad–RPE interaction in murine retina and determined that the RGD domain in Ad penton plays a key role in RPE tropism. Deletion of the RGD domain coupled with use of the CBA promoter permitted transgene expression in neural retina approximately 667 times more efficiently than with Ad5 vectors. The use of these vectors in combination with a 4.7 kilobase (kb) rhodopsin promoter enabled transgene expression exclusively in PR cells in vivo. Adenovirus (Ad) vectors can be injected into human ocular tissues without producing adverse events and are therefore a promising means of gene transfer to the retina. However, when administered subretinally, Ad vectors primarily transduce the retinal pigment epithelium (RPE), whereas the majority of mutant gene products that cause photoreceptor (PR) degeneration are expressed exclusively in the PR cells. While it has been shown previously that pseudotyping of Ad can partially overcome the limited PR transduction by Ad5, we found that pseudotyping of Ad is not necessary for transduction of PR cells. We determined that, in the context of Ad, the cytomegalovirus (CMV) promoter is not significantly active in PRs. We compared expression levels from CMV and chicken beta actin (CBA) promoters in neural retina and found that CBA has a 173-fold greater potency than CMV. We also investigated the nature of the Ad–RPE interaction in murine retina and determined that the RGD domain in Ad penton plays a key role in RPE tropism. Deletion of the RGD domain coupled with use of the CBA promoter permitted transgene expression in neural retina approximately 667 times more efficiently than with Ad5 vectors. The use of these vectors in combination with a 4.7 kilobase (kb) rhodopsin promoter enabled transgene expression exclusively in PR cells in vivo.
Maurice Ravel and Alzheimer's Disease
Authors: Donald J. Dalessio
Journal: JAMA (1984)

Maurice Ravel was a man of this century, and we know more about him, including his medical care, than we do of many musicians of older times. The story of his later adult life is of particular interest, especially the rapid decline in his intellectual powers that occurred during his most productive years. We recognize this syndrome now as presenile dementia, or Alzheimer's disease. I believe that one may deduce from the available evidence that Ravel had this disease. Maurice Ravel was, arguably, the premier composer of the 20th century. Born in 1875 in the Pyrenees, he entered the Paris Conservatory in 1889 and was later a student of Fauré. With Debussy, he led the French musical impressionist movement, characterized by fluidity of style within classical forms, a refutation of the ponderous romanticism of Richard Wagner. Ravel excelled at piano composition and especially at orchestration, often scoring works of others
Mutational spectrum and geno‐phenotype correlation in <scp>C</scp>hinese families with <scp>H</scp>ereditary <scp>A</scp>ngioedema
Authors: Y.‐Y. Xu, Y.‐X. Zhi, J. Yin, L.‐L. Wang, L.‐P. Wen, J.‐Q. Gu, K. Guan, T. Craig, H.‐Y. Zhang
Journal: Allergy (2012)

Abstract Background Hereditary angioedema is a rare autosomal dominant disease, and its correlation between genotype and phenotype seems not to exist. So far, there are very few studies on C hinese population. We aimed to establish a C hinese genetic database of hereditary angioedema and investigated the potential correlation between genotype and phenotype. Method All the eight exons and intron–exon boundaries of C 1 inhibitor gene were detected in 48 unrelated families with HAE . The correlations between genotype and clinical parameters were evaluated by R statistical software. Results Thirty‐five different mutations (25 of them were novel) and 7 SNP s (3 of them were novel) were identified. Significant difference was found in the level of C 1 inhibitor antigen ( P = 0.01793) between different groups of mutational types. The correlation between different groups of mutational types and the level of C 1 inhibitor antigen (0.5047, P = 0.00027) was significant. The different groups of mutational types showed neither difference nor correlations of clinical parameters (severity score and the level of C 1 inhibitor function). Conclusion It appears that nonsense, frameshift, and mutations on A rg466 can cause lower level of C 1 inhibitor antigen than missense and in‐frame mutations; however, it does not affect severity of symptoms.
Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy
Authors: Caroline Besson, Aicha Goubar, Jean Gabarre, Willy Rozenbaum, Gilles Pialoux, François-Patrick Châtelet, Christine Katlama, Frédéric Charlotte, Bertrand Dupont, Nicole Brousse, Michel Huerre, Jacqueline Mikol, Philippe Camparo, Karima Mokhtari, Micheline Tulliez, Dominique Salmon-Céron, François Boué, Dominique Costagliola, Martine Raphaël
Journal: Blood (2001)
RESPONSE: Re: Melanocytic Nevi, Solar Keratoses, and Divergent Pathways to Cutaneous Melanoma
Authors: D. C. Whiteman
Journal: JNCI Journal of the National Cancer Institute (2003)

