tbuckley/cabot-search huggingface dataset:
Glomerular preload and afterload reduction as a tool to lower urinary protein leakage
Authors: P E de Jong, S Anderson, D de Zeeuw
Journal: Journal of the American Society of Nephrology (1993)

It has been well documented that different therapeutic strategies, including angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs, and dietary protein restriction, lower urinary protein excretion in patients with diabetic and non-diabetic nephropathy. Experimental evidence suggests that this antiproteinuric effect is, at least in part, related to a reduction in the glomerular capillary hydraulic pressure. ACE inhibitors appear to achieve this reduction in glomerular capillary pressure, mainly through a fall in postglomerular arteriolar resistance, whereas dietary protein restriction and non-steroidal antiinflammatory drugs appear to invoke the response predominantly through an increase in preglomerular resistance. This leads to the suggestion that both "glomerular preload reduction" (afferent vasoconstriction) and "glomerular afterload reduction" (efferent vasodilation) will result in an anti-proteinuric response. Interestingly, these same therapeutic regimens, particularly the ACE inhibitors and low-protein diets, have been proven to prevent progressive glomerulosclerosis in animal models. This concept of influencing glomerular hemodynamics both at the afferent and efferent arteriolar level may open new perspectives in the treatment of patients with renal protein loss and renal failure. At present, however, it is too early to conclude whether the fall in proteinuria induced by these treatments will also contribute to a better renal survival of these patients.
Preventing and managing antimicrobial resistance: imperative for chest physicians
Authors: M.C. Raviglione, C. Lange, G.B. Migliori
Journal: European Respiratory Journal (2011)

World Health Day is celebrated every year on the 7th of April as a major advocacy event promoted by the World Health Organization (WHO) for all ministries of health worldwide. The aim is to bring a specific topic of great importance to national and international attention. This year, the selected theme is antimicrobial resistance (AMR), which is a serious threat to the care and control of all infectious diseases. AMR not only affects the three major pandemics of tuberculosis (TB), malaria and HIV, but most other infectious diseases, including widespread hospital-acquired infections, particularly after the emergence of “superbugs” resistant to all currently available major antibiotics 1, 2.

The identification of AMR as a serious international health issue comes at a crucial point in the global attempt to contain its impact. Strategies have been defined by WHO in the past decade, but rarely implemented 3. In the past few years, the appearance of multidrug-resistant organisms capable of resisting the most potent latest-generation antibiotics and chemotherapeutic agents has generated substantial apprehension among clinicians and public health experts (fig. 1).



Figure 1– 
Simplified mechanism of the development of antimicrobial resistance.



In 2006, the first description of extensively drug-resistant (XDR)-TB, i.e. a disease caused by Mycobacterium tuberculosis strains resistant to the most important first- and second-line anti-TB drugs, prompted international attention 4, 5, particularly following the appearance and spread of XDR-TB amongst people living with HIV in South Africa, which resulted in an unprecedented high case-fatality rate 6. XDR-TB has been reported in nearly 70 countries worldwide, and strains resistant to all first- and second-line drugs are circulating in Europe 7.

Multidrug-resistant (MDR)-TB, a disease that is caused by strains that are at least resistant to the two most potent first-line drugs, is present everywhere; the highest percentage …
Progression-Free Survival in Neuroendocrine Tumors: Preferred End Point, But How Should It Be Defined?
Authors: Rachel P. Riechelmann, Juliana Rego
Journal: Journal of Clinical Oncology (2011)

Russillo et al 1 have reported a discordance in human epidermal growth factor receptor 2 (HER2) expression between primary breast cancers and metastatic lesions in approximately 10% of cases.The HER2 status changed from negative in primary tumors to positive in the metastatic lesions.In addition, the authors reported that a small subset of patients whose tumors showed a loss of phosphatase and tensin homolog (PTEN) or were associated with PI3KCA mutation were resistant to trastuzumab, the humanized monoclonal antibody directed against HER2.The authors then proposed that these patients may benefit from alternative regimens such as the dual tyrosine kinase inhibitor lapatinib.The results of the study 2 described by Russillo et al support the findings reported in our recent article 3 : that patients whose tumors showed loss of PTEN or had PI3KCA mutations were resistant to trastuzumab, as described in previous studies. 4,5However, there are some limitations and caveats to these results.The number of patients who were evaluated in this report 1 is small.From this data set, it is not known if patients whose tumors convert from HER2 negative to HER2 positive do in fact respond to anti-HER2-targeted therapies.There may be multiple redundant pathways in these metastatic lesions, and the primary pathways that are driving the disease may not be dependent on HER2 activation.Although noteworthy, this study is only hypothesis generating, and greater numbers of patients are needed to document the conversion rate from HER2 negative in primary lesions to HER2 positive in metastatic sites, the response to anti-HER2-targeted therapy in these patients with metastases, and possible alternative mechanisms of action.These observations, although interesting, are at this point preliminary until additional studies to evaluate the functional role of different pathways in metastatic disease are performed.
The succinic dehydrogenase and cytochrome c oxidase activities of guinea-pig skin after mild heat damage
Authors: SHIRLEY A. CARNEY, M. HALL, C.R. RICKETTS
Journal: British Journal of Dermatology (1976)

