bluuebunny/crossref_metadata_2025 huggingface dataset:
MAX-DOAS measurements of NO2, HCHO and CHOCHO at a rural site in Southern China
Authors: Li X. , Brauers T. , Hofzumahaus A. , Lu K. , Li Y. P. , Shao M. , Wagner T. , Wahner A.
Published: February 2012

Abstract. We performed MAX-DOAS measurements during the PRIDE-PRD2006 campaign in the Pearl River Delta region (PRD), China, for 4 weeks in July 2006 at a site located 60 km north of Guangzhou. The vertical distributions of NO2, HCHO, and CHOCHO were independently retrieved by an automated iteration method. The MAX-DOAS measured NO2 mixing ratios showed reasonable agreement with the simultaneous, ground based in-situ data. While the tropospheric NO2 vertical column densities (VCDs) observed by OMI on board EOS-Aura satellite agreed with those by MAX-DOAS, the 3-D chemical transport model CMAQ overestimated the NO2 VCDs as well as the surface concentrations by about 40%. From this observation, a reduction of NOX emission strength in CMAQ seems to be necessary in order to well reproduce the NO2 observations. The average mixing ratios of HCHO and CHOCHO were 12 ppb and 1.6 ppb, respectively, substantially higher than in other rural or semirural environments. The high ratio of 0.135 between CHOCHO and HCHO corresponds to the high VOCs reactivity and high HOX turnover rate consistent with other observations during the campaign.
Atmospheric histories and growth trends of C4F10, C5F12, C6F14, C7F16 and C8F18
Authors: Ivy D. J. , Arnold T. , Harth C. M. , Steele L. P. , Mühle J. , Rigby M. , Salameh P. K. , Leist M. , Krummel P. B. , Fraser P. J. , Weiss R. F. , Prinn R. G.
Published: February 2012

Abstract. The first atmospheric observations and trends are presented for the high molecular weight perfluorocarbons (PFCs): decafluorobutane (C4F10), dodecafluoropentane (C5F12), tetradecafluorohexane (C6F14), hexadecafluoroheptane (C7F16) and octadecafluorooctane (C8F18). Their atmospheric histories are based on measurements of 38 Northern Hemisphere and 46 Southern Hemisphere archived air samples collected between 1973 to 2011 using the Advanced Global Atmospheric Gases Experiment (AGAGE) "Medusa" preconcentration gas chromatography-mass spectrometry systems. A new calibration scale was prepared for each PFC, with estimated accuracies of 6.8% for C4F10, 7.8% for C5F12, 4.0% for C6F14, 6.6% for C7F16 and 7.9% for C8F18. Based on our observations the 2011 globally averaged dry air mole fractions of these heavy PFCs are: 0.18 parts-per-trillion (ppt, i.e., parts per 1012) for C4F10, 0.12 ppt for C5F12, 0.28 ppt for C6F14, 0.12 ppt for C7F16 and 0.09 ppt for C8F18. These atmospheric mole fractions combine to contribute to a global average radiative forcing of 0.35 mW m−2, which is 3.6% of the total PFC radiative forcing. The globally averaged mean atmospheric growth rates of these PFCs during 1973–2011 are 4.58 parts per quadrillion (ppq, i.e., parts per 1015) per year (yr) for C4F10, 3.29 ppq yr−1 for C5F12, 7.50 ppq yr−1 for C6F14, 3.19 ppq yr−1 for C7F16 and 2.51 ppq yr−1 for C8F18. The growth rates of the heavy perfluorocarbons were largest in the early 1990s for C4F10 and C5F12 and in the mid-to-late 1990s for C6F14, C7F16 and C8F18. The more recent slow down in the growth rates of the high molecular weight PFCs suggests that emissions are declining as compared to the 1980s and 1990s. Nevertheless continued monitoring of these potent, extremely long-lived greenhouse gases is necessary to verify that global PFC emissions continue to decline.
A monthly precipitation database for Spain (1851–2008): reconstruction, homogeneity and trends
Authors: Luna M. Y. , Guijarro J. A. , López J. A.
Published: February 2012

