300 research outputs found
The Controversial Relationship Between Benign Prostatic Hyperplasia and Prostate Cancer: The Role of Inflammation
No full textContext: Prostate cancer (PCa) is the most common cancer in the adult male, and benign prostatic hyperplasia (BPH) represents the most frequent urologic diagnosis in elderly males. Recent data suggest that prostatic inflammation is involved in the pathogenesis and progression of both conditions. Objective: This review aims to evaluate the available evidence on the role of prostatic inflammation as a possible common denominator of BPH and PCa and to discuss its possible clinical implication for the management, prevention, and treatment of both diseases. Evidence acquisition: The National Library of Medicine Database was searched for the following Patient population, Intervention, Comparison, Outcome (PICO) terms: male, inflammation, benign prostatic hyperplasia, prostate cancer, diagnosis, progression, prognosis, treatment, and prevention. Basic and clinical studies published in the past 10 yr were reviewed. Additional references were obtained from the reference list of full-text manuscripts. Evidence synthesis: The histologic signature of chronic inflammation is a common finding in benign and malignant prostate tissue. The inflammatory infiltrates are mainly represented by CD3(+) T lymphocytes (70-80%, mostly CD4), CD19 or CD20 B lymphocytes (10-15%), and macrophages (15%). Bacterial infections, urine reflux, dietary factors, hormones, and autoimmune response have been considered to cause inflammation in the prostate. From a pathophysiologic standpoint, tissue damage associated with inflammatory response and subsequent chronic tissue healing may result in the development of BPH nodules and proliferative inflammatory atrophy (PIA). The loss of glutathione S-transferase P1(GSTP1) may be responsible in patients with genetic predisposition for the transition of PIA into high-grade intraepithelial neoplasia (HGPIN) and PCa. Although there is growing evidence of the association among inflammatory response, BPH, and PCa, we can only surmise on the immunologic mechanisms involved, and further research is required to better understand the role of prostatic inflammation in the initiation of BPH and PCa. There is not yet proof that targeting prostate inflammation with a pharmacologic agent results in a lower incidence and progression or regression of either BPH or PCa. Conclusions: Evidence in the peer-reviewed literature suggested that chronic prostatic inflammation may be involved in the development and progression of chronic prostatic disease, such as BPH and PCa, although there is still no evidence of a causal relation. Inflammation should be considered a new domain in basic and clinical research in patients with BPH and PCa. (C) 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved
Investing with Confidence : Understanding Political Risk Management in the 21st Century
No full text"A investing with confidence:
understanding political risk management in the 21st
century", is based on papers at the 2008 symposium on
international political risk management, host by the
Multilateral Investment Guarantee Agency (MIGA) and
Georgetown University on December 4, 2008. The symposium was
the sixth such event, and coincided with MIGA 20th
anniversary. Both of these milestones attest to the
importance of political risk insurance (PRI) and the extent
to which the PRI market has developed and grown during this
period. The last 20 years have seen tremendous growth in
both the number and value of projects that have been
insured, and a steady and healthy increase in the number of
PRI providers in the marketplace. MIGA, for one, has written
over $20 billion in guarantees since the agency was
established, and has worked with and received support from a
wide range of private, public, and multilateral insurers.
Events like the MIGA-Georgetown symposium demonstrate that
there is much to be learned through the sharing of
experiences and thinking together about the critical issues
that confront the industry as well as new products and
ideas. The chapters presented in this volume provide the
reader with important and current insights into the evolving
world of political risk insurance and foreign direct
investment. The financial crisis presents us incredible
challenges, and at the same time, incredible opportunities.
