tbuckley/cabot-search huggingface dataset:
Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence
Authors: Karl-Erik Andersson, Alan J. Wein
Journal: Pharmacological Reviews (2004)

The lower urinary tract constitutes a functional unit controlled by a complex interplay between the central and peripheral nervous systems and local regulatory factors. In the adult, micturition is controlled by a spinobulbospinal reflex, which is under suprapontine control. Several central nervous system transmitters can modulate voiding, as well as, potentially, drugs affecting voiding; for example, noradrenaline, GABA, or dopamine receptors and mechanisms may be therapeutically useful. Peripherally, lower urinary tract function is dependent on the concerted action of the smooth and striated muscles of the urinary bladder, urethra, and periurethral region. Various neurotransmitters, including acetylcholine, noradrenaline, adenosine triphosphate, nitric oxide, and neuropeptides, have been implicated in this neural regulation. Muscarinic receptors mediate normal bladder contraction as well as at least the main part of contraction in the overactive bladder. Disorders of micturition can roughly be classified as disturbances of storage or disturbances of emptying. Failure to store urine may lead to various forms of incontinence, the main forms of which are urge and stress incontinence. The etiology and pathophysiology of these disorders remain incompletely known, which is reflected in the fact that current drug treatment includes a relatively small number of more or less well-documented alternatives. Antimuscarinics are the main-stay of pharmacological treatment of the overactive bladder syndrome, which is characterized by urgency, frequency, and urge incontinence. Accepted drug treatments of stress incontinence are currently scarce, but new alternatives are emerging. New targets for control of micturition are being defined, but further research is needed to advance the pharmacological treatment of micturition disorders.
156 EFFECT OF RAMADAN FASTING ON MUSLIM PATIENTS WITH CHRONIC LIVER DISEASES
Authors: M.H. Elnadry, I.A.E. Negm, I.M. Abdel-aziz, A.M. Elshafee, S.S. El-azhary, M.A. Abdelhafez, S.M. Mohii, D.M. Elteeby
Journal: Journal of Hepatology (2011)
Intracellular Localization and Trafficking of Fluorescein-Labeled Cisplatin in Human Ovarian Carcinoma Cells
Authors: Roohangiz Safaei, Kuniyuki Katano, Barrett J. Larson, Goli Samimi, Alison K. Holzer, Wiltrud Naerdemann, Mika Tomioka, Murray Goodman, Stephen B. Howell
Journal: Clinical Cancer Research (2005)

Abstract Purpose: We sought to identify the subcellular compartments in which cisplatin [cis-diamminedichloroplatinum (DDP)] accumulates in human ovarian carcinoma cells and define its export pathways. Experimental Design: Deconvoluting digital microscopy was used to identify the subcellular location of fluorescein-labeled DDP (F-DDP) in 2008 ovarian carcinoma cells stained with organelle-specific markers. Drugs that block vesicle movement were used to map the traffic pattern. Results: F-DDP accumulated in vesicles and were not detectable in the cytoplasm. F-DDP accumulated in the Golgi, in vesicles belonging to the secretory export pathway, and in lysosomes but not in early endosomes. F-DDP extensively colocalized with vesicles expressing the copper efflux protein, ATP7A, whose expression modulates the cellular pharmacology of DDP. Inhibition of vesicle trafficking with brefeldin A, wortmannin, or H89 increased the F-DDP content of vesicles associated with the pre-Golgi compartments and blocked the loading of F-DDP into vesicles of the secretory pathway. The importance of the secretory pathway was confirmed by showing that wortmannin and H89 increased whole cell accumulation of native DDP. Conclusions: F-DDP is extensively sequestered into vesicular structures of the lysosomal, Golgi, and secretory compartments. Much of the distribution to other compartments occurs via vesicle trafficking. F-DDP detection in the vesicles of the secretory pathway is consistent with a major role for this pathway in the efflux of F-DDP and DDP from the cell.
Identification of CD19 and CD20 Peptides for Induction of Antigen-Specific CTLs against B-Cell Malignancies
Authors: Jooeun Bae, Jeffrey A. Martinson, Hans G. Klingemann
Journal: Clinical Cancer Research (2005)