Succinic dehydrogenase and cytochrome c oxidase activities of guinea-pig ear skin were found to be less sensitive than oxygen uptake to mild heat damage. It therefore appears that the failure of oxygen uptake following thermal injury is not directly due to inactivation of the enzymes of the respiratory chain.
On wearing two hats: role conflict in serving as both psychotherapist and expert witness
Authors: L H Strasburger, T G Gutheil, A Brodsky
Journal: American Journal of Psychiatry (1997)

This article explores the clinical, legal, and ethical problems that typically occur when a psychotherapist serves as both a treating clinician and forensic evaluator (or expert witness) in the same case.The professional literature, ethics codes, opinion surveys, and the changing economic and institutional contexts of psychotherapy are reviewed in order to identify obstacles to widespread recognition of this straightforward ethical issue. The processes of psychotherapy and forensic evaluation are then analyzed so as to reveal fundamental incompatibilities between the psychotherapist's clinical and legal functions.Attempting to treat and evaluate the same person typically creates an irreconcilable role conflict. This role conflict manifests itself in different conceptions of truth and causation, different forms of alliance, different types of assessment, and different ethical guidelines.Although circumstances sometimes compel a practitioner to assume the dual role of treater and evaluator, the problems that surround this practice argue for its avoidance whenever possible.
Circulating tumor DNA in plasma of breast cancer patients from India
Authors: S. Bhattacharyya, V. Raina, N. K. Shukla, S. Shukla, R. Kumar, S. Hedau, G. Kumar, A. C. Bharti, G. K. Rath, B. C. Das
Journal: Journal of Clinical Oncology (2009)

e22213 Background: Recently, breast cancer has become the most common cancer among women in all urban population in India. Annually about 80000 new cases and 40000 deaths occur and majority of breast cancers are pre-menopausal. Conventional diagnostic methods are not very sensitive especially in early stages of cancer. This necessitated a more sensitive and reliable method for early diagnosis leading to effective treatment, better prognosis and survival. Recently, the level of cell free circulating tumor DNA in blood plasma or serum of patients with variety of tumors are being considered as reliable non-invasive diagnostic tool but no study has been done in India. The present study has therefore been undertaken to evaluate clinical utility of cell free DNA as potential biomarkers for early diagnosis and management of breast cancer. Methods: 25 newly diagnosed untreated breast cancer patients and 25 healthy subjects having no sign of significant medical illness with informed consent were enrolled for the study. 9 patients after chemotherapy were also included in the study. Blood plasma collected from both patients and controls were employed for DNA isolation, using Qiagen kit. Concentration of cell free plasma DNA was analyzed by 3 methods viz. nanodrop spectro-photometry, integrated density value (IDV) of PCR products of Exon 7 of p53 gene and quantitative real time PCR (cycles threshold converted to genome equivalent). All values of DNA concentration obtained by three methods used as continuous variables and receiver operating characteristic (ROC) were plotted and the cut-of value was determined at 90% sensitivity and 100% specificity level of ROC. Results: Mean free plasma DNA concentration as determined by both Q-RT PCR and IDV in cancer patients was found to be significantly higher in advanced stage breast cancer patients than in controls (genome equivalent 18850 vs 431; IDV 17912 vs 4197; p=0.001). However, no significant difference could be observed in early stage disease as compared to controls possibly due small sample size. Conclusions: Free Plasma DNA concentration is a reliable molecular marker for detection of breast cancer and can serve as a prognostic indicator leading to its potential clinical application either alone or in combination with other conventional methods. No significant financial relationships to disclose.
Factors Associated With Small Abdominal Aortic Aneurysm Expansion Rate
Authors: Rachel H. Bhak, Michael Wininger, Gary R. Johnson, Frank A. Lederle, Louis M. Messina, David J. Ballard, Samuel E. Wilson
Journal: JAMA Surgery (2014)