Through cooperation and innovation, the author can emerge
from the crisis in a stronger position. Making the most of
the lessons the author have learned from the past and
applying new tools puts us in a position to mitigate the
impact of the current crisis on those countries with the
least resilience and with the greatest need for continued
foreign direct investment, as well as to benefit from new
opportunities as the recovery begins and credit flows and
investment levels regain momentum
Radiation of the bark louse genus Kilauella across the Hawaiian Islands
No full textIsland systems serve as important models for studies of evolutionary processes and speciation. The Hawaiian Island group is one of the most isolated island chains in the world, and many groups of insects have undergone dramatic diversification within these islands. Studies of adaptive radiation on Hawaii could promote understanding of the evolutionary process underlying diversification patterns, but studies of Hawaiian taxa from a systematics standpoint are limited. The bark louse genus Kilauella (Psocoptera: Elipsocidae) represents one of the most abundant genera of insects across all islands of the Hawaiian chain, and is a prime candidate for a phylogenetic study. This work aims to explore the diversification pattern of these bark lice across the modern high islands. Kilauella specimens were collected from the islands of Kauai, Oahu, Molokai, Maui Nui, and Hawaii to create a phylogeny exploring the speciation patterns of the genus. Our results show evidence of forward ‘stepping stone’ radiation across the Hawaiian Islands with a potentially significant level of within island radiation, but resolution in the phylogeny is a problem for elucidation of an exact pattern. Molecular dating estimates show that genus Kilauella may be a relatively young radiation, with an origin at approximately 6.74 mya (95% confidence interval 9.48 to 4.38 mya), corresponding roughly with the uplift of the island of Nihoa at 7.2 mya.Submission published under a 24 month embargo labeled 'U of I only', the embargo will last until 2017-08-01The student, Patrick Gero, accepted the attached license on 2015-07-21 at 09:01.The student, Patrick Gero, submitted this Thesis for approval on 2015-07-21 at 09:05.This Thesis was approved for publication on 2015-07-21 at 09:43.DSpace SAF Submission Ingestion Package generated from Vireo submission #8582 on 2015-09-29 at 15:00:53Made available in DSpace on 2015-09-29T20:50:22Z (GMT). No. of bitstreams: 2
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Navigating the mCRPC Landscape: Exploring Key Clinical Decision Points
No full textThe Bayer satellite symposium was introduced by Prof Fred Saad, who gave an introduction into the use of radium-223 in metastatic castration-resistant prostate cancer (mCRPC). Results from the recent Phase III ALpharadin in SYMptomatic Prostate Cancer (ALSYMPCA) study were also presented. Profs Kramer, Tombal, and Gschwend then each presented case studies on patients they had treated with radium-223. Each speaker also provided their own personal view and recommendations for use of radium-223 based on their experience with these patients. Prof Gschwend concluded the symposium with important considerations for the urologist in using radium-223 in mCRPC
STUDIES ON BALNEOTHERAPY OF DIABETES MELLITUS (Ⅱ). EFFECT OF INTERNAL USE OF GERO HOT SPRING ON THE ALIMENTARY HYPERGLYCEMIA IN ALLOXAN-DIABETIC RABBITS
No full textThe author investigated the effect of the internal use of the hot spring water of Gero (Gifu Prefecture, Japan), which contained Cl' 167 mg./L., HCO(3)' 66.0 mg./L. and titrated sulphur 0.6 mg./L. (pH: 6.2) at the time of this experiment, upon the alimentary hyperglycemia in alloxan－diabetic rabbits. 1. The author injected alloxan of 150 mg. per kg. of body weight intravenously into normal rabbits and performed the experiment 5～6 weeks after the injection. At the time of the experiment, the fasting blood sugar levels of alloxan-diabetic rabbits ranged from 107 to 211 mg./dl. (170 mg./dl. on the average). 2. Thirty ml. of 10% glucose solution in thermal water or in plain water per kg. of body weight was administered to the rabbits by stomach tube, and blood sugar level was determined before and 1/2, 1, 2, 3, 4 and 5 hours after the administration. The rejection interval (5%) of the glucose tolerance in 17 normal rabbits is shown in Fig. Ⅰ. Glucose tolerance curves of these alloxan-diabetic rabbits were out of the limit of the normal range. 3. Gero Hot Spring water had no inhibitory action upon the alimentary hyperglycemia of alloxan-diabetic rabbits
Ergebnisse nach modifizierter Norwood-Operation bei Patienten mit Linksherzhypoplasie-Varianten im Vergleich zum typischen Krankheitsbild
No full textWährend die Fehlbildungen des linken Herzens mit Hypoplasie der Mitralklappe, des linken Ventrikels, der Aortenklappe und des Aortenbogens als hypoplastisches Linksherzsyndrom (HLHS) bezeichnet werden, fasst man die anderen komplexen Herzfehler, die mit einer Hypoplasie des Aortenbogens bei verschiedener dominanter oder balancierter Ventrikelmorphologie einhergehen, als Non-HLHS zusammen. Diese Gruppe ist inhomogen und klein. Das Behandlungskonzept ist ebenfalls dreistufig wie beim klassischen hypoplastischen Linksherzsyndrom.