We note with interest the findings of Carli and Palli, which replicate our observations (1) that patients with melanomas of the head and neck were older and were statistically significantly less likely to have numerous nevi than patients with truncal melanoma. Patients in this Italian study were not originally selected with the specific intention of testing the divergent pathway hypothesis; nevertheless, particular aspects of the study design serve to strengthen our belief that the observed effects are real.
ASTHMA WITH MAXILLARY SINUSITIS AND A HEALTHY SUPERNUMERARY PARANASAL SINUS
Authors: W. S. T. Neville
Journal: BMJ (1927)

1!'EB.'2, 19271 ASTHMA WITH MAXILLARS UB ulTgS.[T>Iz 277 specimens which had not been radiated were sitnilarly prepared.Using a square graticule in-the eyepiece of the microscope, drawings were made, on squared paper, of the red cells seen.In this way a picture of the amount of blood in the capillaries was obtained.No differences between experiment and, controlwere found in the twelve-hour and twenty-four-hour specimens.The results obtained with intervals of-two, three, and four days
Obesity and Undiagnosed Diabetes in the U.S.
Authors: Christina C. Wee, Mary Beth Hamel, Annong Huang, Roger B. Davis, Murray A. Mittleman, Ellen P. McCarthy
Journal: Diabetes Care (2008)

OBJECTIVE—To study whether obese individuals, who are at higher risk for diabetes and disparities in care than nonobese individuals, are more likely to have undiagnosed diabetes. RESEARCH DESIGN AND METHODS—We performed an analysis of 5,514 adult participants in the 1999–2004 National Health and Nutrition Examination Survey. Particpants were interviewed about sociodemographic and medical data, including whether they had been diagnosed with diabetes, and were examined for height, weight, and fasting plasma glucose level ≥126 mg/dl or by previous physician diagnosis. After categorizing participants into normal weight, overweight, and obese according to BMI, the prevalance and diagnosis of diabetes across BMI categories was compared using χ2. RESULTS—Of the 9.8% (weighted sample) of participants who had diabetes, based on fasting glucose levels and self-reported diagnosis, 28.1% were undiagnosed, translating to an estimated 5.2 million people in the U.S. population. The proportion undiagnosed was not significantly different among normal-weight (22.2%), overweight (32.5%), or obese adults (27.4%). Nevertheless, obese adults comprise more than half of the undiagnosed diabetes cases (2.7 million). Relative to normal-weight adults, the adjusted odds ratio (OR) for having undiagnosed diabetes was 1.50 (0.73–3.08) in overweight and 1.37 (0.72–2.63) in obese adults. CONCLUSIONS—Despite a higher underlying risk of diabetes and widespread clinical recognition of this higher risk, obesity does not increase the likelihood that an individual's diabetes will be diagnosed.
Prediction of Lynch Syndrome in Consecutive Patients With Colorectal Cancer
Authors: Roger C. Green, Patrick S. Parfrey, Michael O. Woods, H. Banfield Younghusband
Journal: JNCI Journal of the National Cancer Institute (2009)