Because of the high mortality rate after rupture of small abdominal aortic aneurysms (AAAs), surveillance is recommended to detect aneurysm expansion; however, the effects of clinical risk factors on long-term patterns of AAA expansion are poorly characterized.To identify significant clinical risk factors associated with the AAA expansion rate for both constant and accelerated expansion trajectories.A multivariate mixed-effects model was established to identify clinical risk factors associated with the AAA expansion rate. Separate shape factor analysis was used to characterize steady vs accelerated expansion over time. Five hundred sixty-seven patients hospitalized at Veterans Affairs medical centers were randomized to the surveillance arm of the Aneurysm Detection and Management (ADAM) study conducted by the Veterans Affairs Cooperative Studies Program from 1992 to 2000. The patients had an AAA with a maximum diameter from 3.0 to 5.4 cm, which was monitored until a 5.5-cm maximum diameter was reached or the aneurysm became symptomatic. Thirty-three participants were not included in this analysis owing to missing or extraneous values in key predictor variables. The mean (SD) follow-up time was 3.7 (2.0) years.The primary outcome measure was the AAA expansion rate, determined by measurement of the maximum diameter by ultrasonography at regular intervals. The objective to assess the association of clinical variables with the expansion of the AAA was formulated after data collection.The mean (SD) linear expansion rate of AAAs was 0.26 (0.01) cm/y. Current smoking was associated with a 0.05 (0.01)-cm/y increase in the linear expansion rate (95% CI, 0.25-0.28; P < .001), diastolic blood pressure with a 0.02 (0.01)-cm/y increase per 10 mm Hg (95% CI, 0.01-0.04; P = .001), and diabetes mellitus with a 0.11 (0.02)-cm/y decrease (95% CI, 0.07-0.16; P < .001). Diastolic blood pressure and baseline AAA diameter were associated with accelerated AAA expansion (P = .001 and P < .001, respectively).Smoking cessation and control of diastolic blood pressure are direct actions that should be taken to reduce the rate of AAA expansion. Other clinical risk factors, except for diabetes, were not associated with the AAA expansion rate. This study also provides evidence of differing trajectories in AAA expansion over time, a finding that merits further investigation.
C-Peptide Induces Vascular Smooth Muscle Cell Proliferation
Authors: Daniel Walcher, Christina Babiak, Paulina Poletek, Stephan Rosenkranz, Helga Bach, Susanne Betz, Renate Durst, Miriam Grüb, Vinzenz Hombach, Jack Strong, Nikolaus Marx
Journal: Circulation Research (2006)

Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest a potential causal role of C-peptide in atherogenesis by promoting monocyte and T-lymphocyte recruitment into the vessel wall. The present study examined the effect of C-peptide on vascular smooth muscle cells (VSMCs) proliferation and evaluated intracellular signaling pathways involved. In early arteriosclerotic lesions of diabetic subjects, C-peptide colocalized with VSMCs in the media. In vitro, stimulation of human or rat VSMCs with C-peptide induced cell proliferation in a concentration-dependent manner with a maximal 2.6±0.8-fold induction at 10 nmol/L human C-peptide ( P &lt;0.05 compared with unstimulated cells; n=9) and a 1.8±0.2-fold induction at 0.5 nmol/L rat C-peptide ( P &lt;0.05 compared with unstimulated cells; n=7), respectively, as shown by [H3]-thymidin incorporation. The proliferative effect of C-peptide on VSMCs was inhibited by Src short interference RNA transfection, PP2, an inhibitor of Src-kinase, LY294002, an inhibitor of PI-3 kinase, and the ERK1/2 inhibitor PD98059. Moreover, C-peptide induced phosphorylation of Src, as well as activation of PI-3 kinase and ERK1/2, suggesting that these signaling molecules are involved in C-peptide–induced VSMC proliferation. Finally, C-peptide induced cyclin D1 expression as well as phosphorylation of Rb in VSMCs. Our results demonstrate that C-peptide induces VSMC proliferation through activation of Src- and PI-3 kinase as well as ERK1/2. These data suggest a novel mechanism how C-peptide may contribute to plaque development and restenosis formation in patients with insulin resistance and early type 2 diabetes mellitus.
A study of hydrogen peroxide generation by, and antioxidant activity of, Granuflex™ (DuoDERM™) Hydrocolloid Granules and some other hydrogel/hydrocolloid wound management materials
Authors: L.Y. CHUNG, R.J. SCHMIDT, A.M. ANDREWS, T.D. TURNER
Journal: British Journal of Dermatology (1993)