In der vorliegenden Arbeit wurden die früh- und spätpostoperativen Verläufe und die jeweilige Letalität der Patientengruppe mit Non-HLHS (n = 26), die zwischen November 1993 und Juni 2006 im Kinderherzzentrum Kiel des Universitätsklinikums Schleswig-Holstein behandelt wurden, analysiert und mit einer Gruppe von Patienten mit HLHS (n = 157) verglichen.
Alle Patientendaten wurden retrospektiv analysiert und anonymisiert ausgewertet. Das Follow-up erfolgte bis zum 31.12.2009.
Das männliche Geschlecht überwog in allen Gruppen (76 % Non-HLHS/64,3 % HLHS). Zwischen den Gruppen der Non-HLHS-Patienten und der HLHS-Gruppe bestanden keine signifikanten Unterschiede bei der Geschlechtsverteilung, dem Geburtsgewicht, der Frühgeburtlichkeit und dem medianen Durchmesser der Aorta ascendens. 13 Kinder (50 %) in den drei Patientengruppen mit Non-HLHS und 21 Kinder mit HLHS (13,3 %) hatten zusätzliche extrakardiale Fehlbildungen. Dieser Unterschied zwischen beiden Gruppen war signifikant (50 % vs. 13,3 %; p ≤ 0,001).
Alle Kinder mit Non-HLHS und alle Kinder mit HLHS erhielten eine modifizierte Norwood-Operation innerhalb der ersten Lebenstage bis -wochen. In der Non-HLHS-Gruppe gab es keine Hospitalletalität. In der HLHS-Gruppe verstarben dagegen 18 Kinder (11,5 %). Der Unterschied war nicht signifikant (p = 0,080).
Der zweite und dritte Operationsschritt erfolgte je nach Ventrikelmorphologie entweder mit Hemi-Fontan- und späterer Fontan-Operation oder bei biventrikulärer Balance durch eine Rastelli-Operation.
Im Langzeitverlauf verstarben insgesamt sechs Kinder aus allen drei Gruppen mit Non-HLHS. Dies entspricht einer Gesamtletalität von 23,1 %. Letztere war bei den Patienten mit dominantem rechtem Ventrikel signifikant höher als bei den Patienten mit balancierten Ventrikeln bzw. dominantem linkem Ventrikel (p = 0,015).
Im Vergleich der Non-HLHS-Gesamtgruppe mit der Gruppe der HLHS-Patienten (31,6 %) zeigte sich kein signifikanter Unterschied (p = 0,192) in der Gesamtsterblichkeit.
Die fehlende Hospitalletalität der Non-HLHS-Patienten ist im Vergleich zum Großteil der vorliegenden Literatur mit Sterblichkeitsangaben zwischen 17 und 25 % bemerkenswert und identisch mit der von Bradley (2002).
Die im Langzeitverlauf verstorbenen Kinder hatten entweder zusätzliche extrakardiale Fehlbildungen, einen dominanten rechten Ventrikel oder es lagen Lungenvenenfehlmündungen vor. Tendenziell war das Langzeitüberleben in der Non-HLHS-Gruppe besser, besonders dann, wenn ein dominanter linker Ventrikel oder eine biventrikuläre Balance vorlag.
