bluuebunny/crossref_metadata_2025_split huggingface dataset:
Permissive nicotine regulation as a complement to traditional tobacco control
Authors: Sumner Walton 
Published: February 2005

Abstract
Background
Cigarette smoking takes a staggering toll on human health and attracts considerable public health attention, yet real solutions seem distant. The 2004 Family Smoking Prevention and Tobacco Control Act (US Senate bill S2461) would have given the US Food and Drug Administration limited authority to regulate cigarettes to "protect the public health." However, such legislation is unlikely to substantially reduce smoking or related deaths.

Discussion
The past 500 years of tobacco control efforts demonstrate that nicotine prohibition is a practical impossibility for numerous reasons, state revenue being one of the most ominous. The FDA already has regulatory authority over pharmaceutical grade nicotine products, and requires pharmacists to dispense the most addictive of these only with prescriptions. Meanwhile, every corner store can sell far more addictive and dangerous cigarettes to any adult. The FDA could immediately increase competition between cigarettes and clean nicotine products by approving available nicotine products for over-the-counter sales to adults. Similarly permissive regulation of cigarettes and addictive nicotine products will reduce tobacco use and improve smokers' health, but increase nicotine use in the population. Fortunately, restricted youth access and accurate labeling of nicotine's absolute risks will dissuade many non-smokers from experimenting with it, while accurate depiction of its risks relative to cigarette smoking will encourage many smokers to switch. The FDA could take a series of small steps that might ultimately replace a large proportion of cigarette smoking with equally addictive nicotine products, without risking serious public health setbacks. Vaccine, methadone, and injury prevention policies establish relevant public health precedents.

Summary
Cigarettes, or an equally addictive alternative, will be a permanent and common product in most societies. Regulations restricting only the safest addictive nicotine products are hard to justify. Addictive nicotine compliments other tobacco control strategies. Modern tobacco control policies are applicable to addictive nicotine. Controlled trials and test market studies are urgently needed to evaluate addictive nicotine as an alternative to smoking. Meanwhile, legislators should preserve the Food and Drug Administration's option to permit non-prescription sales of addictive nicotine.
Do malaria ookinete surface proteins P25 and P28 mediate parasite entry into mosquito midgut epithelial cells?
Authors: Baton Luke A , Ranford-Cartwright Lisa C 
Published: February 2005

Abstract

Background
P25 and P28 are related ookinete surface proteins highly conserved throughout the Plasmodium genus that are under consideration as candidates for inclusion in transmission-blocking vaccines. Previous research using transgenic rodent malaria parasites lacking P25 and P28 has demonstrated that these proteins have multiple partially redundant functions during parasite infection of the mosquito vector, including an undefined role in ookinete traversal of the mosquito midgut epithelium, and it has been suggested that, unlike wild-type parasites, Dko P25/P28 parasites migrate across the midgut epithelium via an intercellular, rather than intracellular, route.

Presentation of the hypothesis
This paper presents an alternative interpretation for the previous observations of Dko P25/P28 parasites, based upon a recently published model of the route of ookinete invasion across the midgut epithelium. This model claims ookinete invasion is intracellular, with entry occurring through the lateral apical plasma membrane of midgut epithelial cells, and is associated with significant invagination of the midgut epithelium localised at the site of parasite penetration. Following this model, it is hypothesized that: (1) a sub-population of Dko P25/P28 ookinetes invaginate, but do not penetrate, the apical surface of the midgut epithelium and thus remain within the midgut lumen; and (2) another sub-population of Dko P25/P28 parasites successfully enters and migrates across the midgut epithelium via an intracellular route similar to wild-type parasites and subsequently develops into oocysts.

Testing the hypothesis
These hypotheses are tested by showing how they can account for previously published observations and incorporate them into a coherent and consistent explanatory framework. Based upon these hypotheses, several quantitative predictions are made, which can be experimentally tested, about the relationship between the densities of invading Dko P25/P28 ookinetes in different regions of the midgut epithelium and the number of oocyst stage parasites to which these mutant ookinetes give rise.