Abstract. The compilation and reconstruction of a dataset integrated by 66 long monthly precipitation series, covering mainland Spain and the Balearic Islands, is presented. The reconstruction is based on the hypothesis that the cessation of data recording at one observatory is followed by the establishment of a new observatory very close to the closed one. In order to detect and adjust for possible multiple change points or shifts that could exist in the precipitation series, the R-package CLIMATOL V2.0 is used. This method enables to take advantage of the whole historical Spanish precipitation network in the detection and correction of inhomogeneities. The analysis of annual precipitation trends indicate a high temporal variability. Negative trends dominate for the period 1951–2008 but not for all observatories. On the other hand, positive trends can be detected in the northern Spain for 1902–2008.
Estimating the near-surface permafrost-carbon feedback on global warming
Authors: Schneider von Deimling T. , Meinshausen M. , Levermann A. , Huber V. , Frieler K. , Lawrence D. M. , Brovkin V.
Published: February 2012

Abstract. Thawing of permafrost and the associated release of carbon constitutes a positive feedback in the climate system, elevating the effect of anthropogenic GHG emissions on global-mean temperatures. Multiple factors have hindered the quantification of this feedback, which was not included in climate carbon-cycle models which participated in recent model intercomparisons (such as the Coupled Carbon Cycle Climate Model Intercomparison Project – C4MIP) . There are considerable uncertainties in the rate and extent of permafrost thaw, the hydrological and vegetation response to permafrost thaw, the decomposition timescales of freshly thawed organic material, the proportion of soil carbon that might be emitted as carbon dioxide via aerobic decomposition or as methane via anaerobic decomposition, and in the magnitude of the high latitude amplification of global warming that will drive permafrost degradation. Additionally, there are extensive and poorly characterized regional heterogeneities in soil properties, carbon content, and hydrology. Here, we couple a new permafrost module to a reduced complexity carbon-cycle climate model, which allows us to perform a large ensemble of simulations. The ensemble is designed to span the uncertainties listed above and thereby the results provide an estimate of the potential strength of the feedback from newly thawed permafrost carbon. For the high CO2 concentration scenario (RCP8.5), 33–114 GtC (giga tons of Carbon) are released by 2100 (68 % uncertainty range). This leads to an additional warming of 0.04–0.23 °C. Though projected 21st century permafrost carbon emissions are relatively modest, ongoing permafrost thaw and slow but steady soil carbon decomposition means that, by 2300, about half of the potentially vulnerable permafrost carbon stock in the upper 3 m of soil layer (600–1000 GtC) could be released as CO2, with an extra 1–4 % being released as methane. Our results also suggest that mitigation action in line with the lower scenario RCP3-PD could contain Arctic temperature increase sufficiently that thawing of the permafrost area is limited to 9–23 % and the permafrost-carbon induced temperature increase does not exceed 0.04–0.16 °C by 2300.
High resolution reflection seismic profiling over the Tjellefonna fault in the Møre-Trøndelag Fault Complex, Norway
Authors: Lundberg E. , Juhlin C. , Nasuti A.
Published: February 2012

Abstract. The Møre-Trøndelag Fault Complex (MTFC) is one of the most prominent fault zones of Norway, both onshore and offshore. In spite of its importance, very little is known of the deeper structure of the individual fault segments comprising the fault complex. Most seismic lines have been recorded offshore or focused on deeper structures. This paper presents results from two reflection seismic profiles, located on each side of the Tingvollfjord, acquired over the Tjellefonna fault in the south-eastern part of the MTFC. Possible kilometer scale vertical offsets reflecting, large scale north-west dipping normal faulting separating the high topography to the south-east from lower topography to the north-west have been proposed for the Tjellefonna fault. In this study, however, the Tjellefonna fault is interpreted to dip approximately 50–60° towards the south-east to depths of at least 1.4 km. Travel-time modeling of reflections associated with the fault was used to establish the geometry of the fault structure at depth and detailed analysis of first P-wave arrivals in shot-gathers together with resistivity profiles were used to define the near surface geometry of the fault zone. A continuation of the structure on the north-eastern side of the Tingvollfjord is suggested by correlation of an in strike direction P-S converted reflection (generated by a fracture zone) seen on the reflection data from that side of the Tingvollfjord. The reflection seismic data correlate well with resistivity profiles and recently published near surface geophysical data. A highly reflective package forming a gentle antiform structure was also identified on both seismic profiles. The structure may be an important boundary within the gneissic basement rocks of the Western Gneiss Region. The Fold Hinge Line is parallel with the Tjellefonna fault trace while the topographic lineament diverges, following secondary fracture zones towards north-east.
Quantification of ikaite in Antarctic sea ice
Authors: Fischer M. , Thomas D. N. , Krell A. , Nehrke G. , Göttlicher J. , Norman L. , Riaux-Gobin C. , Dieckmann G. S.
Published: February 2012