The effect of Granuflex Hydrocolloid Granules (0.01-0.50% w/v) on the rate of proliferation of murine (L929) fibroblasts was examined. The dose-response curve showed a significant (P < 0.02) pro-proliferant effect at 0.05%, and a significant (P < 0.02) antiproliferant effect at 0.50%, mirroring the dose-response curve produced by hydrogen peroxide in the concentration range 10(-9) - 10(-4) mol/l. The antiproliferant effect at 0.20% w/v was abolished by catalase, suggesting that the biological activity of Granuflex was mediated by the in situ generation of hydrogen peroxide. Formation of hydrogen peroxide by Granuflex was confirmed by performing the scopoletin-horseradish peroxidase assay in the presence and absence of catalase. The total concentration of hydrogen peroxide detected was about 8 x 10(-6) mol/l (using 0.5% w/v Granuflex) after 48 h at 37 degrees C. In contrast, when hydrogen peroxide itself was added to L929 cultures, a similar antiproliferant activity was observed at concentrations between 10(-4) and 10(-5) mol/l. These results suggested that Granuflex was undergoing autoxidation in the culture medium, and hence that it might possess antioxidant activity. In assays for antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH), Granuflex, and two other hydrocolloid dressings (Comfeel Powder and Bard Absorption Dressing) showed significant ability to reduce DPPH to DPPH2. These three dressings also displayed superoxide scavenging activity in a nitroblue tetrazolium reduction assay. We conclude that, in addition to providing a moist wound-healing environment, Granuflex and certain other hydrocolloids might contribute to the establishment and maintenance of the reducing environment necessary for energy production and hence cell division.(ABSTRACT TRUNCATED AT 250 WORDS)
The RTE class of non-LTR retrotransposons is widely distributed in animals and is the origin of many SINEs
Authors: H. S. Malik, T. H. Eickbush
Journal: Molecular Biology and Evolution (1998)

RTE-1 is a non-long-terminal-repeat (non-LTR) retrotransposable element first found in the Caenorhabditis elegans genome. It encodes a 1,024-amino-acid open reading frame (ORF) containing both apurinic-apyrimidic endonuclease and reverse-transcriptase domains. A possible first ORF of only 43 amino acids overlaps with the larger ORF and may be the site of translation initiation. Database searches and phylogenetic analysis indicate that representatives of the RTE clade of non-LTR retrotransposons are found in the bovine and sheep genomes of mammals and in the silkmoth and mosquito genomes of insects. In addition, the previously identified SINEs, Art2 and Pst, from ruminate and viper genomes are shown to be truncated RTE-like retrotransposable elements. RTE-derived SINE elements are also found in mollusc and flatworm genomes. Members of the RTE clade are characterized by unusually short 3' untranslated regions that are predominantly composed of AT-rich trimer, tetramer, and/or pentamer repeats. This study establishes RTE as a very widespread clade of non-LTR retrotransposons. RTE represents the third distinct class of non-LTR retrotransposons in the vertebrate lineage (after Line 1 elements in mammals and CR1 elements in birds and reptiles).
Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection
Authors: Arthur Y Kim, Julian Schulze zur Wiesch, Thomas Kuntzen, Joerg Timm, Daniel E Kaufmann, Jared E Duncan, Andrea M Jones, Alysse G Wurcel, Benjamin T Davis, Rajesh T Gandhi, Gregory K Robbins, Todd M Allen, Raymond T Chung, Georg M Lauer, Bruce D Walker
Journal: PLoS Medicine (2006)

Background Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection. Methods and Findings We measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017). Conclusions These results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.
Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension
Authors: A Chaouat
Journal: Thorax (2004)

Dexfenfluramine associated pulmonary arterial hypertension occurring in a patient with hereditary haemorrhagic telangiectasia related to a mutation within the endoglin gene is described. This report highlights the critical role of the TGF-beta signalling pathway in this condition.
Effects of Methyl Testosterone on Thyroid Function, Thyroxine Metabolism, and Thyroxine-Binding Protein
Authors: Daniel D. Federman, Jacob Robbins, J. E. Rall
Journal: Journal of Clinical Investigation (1958)

Studies on the effect of androgenic steroids on thyroid function are difficult to evaluate because of a number of apparent discrepancies. Money, Kirschner, Kraintz, Merrill, and Rawson (1), using castrate rats on a low iodine diet, found that testosterone propionate had no influence on thyroid weight or on thyroid weight: body weight ratio, but did increase the radioiodine uptake. Kochakian and Evans (2) recently reported that this form of testosterone failed to influence the uptake or release of radioiodine by the thyroid of the castrate rat. Burris, Bogart, and Krueger (3), using heifers and young steers, found that testosterone propionate produced an increased gain in weight; furthermore, the thyroids of the treated animals weighed more, contained less colloid, and exhibited an increase in thyroid cell height. Voitkevich (4) is cited as stating that the goiters produced by propylthiouracil in guinea pigs and cocks are very considerably decreased by simultaneously administered methyl testosterone, and that propylthiouracil goiters are larger in castrate than -in normal cocks.