Implications of the hypothesis
The recently published model of ookinete invasion implies that Dko P25/P28 parasites are greatly, although not completely, impaired in their ability to enter the midgut epithelium. Therefore, P25 and/or P28 have a novel, previously unrecognized, function in mediating ookinete entry into midgut epithelial cells, suggesting that one mode of action of transmission-blocking antibodies to these ookinete surface proteins is to inhibit this function.
Impact of tetrachloroethylene-contaminated drinking water on the risk of breast cancer: Using a dose model to assess exposure in a case-control study
Authors: Vieira Verónica , Aschengrau Ann , Ozonoff David 
Published: February 2005

Abstract
Background
A population-based case-control study was undertaken in 1997 to investigate the association between tetrachloroethylene (PCE) exposure from public drinking water and breast cancer among permanent residents of the Cape Cod region of Massachusetts. PCE, a volatile organic chemical, leached from the vinyl lining of certain water distribution pipes into drinking water from the late 1960s through the early 1980s. The measure of exposure in the original study, referred to as the relative delivered dose (RDD), was based on an amount of PCE in the tap water entering the home and estimated with a mathematical model that involved only characteristics of the distribution system.

Methods
In the current analysis, we constructed a personal delivered dose (PDD) model that included personal information on tap water consumption and bathing habits so that inhalation, ingestion, and dermal absorption were also considered. We reanalyzed the association between PCE and breast cancer and compared the results to the original RDD analysis of subjects with complete data.

Results
The PDD model produced higher adjusted odds ratios than the RDD model for exposures > 50th and >75th percentile when shorter latency periods were considered, and for exposures < 50th and >90th percentile when longer latency periods were considered. Overall, however, the results from the PDD analysis did not differ greatly from the RDD analysis.

Conclusion
The inputs that most heavily influenced the PDD model were initial water concentration and duration of exposure. These variables were also included in the RDD model. In this study population, personal factors like bath and shower temperature, bathing frequencies and durations, and water consumption did not differ greatly among subjects, so including this information in the model did not significantly change subjects' exposure classification.
Maternal plasma viral load and neutralizing/enhancing antibodies in vertical transmission of HIV: A non-randomized prospective study
Authors: Kamara Paul , Melendez-Guerrero Loyda , Arroyo Miguel , Weiss Heidi , Jolly Pauline 
Published: February 2005

Abstract
Background
We examined the association and interaction between maternal viral load and antibodies in vertical transmission of HIV in a non-randomized prospective study of 43 HIV-1 infected pregnant women who attended the San Juan City Hospital, Puerto Rico, and their 45 newborn infants. The women and infants received antiretroviral therapy.

Methods
A nested PCR assay of the HIV-1 envelope V3 region and infant PBMC culture were performed to determine HIV status of the infants. Maternal and infant plasma were tested for HIV neutralization or enhancement in monocyte-derived macrophages.

Results
Twelve (26.7%) infants were positive by the HIV V3 PCR assay and 3 of the 12 were also positive by culture. There was a trend of agreement between high maternal viral load and HIV transmission by multivariate analysis (OR = 2.5, CI = 0.92, p = 0.0681). Both maternal and infant plasma significantly (p = 0.001 for both) reduced HIV replication at 10-1 dilution compared with HIV negative plasma. Infant plasma neutralized HIV (p = 0.001) at 10-2 dilution but maternal plasma lost neutralizing effect at this dilution. At 10-3 dilution both maternal and infant plasma increased virus replication above that obtained with HIV negative plasma but only the increase by maternal plasma was statistically significant (p = 0.005). There were good agreements in enhancing activity in plasma between mother-infant pairs, but there was no significant association between HIV enhancement by maternal plasma and vertical transmission.