Abstract The purpose of these studies was to develop immunogenic peptides derived from the CD19 and CD20 self-antigens for the induction of antigen-specific CTLs against B-cell malignancies. A total of seven peptides were designed and examined for their HLA-A2.1 affinity and immunogenicity. Of these peptides, we identified two highly immunogenic HLA-A2.1-specific peptides, CD19150-158 (KLMSPKLYV) and CD20188-196 (SLFLGILSV), which were capable of inducing peptide-specific CTLs. The CTLs displayed HLA-A2.1-restricted and antigen-specific cytotoxicity against Burkitt's lymphoma, chronic B cell leukemia, and multiple myeloma cell lines. The CD19 or CD20 peptide–specific CTL cytotoxicity was confirmed using HLA-A2.1+ T2 cells presenting the appropriate peptide. No cytotoxic activity was observed against T2 cells presenting the irrelevant MAGE-3 peptide or T2 cells alone. In addition, the CTLs displayed a significant (P &amp;lt; 0.05) increase in cell proliferation and IFN-γ secretion (&amp;gt;830 ng/mL) following restimulation with HLA-A2.1+/CD19+/CD20+ tumor cells. The CTLs also displayed a distinct phenotype consisting of a high percentage of CD69+/CD45RO+ and a low percentage of CD45RA+/CCR7+ CD4+ or CD8+ T cells characteristic of effector memory cell population. Cyclic guanosine 3′,5′-monophosphate culture conditions using serum-free AIM-V medium containing human AB serum, recombinant human interleukin 2 (Proleukin) and CD3/CD28 Dynabeads were developed resulting in a 35-fold expansion of CD20 peptide–specific CTLs. The expanded CD20-CTLs retained their cytotoxic activity (28-49%) against the Burkitt's lymphoma cell line. In conclusion, we report here on the identification of novel immunogenic CD19150-158 (KLMSPKLYV) and CD20188-196 (SLFLGILSV) peptides that have immunotherapeutic potentials as peptide vaccines or targeted T-cell therapies for treating B-cell malignancies.
Fewer allergic respiratory disorders among farmers' children in a closed birth cohort from Sweden
Authors: B. Klintberg, N. Berglund, G. Lilja, M. Wickman, M. van Hage-Hamsten
Journal: European Respiratory Journal (2001)

The aim of this study was to investigate the prevalence of respiratory allergy, eczema and atopic sensitization in a closed birth cohort of Swedish schoolchildren, 7–8 yrs of age (n=707), of farmers and nonfarmers on the island of Gotland, in the Baltic Sea. All children were born and raised on the island. The survey comprised a questionnaire on atopic diseases and lifestyle factors. Atopic sensitization was assessed by the skin-prick test (SPT) with 15 standardized allergens. The risk ratio (RR) for ever having asthma and/or allergic rhinoconjunctivitis was significantly lower among children of farmers compared to children of nonfarmers (RR=0.38, confidence interval (CI) 95% 0.19–0.77). SPTs (test rate 92%) showed that 32% of the children had at least one positive test. Although the number of positive SPTs did not differ between the groups, there was a reduced risk among children of farmers for having both respiratory symptoms and sensitization to any International Study on Asthma and Allergy in Childhood allergen (RR=0.28, CI 95% 0.09–0.88). The present indicate that living in a farming population seems to protect against development of respiratory allergic disorders but not against allergic sensitization.
Extracts from a Paper on Hospital Out-Patient Reform: Its Helpers, its Hinderers, and its Passers-By
Authors: H. N. Hardy
Journal: BMJ (1877)