Limitiert wurden unsere Ergebnisse durch die sehr kleinen Fallzahlen und individuellen Ausprägungen der komplexen Herzfehler der Non-HLHS-Gruppe
Elevated preoperative neutrophil–lymphocyte ratio predicts upgrading at radical prostatectomy
No full textBackground: Neutrophilâlymphocyte ratio (NLR) is a widely used, representative marker of systemic inflammatory response within the body. NLR can be calculated from simple, inexpensive peripheral blood samples. High NLR is a negative prognostic factor in a variety of malignancies including urological tumors. In this study, we aim to assess the prognostic value of preoperative neutrophil- lymphocyte ratio (NLR) in patients treated with radical prostatectomy (RP) for localized prostate cancer (PCa). Materials and methods: Records of 7426 patients were retrospectively analyzed from prospectively collected datasets. A cut-off point of 3 was taken for NLR based on ROC analyses and previous literature. Results: 23% (n = 1707) of patients had an NLR of â¥3. Patients with NLR â¥3 were more likely to harbor unfavorable pathological features such as higher biopsy Gleason score (GS), higher RP GS, higher rates of extra capsular extension, nodal involvement (all p < 0.001) and positive surgical margins (p = 0.002). On multivariable analyses, NLR ⥠3 was associated with higher RP GS (OR 2.32; p < 0.001), seminal vesicle invasion (OR 1.60; p < 0.001) and nodal involvement (OR 1.43; p < 0.001). On multivariable analyses, NLR ⥠3 was significantly associated with GS upgrading at RP (OR 1.39 p < 0.001). During a median follow up of 45 months, NLR ⥠3 was associated with higher risk of BCR (p = 0.001). However, on multivariable Cox regression analysis such association was not shown (HR 0.86; p = 0.4). Conclusion: Preoperative NLR ⥠3 was associated with aggressive PCa, such as upgrading at RP. Even though its effect on clinical-decision making seems to be limited when all clinical and pathological confounders are taken into account, preoperative NLR may still be useful in selected patients to identify aggressive PCa helping patient selection for active surveillance protocols. Conversely, it does not predict BCR when adjusted for the effect of pathological features
Axularren Gero liburuaren ale kasi birjinaleko "M" pleguaz
No full text[EUS] Aurreko mendeetako Euskal Literaturak aukera gutxi izan du liburuak irarkolan ezagutu ohi duen prozesuaz mintzatzeko; eta are gutxiago, idazleek bertara eramandako bertsioen eta ondoko zuzenketen berri emateko. Euskal Literaturako obra klasikoak oro har, eta, honen barnean, XVI-XVII. mendeetako denbora-leizean erdi galduak ditugunak batik bat, inprimatutako aleen bidez baino ezin mintza daitezke eskuarki. Lekukotasun hori, tamalez, inoren erreferentzia hutsera edo, hoberenean, edizioaren ale bakan batenera mugatu ohi da nahi baino gehiagotan. Eta honetan ez da desberdintasunik autore handien eta autore txikien obren artean, arlo horretan, nonbait, gure klasiko gehienak suertatu baitira idor. Guztiarekin ere, artikulu honek Euskal Literaturak eman duen idazle funtsezkoenaren obraz baliatu nahi izan du bazterturik ditugun liburuetan inoiz aurkikuntza bitxirik ere gerta daitekeela erakusteko eta, bidenabar, inprimatu aurrekoez eta bestelakoez ere hitz egiteko. Izatez, Axularrek idatzitako Gero liburuaren lehen ediziotik iritsi zaizkigun dozena eskas aleren artean, bada bat, Julio Urkixok gordea nahiz eta ez bereziki onetsia, non, besteak beste, gainerakoetan azaltzen ez diren hainbat gauza interesgarri agertzen baitira. “M” plegua edo koadernotxoa da horietako nabarmenena eta garrantzitsuena.