Conclusion
Although not statistically significant, the trend of association between maternal viral load and maternal-infant transmission of HIV supports the finding that viral load is a predictor of maternal-infant transmission. Both maternal and infant plasma neutralized HIV at low dilution and enhanced virus replication at high dilution. The antiretroviral treatments that the women received and the small sample size may have contributed to the lack of association between HIV enhancement by maternal plasma and vertical transmission.
Outcome and prognostic factors in critically ill patients with systemic lupus erythematosus: a retrospective study
Authors: Hsu Chia-Lin , Chen Kuan-Yu , Yeh Pu-Sheng , Hsu Yeong-Long , Chang Hou-Tai , Shau Wen-Yi , Yu Chia-Li , Yang Pan-Chyr 
Published: February 2005

Abstract
Introduction
Systemic lupus erythematosus (SLE) is an archetypal autoimmune disease, involving multiple organ systems with varying course and prognosis. However, there is a paucity of clinical data regarding prognostic factors in SLE patients admitted to the intensive care unit (ICU).

Methods
From January 1992 to December 2000, all patients admitted to the ICU with a diagnosis of SLE were included. Patients were excluded if the diagnosis of SLE was established at or after ICU admission. A multivariate logistic regression model was applied using Acute Physiology and Chronic Health Evaluation II scores and variables that were at least moderately associated (P < 0.2) with survival in the univariate analysis.

Results
A total of 51 patients meeting the criteria were included. The mortality rate was 47%. The most common cause of admission was pneumonia with acute respiratory distress syndrome. Multivariate logistic regression analysis showed that intracranial haemorrhage occurring while the patient was in the ICU (relative risk = 18.68), complicating gastrointestinal bleeding (relative risk = 6.97) and concurrent septic shock (relative risk = 77.06) were associated with greater risk of dying, whereas causes of ICU admission and Acute Physiology and Chronic Health Evaluation II score were not significantly associated with death.

Conclusion
The mortality rate in critically ill SLE patients was high. Gastrointestinal bleeding, intracranial haemorrhage and septic shock were significant prognostic factors in SLE patients admitted to the ICU.
Common Polymorphism G(-248)A in the Promoter Region of the bax Gene Results in Significantly Shorter Survival in Patients With Chronic Lymphocytic Leukemia Once Treatment Is Initiated
Authors: Starczynski Jane , Pepper Chris , Pratt Guy , Hooper Laura , Thomas Alun , Milligan Donald , Bentley Paul , Fegan Christopher 
Published: February 2005

Purpose Chronic lymphocytic leukemia (CLL) is characterized by the development of drug resistance. The underlying biologic and genetic reasons for this resistance are complex, but the bcl-2 gene family seems to play a critical role. This retrospective study assessed the clinical impact of a common single nucleotide polymorphism of the pro-apoptotic bax gene in patients with chronic lymphocytic leukemia. Patients and Methods The frequency of the novel polymorphism, G(−248)A, in the promoter region of the bax gene and bax protein expression was assessed in 203 CLL patients. The results were correlated with clinical outcome. Results The polymorphism was found in 23% of the CLL cohort and 15% of normal controls with no significant difference in allele frequency between the two groups (P = .15). It was associated with lower Bax protein expression and a shorter overall survival, especially in the treated patient group (P = .03). Furthermore, the adverse impact of the polymorphism was accentuated when comparing survival from the date of first treatment rather than diagnosis (P = .012). No significant difference in age at diagnosis, stage of disease at presentation, lymphocyte doubling time, time to first treatment, or progression-free survival were observed. Conclusion The presence of this single nucleotide polymorphism in CLL critically influences the response to treatment and overall survival. Given the relatively high prevalence of this polymorphism in the normal population, further prospective studies in CLL and other human malignancies are indicated.
Thymidylate Synthase and Methylenetetrahydrofolate Reductase Gene Polymorphism in Normal Tissue As Predictors of Fluorouracil Sensitivity
Authors: Jakobsen Anders , Nielsen Jens Nederby , Gyldenkerne Niels , Lindeberg Jan 
Published: February 2005