THE BRITISH MEDICAL YOURNAL. 62! No,317_appeared, while others had gone.As regarded the buttocks, and the outer surfaces of the thighs also, and the legs (the latter more espe- cially), the eruption was somewhat' more copious than before.The perles caused no inconvenience.She was now ordered to have four perles, instead of three, three times a day.April i2th.She had taken four perles for seven days only, when pain in the stomach came on.From that time, the perles were alto- gether discontinued.The eruption did not seem to have varied no- tably.The impression produced on my mind was, that the phosphorus had attained its maximum of effect, or nearly so; or, anyhow, that it was a much slower remedy than efficient local applications often proved to be.She was now ordered to discontinue the phosphorus, and use only chrysophanic acid ointment (acidi chrysophanici 3 ij, adipis si).April 2ISt.Very considerable improvement was obvious, only faint traces of the eruption remaining, except on the nates and on the legs below the knees._ May gth.Every portion of the eruption had disappeared, the only traces remaining of it being faint stains on the front of the legs aild on the knees and elbows.May 22nd.Since May gth, she had used the chrysophanic acid ointment (after first washing the skin each time witlh soft soap and:warm water) twice a day to the legs' only.No inflammation had re- sulted from this application, and the patient was everywhere quite free from all traces of the eruption.COMMENTARY.-It will be seen from the report that this case, not only as regards the nature and extent of it, but also as to the treatment pursued and the result of that treatment, very closely resembles Dr. Whipham's case, and that it occurred at about the same time.Each patient was a healthy girl at about the age of puberty.In both cases, the eruption was very copious, although in Dr. Whipham's case it was of much longer standing than in mine.But that circumstance, accord- ing to my experience, makes little or no difference as to the difficulty of curing the disease, although I am aware that the contrary opinion is generally entertained.In both instances, the case was treated at first by phosphorus alone.Dr. Whipham's case was treated by means of one-seventh of a grain of phosphorus in the twenty-four hours throughout (for apparently two months), with marked improvement for the first month, but with a return to the original condition at the end of the second month.By the way, is Dr. Whipham quite sure that his patient continued to take the pills ?I am sure that my patient took the perles.Mine was an in-patient, and the matron of the hospital administered in person every single dose.Dr. Whipham's patient was an out-patient, and phosphorus pills are apt to cause disagreeable eructations tasting of
Use of a Cryptic Splice Site for the Expression of Huntingtin Interacting Protein 1 in Select Normal and Neoplastic Tissues
Authors: Chiron W. Graves, Steven T. Philips, Sarah V. Bradley, Katherine I. Oravecz-Wilson, Lina Li, Alice Gauvin, Theodora S. Ross
Journal: Cancer Research (2008)

Huntingtin interacting protein 1 (HIP1) is a 116-kDa endocytic protein, which is necessary for the maintenance of several tissues in vivo as its deficiency leads to degenerative adult phenotypes. HIP1 deficiency also inhibits prostate tumor progression in mice. To better understand how deficiency of HIP1 leads to such phenotypes, we analyzed tumorigenic potential in mice homozygous for a Hip1 mutant allele, designated Hip1(Delta 3-5), which is predicted to result in a frame-shifted, nonsense mutation in the NH(2) terminus of HIP1. In contrast to our previous studies using the Hip1 null allele, an inhibition of tumorigenesis was not observed as a result of the homozygosity of the nonsense Delta 3-5 allele. To further examine the contrasting results from the prior Hip1 mutant mice, we cultured tumor cells from homozygous Delta 3-5 allele-bearing mice and discovered the presence of a 110-kDa form of HIP1 in tumor cells. Upon sequencing of Hip1 DNA and message from these tumors, we determined that this 110-kDa form of HIP1 is the product of splicing of a cryptic U12-type AT-AC intron. This event results in the insertion of an AG dinucleotide between exons 2 and 6 and restoration of the reading frame. Remarkably, this mutant protein retains its capacity to bind lipids, clathrin, AP2, and epidermal growth factor receptor providing a possible explanation for why tumorigenesis was not altered after this knockout mutation. Our data show how knowledge of the transcript that is produced by a knockout allele can lead to discovery of novel types of molecular compensation at the level of splicing.
Sympathetic modulation of hypercapnic cerebral vasodilation in dogs.
Authors: L G D'Alecy, C J Rose, S A Sellers
Journal: Circulation Research (1979)