[ES] Si pocas han sido las oportunidades de que la literatura vasca de los siglos precedentes ha gozado para mostrar el proceso que sigue el libro en la imprenta, menor, incluso, ha sido el número de las que ha dispuesto para reflejar la problemática de las versiones aportadas por los escritores y de sus correspondientes correcciones. En este sentido, las obras clásicas de la literatura vasca, y en especial las relegadas en los abismos de los siglos XVI y XVII, apenas si pueden hablar más allá del texto impreso en que vieron la luz. Son testimonios que a menudo se basan en ejemplares únicos y/o incompletos, y, no infrecuentemente, se nutren sólo de referencias ajenas. Y en esto no hay diferencias entre nuestros autores: mayores o menores, los más de nuestros clásicos han resultado baldíos en este aspecto. Con todo, este artículo ha querido valerse de la obra del principal autor de la literatura vasca para demostrar que aún es posible la sorpresa y el descubrimiento precioso y, a su vez, tratar acerca de los trabajos previos a la impresión definitiva de una obra. De hecho, entre la escasa docena de ejemplares que ha llegado a nosotros de la primera edición del Gero de Axular hay uno, recogido –pero no especialmente valorado– por Julio de Urquijo, donde aparecen interesantes elementos que no constan en los ejemplares restantes. El pliego o cuadernillo "M" es uno de los más notables e interesantes.[FR] La littérature basque des siècles passés a eu peu d’opportunités de traiter le processus que les livres subissent aux imprimeries, et beaucoup moins d’opportunités de traiter les versions que les écrivains y amènent et les corrections ultérieures que l’on y fait. Dans le cas des œuvres classiques de la littérature basque et, parmi elles celles qui sont tombées dans les oubliettes des XVIe et XVIIe siècles, on ne peut, en général, parler que d’exemplaires déjà imprimés.
Ce témoignage, malheureusement, plus souvent que l’on ne voudrait, se limite à la simple référence de quelqu’un ou, dans le meilleur des cas, à la référence de quelque exemplaire isolé de l’édition. Et il n’y a pas beaucoup de différence entre les grand auteurs et ceux qui sont plus modestes, car il semble que dans ce sens, le travail de la plupart de nos classiques ait été fait en vain. Malgré tout, dans cet article j’ai voulu me servir de l’œuvre écrite par l’auteur principal de la littérature basque, pour démontrer que l’on peut aussi faire des découvertes importantes dans les livres que nous avons laissés de côté, je profite aussi de l’occasion pour parler du processus avant d’imprimer et d’autres sujets. En fait, parmi les quelques douze exemplaires qui nous sont parvenus de la première édition de Gero de Axular, il y en a un, conservé par Julio de Urquijo, qui n’est pas spécialement apprécié, où il y a pourtant beau coup de choses intéressantes qui n’apparaissent pas dans d’autres exemplaires. Le cahier ou carnet «M» est l’une des plus remarquables et importantes.[EN] Basque literature from past centuries has had few opportunities of dealing with the process which books undergo at the printers and fewer still of looking into the versions taken to printers by writers and the corrections made to them afterwards. In the case of classical works from Basque literature and of these, in general, those which were practically lost in the time abysm of the XVI and XVII centuries, we can, as a rule, speak of little more than copies already printed. Unfortunately, on more occasions than one would wish, such testimony is limited to mere reference by somebody or, in the best of events, to reference in an odd copy from the edition. And in this respect, there would appear to be little difference between great and lesser authors because apparently the work of most of our classics was futile. Nevertheless, in this article,