Purpose To analyze thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with respect to fluorouracil (FU) sensitivity. Patients and Methods The study included a retrospective analysis of 88 patients with metastatic colorectal cancer and a prospective trial with 51 patients also with measurable metastases. All patients were treated with FU and leucovorin. The analysis of gene polymorphism was performed on normal intestinal tissue and lymphocytes. Results The response rate was significantly higher in patients with TS 3R/3R or MTHFR 677 TT gene polymorphism compared with the other groups. The difference of response rate translated to a difference in time to progression. Similar results were observed in the retrospective analysis and the prospective confirmatory trial. Conclusion The analysis of gene polymorphism allows delineation of a group of patients (30%) with a response rate to a single drug of approximately 50%. This information should be used in the design of tailored treatment.
Gemcitabine, Epirubicin, and Paclitaxel Versus Fluorouracil, Epirubicin, and Cyclophosphamide As First-Line Chemotherapy in Metastatic Breast Cancer: A Central European Cooperative Oncology Group International, Multicenter, Prospective, Randomized Phase III Trial
Authors: Zielinski Christoph , Beslija Semir , Mrsic-Krmpotic Zrinka , Welnicka-Jaskiewicz Marzena , Wiltschke Christoph , Kahan Zsuzsanna , Grgic Mislav , Tzekova Valentina , Inbar Moshe , Cervek Jozika , Chernozemsky Ivan , Szanto Janos , Spanik Stanislav , Wagnerova Maria , Ghilezan Nicolae , Pawlega Janusz , Vrbanec Damir , Khamtsov Dmitry , Soldatenkova Victoria , Brodowicz Thomas 
Published: February 2005

Background The objectives of this phase III trial were to compare the time to progressive disease (TtPD), overall response rate (ORR), overall survival, and toxicity of gemcitabine, epirubicin, and paclitaxel (GET) versus fluorouracil (FU), epirubicin, and cyclophosphamide (FEC) as first-line therapy in patients with metastatic breast cancer (MBC). Patients and Methods Female patients aged 18 to 75 years with stage IV and measurable MBC were enrolled and randomly assigned to either gemcitabine (1,000 mg/m2, days 1 and 4), epirubicin (90 mg/m2, day 1), and paclitaxel (175 mg/m2, day 1) or FU (500 mg/m2, day 1), epirubicin (90 mg/m2, day 1), and cyclophosphamide (500 mg/m2, day 1). Both regimens were administered every 21 days for a maximum of eight cycles. Results Between October 1999 and November 2002, 259 patients (GET, n = 124; FEC, n = 135) were enrolled. Baseline characteristics were well balanced across treatment arms. After a median of 20.4 months of follow-up, median TtPD was 9.1 months and 9.0 months in the GET and FEC arms, respectively (P = .557). The ORR was 62.3% in the GET arm (n = 114) and 51.2% in the FEC arm (n = 129; P = .093). Grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, anemia, stomatitis, neurosensory toxicity, and allergy, occurred significantly more often in the GET arm. Conclusion No significant differences in terms of TtPD and ORR were observed between the two treatment arms. Treatment-related toxicity was higher in the GET arm.
Richtlinie: Labormedizinische Diagnostik bei der Therapie mit TPMT (Thiopurin-S-Methyltransferase)-abhängigen Pharmaka. Guidelines for the laboratory management of thiopurine drug therapy
Authors: Deufel (Vorsitz) Thomas , Geßner Reinhard , Lackner Karl J. , Schwab Matthias , Steimer Werner , Steiner Michael , von Ahsen Nicolas , Kiehntopf Michael 
Published: February 2005