Lynch syndrome is caused by inherited mutations in DNA mismatch repair genes (primarily MSH2, MLH1, MSH6, and PMS2) and is one of the most prevalent inherited cancer syndromes. Several models have been developed to predict the occurrence of Lynch syndrome in high-risk patients and families, but it is not known how these models compare with one another or how they perform for colorectal cancer patients from the general population. We used data from such patients to test the ability of four models--Leiden, MMRpredict, PREMM(1,2), and MMRpro--to distinguish between those who did and did not carry DNA mismatch repair gene mutations.We studied a consecutive series of 725 patients who were younger than 75 years at colorectal cancer diagnosis and whose DNA mismatch repair gene mutation status was available; 18 of the 725 patients carried such a mutation. For each model, we calculated the risk score, compared the observed number of mutations with the expected number, and determined the receiver operating characteristics. All statistical tests were two-sided.Although all four models overestimated the probability of a mutation (range = 1.2- to 4.3-fold), especially in low-risk patients, they could discriminate between carriers and noncarriers of a mismatch repair mutation. The areas under the receiver operating characteristics curves from the four models ranged from 0.91 to 0.96. Carriers of mutations in the MSH6 or PMS2 genes had lower risk scores than carriers of MSH2 or MLH1 mutations. For example, the MMRpredict model gave median risk scores of 24% and 94% (P < .015) for MSH6-PMS2 and MSH2-MLH1 mutation carriers, respectively. For the Leiden, MMRpredict, and PREMM(1,2) models, correcting the risk scores for bias introduced by family size improved their power to discriminate between carriers and noncarriers. After correcting for family size, the best model was MMRpredict, which achieved a sensitivity of 94% (95% confidence interval [CI] = 73% to 99%) and a specificity of 91% (95% CI = 88% to 93%) and identified a smaller proportion of patients than the revised Bethesda criteria as those who should undergo additional molecular or immunohistochemical testing (11% vs 50%).MMRpredict was the best-performing model for identifying colorectal cancer patients who are at high risk of carrying a DNA mismatch repair gene mutation and thus should be screened for Lynch syndrome.
Volutrauma and Regional Ventilation Revisited
Authors: Rolf D. Hubmayr
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

a group enriched for "faster" decliners as required for some clinical studies, its addition to already known markers is minimal (although again statistically significant, reflecting the large number of patients studied), and the decline in an individual identified in such a way can range from none to 250 ml/yr.The relative weakness of the relationships probably (at least in part) explains the lack of an association between CC16 and subsequent mortality.The associated animal knockout studies add credence to this (even though in mice) with no influence of CC16 or its lack on lung morphology after smoke exposure.Clearly the number of mice required to detect an impact as little as that based on the human studies would be prohibitive and not worth the effort.So despite a sound hypothesis and comprehensive human and relevant animal experiments, the CC16 data are disappointing and yet provide a highly important lesson to researchers.It remains possible that CC16 still has a role as a biomarker in some subset of patients with COPD, although this will require a prospective study with state-of-the-art phenotyping together with an understanding of what a measure of CC16 in the blood means.Does it reflect a pathophysiological process specific to COPD or is it just a byproduct of tissue/cell damage as seen in more general lung injury (6)?Does the degree of general pulmonary inflammation alone influence its detection and quantification in the blood due to degree of "back leakage" even if the damage is low?In reality, these questions would need resolving, but the study of CC16 alone would not be a reason for initiating a prospective study, although with sufficient understanding of what a measurement is telling us, CC16 could be included as part of a prospective panel of markers in highly phenotyped patients.Big cohorts with long-term follow-up provide greater power for biomarker validation, although a "very weak" but "highly significant" relationship such as that described in the current issue provides little support for CC16 as a biomarker to understand the pathophysiology of the COPD syndrome or to be used to identify rapid decliners for interventional studies.Nevertheless, the data provide a vital lesson in interpretation for researchers.
Cytotoxic T lymphocytes specific for self tumor immunoglobulin express T cell receptor delta chain.
Authors: A Wright, J E Lee, M P Link, S D Smith, W Carroll, R Levy, C Clayberger, A M Krensky
Journal: The Journal of Experimental Medicine (1989)