I wished to use the work provided by the main author of Basque literature to demonstrate that it is possible to make precious discoveries in the books we have hidden away and, making use of the occasion, to speak about the process prior to printing and other matters. In fact, of the mere dozen copies known to us of the first edition of Axular’s Gero, there is one not particularly
valued copy, belonging to Julio de Urquijo, which contains many interesting things which fail to appear in the other copies. The booklet “M” is one of the most remarkable and important of these
Axularren "Gero" liburuaren ale kasi birjinaleko 'M' pleguaz
No full text[EUS] Aurreko mendeetako Euskal Literaturak aukera gutxi izan du liburuak irarkolan ezagutu ohi duen prozesuaz mintzatzeko; eta are gutxiago, idazleek bertara eramandako bertsioen eta ondoko zuzenketen berri emateko. Euskal Literaturako obra klasikoak oro har, eta, honen barnean, XVI-XVII. mendeetako denbora-leizean erdi galduak ditugunak batik bat, inprimatutako aleen bidez baino ezin mintza daitezke eskuarki. Lekukotasun hori, tamalez, inoren erreferentzia hutsera edo, hoberenean, edizioaren ale bakan batenera mugatu ohi da nahi baino gehiagotan. Eta honetan ez da desberdintasunik autore handien eta autore txikien obren artean, arlo horretan, nonbait, gure klasiko gehienak suertatu baitira idor. Guztiarekin ere, artikulu honek Euskal Literaturak eman duen idazle funtsezkoenaren obraz baliatu nahi izan du bazterturik ditugun liburuetan inoiz aurkikuntza bitxirik ere gerta daitekeela erakusteko eta, bidenabar, inprimatu aurrekoez eta bestelakoez ere hitz egiteko. Izatez, Axularrek idatzitako Gero liburuaren lehen ediziotik iritsi zaizkigun dozena eskas aleren artean, bada bat, Julio Urkixok gordea nahiz eta ez bereziki onetsia, non, besteak beste, gainerakoetan azaltzen ez diren hainbat gauza interesgarri agertzen baitira. “M” plegua edo koadernotxoa da horietako nabarmenena eta garrantzitsuena.[ES] Si pocas han sido las oportunidades de que la literatura vasca de los siglos precedentes ha gozado para mostrar el proceso que sigue el libro en la imprenta, menor, incluso, ha sido el número de las que ha dispuesto para reflejar la problemática de las versiones aportadas por los escritores y de sus correspondientes correcciones. En este sentido, las obras clásicas de la literatura vasca, y en especial las relegadas en los abismos de los siglos XVI y XVII, apenas si pueden hablar más allá del texto impreso en que vieron la luz. Son testimonios que a menudo se basan en ejemplares únicos y/o incompletos, y, no infrecuentemente, se nutren sólo de referencias ajenas. Y en esto no hay diferencias entre nuestros autores: mayores o menores, los más de nuestros clásicos han resultado baldíos en este aspecto. Con todo, este artículo ha querido valerse de la obra del principal autor de la literatura vasca para demostrar que aún es posible la sorpresa y el descubrimiento precioso y, a su vez, tratar acerca de los trabajos previos a la impresión definitiva de una obra. De hecho, entre la escasa docena de ejemplares que ha llegado a nosotros de la primera edición del Gero de Axular hay uno, recogido –pero no especialmente valorado– por Julio de Urquijo, donde aparecen interesantes elementos que no constan en los ejemplares restantes. El pliego o cuadernillo "M" es uno de los más notables e interesantes.[FR] La littérature basque des siècles passés a eu peu d’opportunités de traiter le processus que les livres subissent aux imprimeries, et beaucoup moins d’opportunités de traiter les versions que les écrivains y amènent et les corrections ultérieures que l’on y fait. Dans le cas des œuvres classiques de la littérature basque et, parmi elles celles qui sont tombées dans les oubliettes des XVIe et XVIIe siècles, on ne peut, en général, parler que d’exemplaires déjà imprimés.