Zusammenfassung

Zusammenfassung Thiopurine (Azathioprin, 6-Mercaptopurin, 6-Thioguanin) werden als Immunsuppressiva und Zytostatika eingesetzt. Bei Patienten mit einer genetisch bedingten kompletten Defizienz der Thiopurin-S-Methyltransferase (TPMT) kommt es regelmäßig zu schwerwiegenden myelotoxischen Nebenwirkungen. Aus diesem Grund muss eine komplette TPMT-Defizienz vor Beginn der Therapie ausgeschlossen werden.
Dazu können eine Bestimmung der TPMT-Aktivität in Erythrozyten (Phänotypisierung) oder eine Mutationsanalyse des TPMT-Gens (Genotypisierung) vorgenommen werden. Bei Beachtung geltender Limitationen können beide Methoden alternativ verwendet werden. Die Beurteilung komplexer Befundkonstellationen erfordert die Überprüfung des vorliegenden Befundes mit der jeweils alternativen Methode (Genotypisierung/Phänotypisie-rung).
Von Willebrand Faktor spaltende Protease und thrombotische Mikroangiopathien. Von Willebrand factor cleaving protease and thrombotic microangiopathy
Authors: Budde Ulrich , Schneppenheim Reinhard 
Published: February 2005

Zusammenfassung

Zusammenfassung Die thrombotisch thrombozytopenische Purpura (TTP) ist durch das generalisierte Auftreten von hyalinen Thromben in der Mikrozirkulation gekennzeichnet. Die hyalinen Thromben enthalten neben den Plättchen überwiegend von Willebrand Faktor (VWF). Bei allen bisher bekannten Fällen der angeborenen TTP ist die von Willebrand Faktor spaltende Protease (VWF-CP) stark vermindert. Auch bei einem derzeit noch umstrittenen Prozentsatz der Patienten mit erworbener TTP ist die Protease infolge Autoantikörper-Bildung nicht nachweisbar oder stark vermindert (<10%). Daher sind neben der konventionellen Diagnostik die Untersuchung der VWF-CP und der Nachweis von Antikörpern gegen die Protease ein wichtiger Bestandteil der diagnostischen Aufarbeitung von Fällen mit thrombotischer Mikroangiopathie. Dagegen treten Surrogat-Marker wie der Nachweis supranormaler Multimere mehr und mehr in den Hintergrund. Allen Methoden zum Nachweis der VWF-CP gemeinsam ist der initiale Verdau des Substrates (gereinigter VWF, rekombinanter VWF, Plasma, dessen endogene VWF-CP zerstört wurde, Fragmente, die die spezifische Spaltstelle enthalten oder das Patientenplasma mit dessen endogener Protease). Der Nachweis des erfolgten Verdaus geschieht mittels Analyse der residualen Multimere, des Auftretens spezifischer Spaltprodukte, der Bestimmung der residualen VWF:CB oder des residualen VWF:RCo, oder mit Hilfe von fragmentspezifischen monoklonalen Antikörpern. In einer sogenannten Schnellmethode wird das Patientenplasma im denaturierenden Puffer dialysiert und die VWF:CB vor und nach der Dialyse bestimmt. Wirklich schnell (<30 Minuten) funktioniert die Messung im Cone and Plate(let) Aggregometer. Hier kommt es nach Zusatz einer geringen Plasmamenge eines Patienten mit TTP zu einer starken Erhöhung von Adhäsion und Aggregation der Thrombozyten einer Normalperson, während bei den übrigen thrombotischen Mikroangiopathien beide durch den Verdünnungseffekt absinken. Die Molekulargenetik spielt eine wichtige Rolle für die Unterscheidung der angeborenen und erworbenen TTP.
Interaktion des von Willebrand Faktors mit Thrombozyten und der Gefäßwand. Interaction of von Willebrand factor and platelets at the vessel wall
Authors: Reininger Armin J. , Spannagl Michael 
Published: February 2005