CTL are thought to play a role in the elimination of transformed cells in vivo. The effectiveness of such CTL is in part dependent on recognition of tumor specific antigens. Among the best characterized tumor-specific antigens are the unique or idiotypic determinants on the Ig of B cell lymphomas. Here we describe the generation and properties of human CTL specific for the idiotype on autologous B cell tumors. These cells are CD3+,CD4-,CD8- and express the delta chain of the TCR. Such cells may prove useful in tumor-specific adoptive therapy.
Obesity and colorectal cancer
Authors: Marc Bardou, Alan N Barkun, Myriam Martel
Journal: Gut (2013)

Excess body weight, as defined by the body mass index (BMI), has been associated with several diseases and includes subjects who are overweight (BMI≥25–29.9 kg/m<sup>2</sup>) or obese (BMI≥30 kg/m<sup>2</sup>). Overweight and obesity constitute the fifth leading risk for overall mortality, accounting for at least 2.8 million adult deaths each year. In addition around 11% of colorectal cancer (CRC) cases have been attributed to overweight and obesity in Europe. Epidemiological data suggest that obesity is associated with a 30–70% increased risk of colon cancer in men, whereas the association is less consistent in women. Similar trends exist for colorectal adenoma, although the risk appears lower. Visceral fat, or abdominal obesity, seems to be of greater concern than subcutaneous fat obesity, and any 1 kg/m<sup>2</sup> increase in BMI confers additional risk (HR 1.03). Obesity might be associated with worse cancer outcomes, such as recurrence of the primary cancer or mortality. Several factors, including reduced sensitivity to antiangiogenic-therapeutic regimens, might explain these differences. Except for wound infection, obesity has no significant impact on surgical procedures. The underlying mechanisms linking obesity to CRC are still a matter of debate, but metabolic syndrome, insulin resistance and modifications in levels of adipocytokines seem to be of great importance. Other biological factors such as the gut microbita or bile acids are emerging. Many questions still remain unanswered: should preventive strategies specifically target obese patients? Is the risk of cancer great enough to propose prophylactic bariatric surgery in certain patients with obesity?
Statistics and Truth in Phylogenomics
Authors: S. Kumar, A. J. Filipski, F. U. Battistuzzi, S. L. Kosakovsky Pond, K. Tamura
Journal: Molecular Biology and Evolution (2011)

Phylogenomics refers to the inference of historical relationships among species using genome-scale sequence data and to the use of phylogenetic analysis to infer protein function in multigene families. With rapidly decreasing sequencing costs, phylogenomics is becoming synonymous with evolutionary analysis of genome-scale and taxonomically densely sampled data sets. In phylogenetic inference applications, this translates into very large data sets that yield evolutionary and functional inferences with extremely small variances and high statistical confidence (P value). However, reports of highly significant P values are increasing even for contrasting phylogenetic hypotheses depending on the evolutionary model and inference method used, making it difficult to establish true relationships. We argue that the assessment of the robustness of results to biological factors, that may systematically mislead (bias) the outcomes of statistical estimation, will be a key to avoiding incorrect phylogenomic inferences. In fact, there is a need for increased emphasis on the magnitude of differences (effect sizes) in addition to the P values of the statistical test of the null hypothesis. On the other hand, the amount of sequence data available will likely always remain inadequate for some phylogenomic applications, for example, those involving episodic positive selection at individual codon positions and in specific lineages. Again, a focus on effect size and biological relevance, rather than the P value, may be warranted. Here, we present a theoretical overview and discuss practical aspects of the interplay between effect sizes, bias, and P values as it relates to the statistical inference of evolutionary truth in phylogenomics.
Vehicle effects on percutaneous absorption: in vivo and in vitro comparisons with human skin
Authors: R.L. BRONAUGH, T.J. FRANZ
Journal: British Journal of Dermatology (1986)

The percutaneous absorption of benzoic acid, caffeine and testosterone through human skin was measured by using in vivo and in vitro techniques. The compounds were applied to the skin in solution in three vehicles: petrolatum, ethylene glycol gel and water gel. Because benzoic acid was ionized at the neutral pH of the gels, these data were difficult to interpret and are not reported. The stratum corneum/vehicle partition coefficients (Km) and percent saturation of the vehicles with substrate were determined to aid in the interpretation of the absorption results. In the in vitro studies, the permeability constants determined for the compounds in each vehicle correlated with either the Km value or the percent saturation of the vehicle. Caffeine penetrated most readily from a petrolatum vehicle, and the greatest testosterone absorption was from a water gel. Permeation was also expressed in terms of the percentage of the applied dose absorbed. Reasonable agreement was obtained between the in vivo and in vitro values. Although no significant differences occurred between most values compared, there was trend toward lower penetration in the in vitro system.
Long-term effects on offspring of intrauterine exposure to deficits in nutrition
Authors: C. J. Petry
Journal: Human Reproduction Update (2000)