We measured cerebral blood flow using both the radioactive microsphere technique and the cerebral venous outflow technique in dogs anesthetized with chloralase. The effect of sympathetic stimulation on cerebral blood flow was observed during both normocapnia and prolonged hypercapnia using both blood flow techniques. The increase in blood flow with hypercapnia was the same with both methods. During hypercapnia the venous outflow method showed a 38% decrease and microspheres an 18% decrease in cerebral blood flow with sympathetic stimulation. At normal CO2, stimulation caused a decrease in cerebral venous flow: no change was observed with the microsphere method. Analysis of the blood flow patterns to extracerebral tissues and evaluation of extracerebral arterial reference samples failed to prove the existence of axial streaming and subsequent skimming of microspheres within the cephalic circulation. It is concluded that direct electrical stimulation of the sympathetic innervation of the cerebral vessels is capable of reducing cerebral blood flow even during a profound hypercapnic vasodilation.
Exacerbations and Time Spent Outdoors in Chronic Obstructive Pulmonary Disease
Authors: Gavin C. Donaldson, Tom M. A. Wilkinson, John R. Hurst, Wayomi R. Perera, Jadwiga A. Wedzicha
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Patients with chronic obstructive pulmonary disease have a progressive reduction in activity, although its time scale and the contribution of exacerbations are unknown. A rolling cohort of 147 patients (101 male; mean age, 88.5 years; and forced expiratory volume in 1 second as percent predicted, 38.4%) were monitored for a median of 1,044 days (interquartile range, 685 to 1,779) over an 8-year period starting in March 1996. Patients recorded any increase in daily respiratory symptoms and time spent outside their home. They completed the St. George's Respiratory Questionnaire yearly. They experienced 1,465 exacerbations and time outdoors decreased by -0.16 hours/day per year (p < 0.001). This decline was faster in frequent exacerbators (p = 0.011). Before exacerbation, the patients stayed indoors all day for 2.1 days/week (on any day 34.1% were at home), but for 5 weeks postexacerbation they spent 2.5 days/week at home (p < 0.001) (44.4% remaining at home at onset; p = 0.021). St. George's total, activity, and impact scores were independently associated with time outdoors (p < 0.005), but not with symptom score. In conclusion, time spent outside the home declines over time and acutely at exacerbation. Patients with frequent exacerbations are more likely to become housebound and need targeting in rehabilitation programs.
Effects of prolonged strenuous exercise (marathon running) on biochemical and haematological markers used in the investigation of patients in the emergency department
Authors: J E Smith, G Garbutt, P Lopes, D Tunstall Pedoe
Journal: British Journal of Sports Medicine (2004)

Objectives: To investigate the effects of strenuous exercise on commonly used biochemical and haematological variables in subjects running the 2002 London marathon. Methods: 34 healthy volunteers (7 female, 27 male) were recruited for the study. Blood was taken before the start (at registration) and immediately after completion of the marathon. Samples were analysed for urea and electrolytes, liver function tests, creatine kinase (CK), CK-MB isoenzyme, myoglobin, troponin I, full blood count, a clotting screen, and D-dimers. The results before and after exercise were compared. Pearson’s correlation coefficients were calculated for all variables. Results: Significant increases were found in CK, CK-MB, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and myoglobin following the marathon. However, there was no significant change in the level of troponin I. There was also evidence of activation of the coagulation and fibrinolytic cascades following the marathon, with a reduction in activated partial thromboplastin time, a reduction in fibrinogen, and an increase in D-dimers. Conclusions: The results confirm previous individual studies on marathon running and the biochemical and haematological tests routinely carried out in hospital. These are affected by prolonged exercise, and “abnormal” results in these tests may be normal after prolonged exercise and therefore not diagnostic of a disease process. The results of investigations in patients who have been exercising should be interpreted with caution.
Genetic analysis to predict prognosis at the onset of Crohn's disease: not yet ready for prime time?
Authors: S. Vermeire, G. Van Assche, P. Rutgeerts
Journal: Gut (2009)

In this issue of Gut , Weersma et al ( see page 388 ) report the results of their study on molecular prediction of disease risk and severity in a large Crohn’s disease cohort.1 This study, performed by the Dutch initiative on Crohn’s disease and colitis (ICC), assessed the risk for disease development and severity by combining information from five Crohn’s disease susceptibility genes. A total of 1684 patients with Crohn’s disease from seven university hospitals were included. The odds ratio for Crohn’s disease susceptibility progressively increased with increasing number of risk alleles and genotypes, a finding that is not unexpected and has also been shown for other common diseases, such as type 2 diabetes, breast cancer and atherosclerosis.2 3 Second, and probably more interesting, was the finding that patients with a more severe disease, patients needing surgery or patients in whom the age at onset of disease was below 40 years carried, on average, more risk alleles compared to patients not meeting these characteristics.

With the identification of several susceptibility genes through genome-wide association scanning, the research on molecular markers in common disorders has gained more attention and comes at a time where the introduction of biological therapies has opened the debate on which therapy to choose for a given patient.