Zusammenfassung

Zusammenfassung Thrombozyten patroullieren ständig die Gefäßinnenwand auf der Suche nach Defekten, um sie zu verschließen und so ein Ausbluten zu verhindern. In der Abfolge der Prozesse kommt es dabei zunächst zum Abbremsen und ersten Anhaften der Thrombozyten, gefolgt von permanenter Adhäsion und anschließender Plättchen-Plättchen-Reaktion, der Aggregation. Im arteriellen Gefäß system ist der erste Schritt nicht ohne den von Willebrand Faktor möglich. Im der folgenden Übersicht werden die einzelnen Aspekte des komplexen Zusammenspiels von Blut und Strömung – mit Fokus auf von Willebrand Faktor und Thrombozyten – anhand von experimentellen Daten erläutert und diagnostische Laborverfahren vorgestellt, die sie teilweise abbilden.
Validierung des MELISA®-Tests zum Nachweis einer Metallüberempfindlichkeit. Validity of MELISA® for metal sensitivity testing
Authors: Valentine-Thon Elizabeth , Schiwara Hans-Walter 
Published: February 2005

Zusammenfassung

Zusammenfassung In dieser Studie wurden Reproduzierbarkeit, Sensitivität, Spezifität und Zuverlässigkeit des MELISA®-Tests zum Nachweis von Metallüberempfindlichkeiten bei Patienten mit klinischen Symptomen einer Typ IV-Allergie gegen Metalle untersucht.
Von 250 Patienten wurde Blut im MELISA® gegen bis zu 20 Metalle in 2 bis 3 verschiedenen Konzentrationen getestet. Häufigkeit und Verteilung positiver Testergebnisse, Sensitivität und Spezifität des Tests bei Patienten mit und ohne gesicherte oder vermutete Nickelallergie sowie die Bedeutung der Lymphozytenzahl und der Konzentration von anorganischem Quecksilber im Testsystem wurden untersucht. Darüberhinaus wurden für die Reproduzierbarkeitstestung 196 MELISA®-Tests im Doppelansatz durchgeführt und die Intra- und Interassay-Variationen bei Patienten mit positivem Epikutan-Test für die entsprechenden Metalle bestimmt.
Von den 250 Patienten reagierten 26% gegen kein Metall, 36% gegen 1, 15% gegen 2, 12% gegen 3, 6% gegen 4 und 5% gegen ≥5 Metalle positiv im MELISA®-Test. Die positiven Ergebnisse gegen die einzelnen Metalle wiesen folgende Häufigkeiten auf: Nickel (73%), Titan (42%), Cadmium (18%), Gold (17%), Palladium (13%), Blei (11%), Beryllium (9%), anorganisches Quecksilber (8%), Zinn (8%) und Phenylquecksilber (6%). Alle Patienten, bei denen eine Nickelallergie vermutet oder gesichert wurde (n=15), reagierten im MELISA®-Test positiv, während Patienten ohne Verdacht auf eine Nickelallergie entweder negativ (n=6) oder sehr schwach positiv (n=4) reagierten. Die Reaktivität des MELISA®-Tests hängt von der Lymphozytenkonzentration ab: je höher die Lymphozytenkonzentration im Test, desto stärker die Reaktion. Eine Konzentration von >0,5 μg/ml anorganischem Quecksilber verursacht bei den meisten Patienten eine nicht antigen-spezifische (mitogene) Reaktion. Die Reproduzierbarkeit betrug 94% bei einem Stimulationsindex von ≥3 und 99% bei einem Index von ≥5 als Cut-off. Während die absoluten Intra- und Interassay-Stimulations-Indices variieren können, sind die qualitativen Ergebnisse in hohem Grade reproduzierbar.
Der MELISA®-Test ist also reproduzierbar, sensitiv, spezifisch und zuverlässig für den Nachweis einer Metall-unverträglichkeit bei gegen Metalle sensibilisierten Patienten.