Ce témoignage, malheureusement, plus souvent que l’on ne voudrait, se limite à la simple référence de quelqu’un ou, dans le meilleur des cas, à la référence de quelque exemplaire isolé de l’édition. Et il n’y a pas beaucoup de différence entre les grand auteurs et ceux qui sont plus modestes, car il semble que dans ce sens, le travail de la plupart de nos classiques ait été fait en vain. Malgré tout, dans cet article j’ai voulu me servir de l’œuvre écrite par l’auteur principal de la littérature basque, pour démontrer que l’on peut aussi faire des découvertes importantes dans les livres que nous avons laissés de côté, je profite aussi de l’occasion pour parler du processus avant d’imprimer et d’autres sujets. En fait, parmi les quelques douze exemplaires qui nous sont parvenus de la première édition de Gero de Axular, il y en a un, conservé par Julio de Urquijo, qui n’est pas spécialement apprécié, où il y a pourtant beau coup de choses intéressantes qui n’apparaissent pas dans d’autres exemplaires. Le cahier ou carnet «M» est l’une des plus remarquables et importantes.[EN] Basque literature from past centuries has had few opportunities of dealing with the process which books undergo at the printers and fewer still of looking into the versions taken to printers by writers and the corrections made to them afterwards. In the case of classical works from Basque literature and of these, in general, those which were practically lost in the time abysm of the XVI and XVII centuries, we can, as a rule, speak of little more than copies already printed. Unfortunately, on more occasions than one would wish, such testimony is limited to mere reference by somebody or, in the best of events, to reference in an odd copy from the edition. And in this respect, there would appear to be little difference between great and lesser authors because apparently the work of most of our classics was futile. Nevertheless, in this article,
I wished to use the work provided by the main author of Basque literature to demonstrate that it is possible to make precious discoveries in the books we have hidden away and, making use of the occasion, to speak about the process prior to printing and other matters. In fact, of the mere dozen copies known to us of the first edition of Axular’s Gero, there is one not particularly
valued copy, belonging to Julio de Urquijo, which contains many interesting things which fail to appear in the other copies. The booklet “M” is one of the most remarkable and important of these
Uptake of purines in <i>Plasmodium falciparum</i>-infected human erythrocytes is mostly mediated by the human Equilibrative Nucleoside Transporter and the human Facilitative Nucleobase Transporter
No full text<b>Background</b>: Plasmodium parasites are unable to synthesize purines de novo and have to salvage them from the host. Due to this limitation in the parasite, purine transporters have been an area of focus in the search for anti-malarial drugs. Although the uptake of purines through the human equilibrative nucleoside transporter (hENT1), the human facilitative nucleobase transporter (hFNT1) and the parasite-induced new permeation pathway (NPP) has been studied, no information appears to exist on the relative contribution of these three transporters to the uptake of adenosine and hypoxanthine. Using the appropriate transporter inhibitors, the role of each of these salvage pathways to the overall purine transport in intraerythrocytic Plasmodium falciparum was systematically investigated.
<b>Methods</b>: The transport of adenosine, hypoxanthine and adenine into uninfected and P. falciparum-infected human erythrocytes was investigated in the presence or absence of classical inhibitors of the hFNT1, hENT1 and NPP. The effective inhibition of the various transporters by the classical inhibitors was verified using appropriate known substrates. The ability of high concentration of unlabelled substrates to saturate these transporters was also studied.
<b>Results</b>: Transport of exogenous purine into infected or uninfected erythrocytes occurred primarily through saturable transporters rather than through the NPP. Hypoxanthine and adenine appeared to enter erythrocytes mainly through the hFNT1 nucleobase transporter whereas adenosine entered predominantly through the hENT1 nucleoside transporter. The rate of purine uptake was approximately doubled in infected cells compared to uninfected erythrocytes. In addition, it was found that the rate of adenosine uptake was considerably higher than the rate of hypoxanthine uptake in infected human red blood cells (RBC). It was also demonstrated that furosemide inhibited the transport of purine bases through hFNT1.
<b>Conclusion</b>: Collectively, the data obtained in this study clearly show that the endogenous host erythrocyte transporters hENT1 and hFNT1, rather than the NPP, are the major route of entry of purine into parasitized RBC. Inhibitors of hENT1 and hFNT1, as well as the NPP, should be considered in the development of anti-malarials targeted to purine transport
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