There are several clinical situations where molecular markers are proposed, a first being prediction of disease. Identifying individuals at risk and hence preventing disease is an important strategy for reducing the overall burden of common complex disorders. However, most of the reported genes and risk alleles have a very low …
Lung function, race and ethnicity: a conundrum
Authors: Philip H. Quanjer
Journal: European Respiratory Journal (2013)

n this issue BRAUN et al.[1] make a plea for an international workshop to review aspects of race and ethnicity in relation to lung function.This is a timely initiative, as many people struggle in epidemiological and genetic studies, and in clinical practice, with the interpretation of test results in an increasingly multi-ethnic society [2].Our notions of race derive from Blumenbach, who defined ''Four varieties of mankind, one species'' (adding a fifth variety in 1781) [3].Definitions of ''race'' and ''ethnic'' are confusing and often used interchangeably.This ambiguity is reflected in the frequent use of race/ethnicity, a transitional concept adopted for use while phasing out ''race'' from the USA census [4].At this stage the USA census recognises two ethnicities: ''Hispanic or Latino'', and ''not Hispanic or Latino'', and five races; Hispanic/Latino individuals have a mixed European, African and native American ancestry [5].American citizens were allowed to selfidentify with more than one race in 2000: 2.4% self-identified as multiracial.In sharp contrast, France passed a law in 1978 barring the government from collecting all racial and ethnic data (the Act prohibits collecting ''any information that shows, directly or indirectly, racial or ethnic origins, political, philosophical or religious opinions, trade union membership, moral principles, or information that relates to health or sexual life'' without either the written consent of the individual or an advance recommendation of the National Commission for Information Technology and Civil Liberties, which must first be approved by the Conseil d'E ´tat) [6].The collection of data on race and ethnicity by governments serves administrative and statistical purposes; the classifications should not be interpreted as being scientific or anthropological in nature.However, this caveat is not heeded, and the classifications are widely used in everyday life, science and medicine, where race/ethnicity is used as a proxy for other phenomena.
The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus
Authors: Brian N. Finck, John J. Lehman, Teresa C. Leone, Michael J. Welch, Michael J. Bennett, Attila Kovacs, Xianlin Han, Richard W. Gross, Ray Kozak, Gary D. Lopaschuk, Daniel P. Kelly
Journal: Journal of Clinical Investigation (2002)

Recent evidence has defined an important role for PPARα in the transcriptional control of cardiac energy metabolism. To investigate the role of PPARα in the genesis of the metabolic and functional derangements of diabetic cardiomyopathy, mice with cardiac-restricted overexpression of PPARα (MHC-PPAR) were produced and characterized. The expression of PPARα target genes involved in cardiac fatty acid uptake and oxidation pathways was increased in MHC-PPAR mice. Surprisingly, the expression of genes involved in glucose transport and utilization was reciprocally repressed in MHC-PPAR hearts. Consistent with the gene expression profile, myocardial fatty acid oxidation rates were increased and glucose uptake and oxidation decreased in MHC-PPAR mice, a metabolic phenotype strikingly similar to that of the diabetic heart. MHC-PPAR hearts exhibited signatures of diabetic cardiomyopathy including ventricular hypertrophy, activation of gene markers of pathologic hypertrophic growth, and transgene expression–dependent alteration in systolic ventricular dysfunction. These results demonstrate that (a) PPARα is a critical regulator of myocardial fatty acid uptake and utilization, (b) activation of cardiac PPARα regulatory pathways results in a reciprocal repression of glucose uptake and utilization pathways, and (c) derangements in myocardial energy metabolism typical of the diabetic heart can become maladaptive, leading to cardiomyopathy.
Nephrotoxicity of Antibiotics
Authors: Calvin M. Kunin
Journal: JAMA (1967)

The potentially nephrotoxic antibiotics in current clinical use are neomycin, kanamycin, paromomycin, bacitracin, the polymyxins (polymyxin B, and colistin), and amphotericin B.<sup>1-3</sup>Nephrotoxicity was reported with early lots of streptomycin, but the drug now commercially available does not appear to have this property. Fortunately, the nephrotoxicity of each of these drugs appears to be reversible provided their administration is stopped soon enough. Patients with underlying renal disease appear to be particularly sensitive to most of these agents. This sensitivity may be attributable in part to the tendency of these drugs to accumulate rapidly in the blood of uremic patients given ordinary therapeutic doses and in part to the diminished renal functional reserve of uremic patients. Tetracycline may now be added to the group of potentially nephrotoxic drugs, because a reversible Fanconi-like syndrome produced by preparations containing degraded tetracycline has been observed. <h3>Tetracyclines.—</h3> A primary renal toxic effect of undegraded