The number of cell divisions during embryonic and fetal life makes the embryo/fetus particularly vulnerable to effects resulting from exposure to an adverse intrauterine environment. Exposure to drugs and irradiation at this stage of development are able to cause congenital malformations and various cancers in later life. In-utero exposure to hyperglycaemia is able to lead to future diabetes that is heritable, but not genetic in origin. Fetal malnutrition causing growth restriction is able to lead to an increased risk of developing type 2 diabetes, hypertension and ischaemic heart disease in later life, especially if the growth restriction is followed by catch-up growth postnatally. This review discusses the various mechanisms by which these effects may occur, and presents the difficulties that will have to be faced if their world-wide health burdens are to be reduced.
Influence of Psychiatric Comorbidity on Recovery and Recurrence in Generalized Anxiety Disorder, Social Phobia, and Panic Disorder: A 12-Year Prospective Study
Authors: Steven E. Bruce, Kimberly A. Yonkers, Michael W. Otto, Jane L. Eisen, Risa B. Weisberg, Maria Pagano, M. Tracie Shea, Martin B. Keller
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The authors sought to observe the long-term clinical course of anxiety disorders over 12 years and to examine the influence of comorbid psychiatric disorders on recovery from or recurrence of panic disorder, generalized anxiety disorder, and social phobia. METHOD: Data were drawn from the Harvard/Brown Anxiety Disorders Research Program, a prospective, naturalistic, longitudinal, multicenter study of adults with a current or past history of anxiety disorders. Probabilities of recovery and recurrence were calculated by using standard survival analysis methods. Proportional hazards regression analyses with time-varying covariates were conducted to determine risk ratios for possible comorbid psychiatric predictors of recovery and recurrence. RESULTS: Survival analyses revealed an overall chronic course for the majority of the anxiety disorders. Social phobia had the smallest probability of recovery after 12 years of follow-up. Moreover, patients who had prospectively observed recovery from their intake anxiety disorder had a high probability of recurrence over the follow-up period. The overall clinical course was worsened by several comorbid psychiatric conditions, including major depression and alcohol and other substance use disorders, and by comorbidity of generalized anxiety disorder and panic disorder with agoraphobia. CONCLUSIONS: These data depict the anxiety disorders as insidious, with a chronic clinical course, low rates of recovery, and relatively high probabilities of recurrence. The presence of particular comorbid psychiatric disorders significantly lowered the likelihood of recovery from anxiety disorders and increased the likelihood of their recurrence. The findings add to the understanding of the nosology and treatment of these disorders.
Plasma and peripheral blood mononuclear cells levels of Zn and Cu among Indian patients with RA
Authors: A Wanchu, A Sud, P Bambery, R Prasad, V Kumar
Journal: Annals of the Rheumatic Diseases (2002)

Plasma and serum levels of zinc (Zn) and copper (Cu) have been reported to be altered in patients with rheumatoid arthritis (RA).1,2 Few studies have measured these levels in tissues, particularly peripheral blood mononuclear cells (PBMCs), the site for a host of immunological aberrations.3 In a previous study we measured levels of Zn and Cu in plasma and PBMCs to see if they correlated with disease activity and reported reduced levels of Zn in the serum of patients with active RA.4

Patients attending the rheumatology clinic at our institute and satisfying the American College of Rheumatology (formerly American Rheumatism Association) criteria for the diagnosis of RA were studied.5 Patients were categorised as either active or inactive RA. All patients classified as active RA had at least three of the following: morning stiffness for more than 45 minutes, five swollen joints, five tender joints, and erythrocyte …