Abstract. Calcium carbonate precipitation in sea ice can increase pCO2 during precipitation in winter and decrease pCO2 during dissolution in spring. CaCO3 precipitation in sea ice is thought to potentially drive significant CO2 uptake by the ocean. However, little is known about the quantitative spatial and temporal distribution of CaCO3 within sea ice. This is the first quantitative study of hydrous calcium carbonate, as ikaite, in sea ice and discusses its potential significance for the carbon cycle in polar oceans. Ice cores and brine samples were collected from pack and land fast sea ice between September and December 2007 during an expedition in the East Antarctic and another off Terre Adélie, Antarctica. Samples were analysed for CaCO3, Salinity, DOC, DON, Phosphate, and total alkalinity. A relationship between the measured parameters and CaCO3 precipitation could not be observed. We found calcium carbonate, as ikaite, mostly in the top layer of sea ice with values up to 126 mg ikaite per liter melted sea ice. This potentially represents a contribution between 0.12 and 9 Tg C to the annual carbon flux in polar oceans. The horizontal distribution of ikaite in sea ice was heterogenous. We also found the precipitate in the snow on top of the sea ice.
Preoperative Mobilization of Bone Marrow-Derived Cells Followed by Revascularization Surgery: Early and Long-Term Outcome
Authors: Actis Dato Guglielmo Mario , Sansone Fabrizio , Omedé Paola , Zingarelli Edoardo , Flocco Roberto , Punta Giuseppe , Parisi Francesco , Giuseppe Forsennati Pier , Luca Bardi Gian , del Ponte Stefano , Casabona Riccardo , Tarella Corrado
Published: February 2012

Introduction

Coronary artery disease (CAD), along with its main complications such as acute myocardial infarction (AMI) and congestive heart failure (CHF), remains a serious worldwide problem and affects many patients despite the improvement of medical treatment. The possibility of the replacement of the infarcted areas by the re-generation of the myocardial cells has been long discussed and the mobilization of the stem cells from bone marrow (BMCs) to the peripheral blood (PB) induced by cytokines, represents a potential pathway to activate the regenerative process.

Patients and Methods

We describe BMC mobilization and direct/indirect revascularization in 15 patients operated on for coronary artery bypass grafting (CABG) and/or mitral valve surgery and/or ventricular remodeling combined to multiple trans-myocardial punctures (Sen technique) in ungraftable non-viable fibrotic areas.

Results

Peak values of circulating BMCs were recorded between day +4 and day +6. We had no in-hospital (0–30 days) mortality. All the patients were discharged from the ICU after a median period of 2 days while the in-hospital length of stay was 10.5+4.2 days (range 7–21) and all patients were discharged in good clinical condition. There were two sudden deaths over the mid-term, at postoperative day (POD) 32 and 45 respectively.

Conclusions

Our study suggests that the combination of BMC mobilization and CABG may be safely performed. However, considering the small series, final conclusions about the benefit of this procedure must await a larger prospective study comparing the role of cytokines alone, myocardial perforation, and the combination of both.
Supervised versus Uncontrolled Rehabilitation of Patients after Rotator Cuff Repair-Clinical and Neurophysiological Comparative Study
Authors: Lisiński Przemysław , Huber Juliusz , Wilkosz Piotr , Witkowska Alicja , Wytrążek Marcin , Samborski Wlodzimierz , Zagłoba Aleksandra
Published: February 2012

Purpose

The purpose of this study was the evaluation of the effectiveness of supervised rehabilitation in comparison to uncontrolled exercise therapy after surgical reconstruction of rotator cuff interrupted tendons.

Methods

Twenty two patients with comparable level of disability after the same type of surgery were randomly divided into two equal groups. The first group took part in a supervised therapy and the second one performed simple exercises without supervision. Clinical and neurophysiological examinations were performed prior to rehabilitation and after 20 and 40 days of treatment. The evaluation included the assessment of the pain level with visual analog scale, active range of motion with goniometer, activity of muscle's motor units at rest and during maximal effort with electromyography and transmission of motor fibers in brachial plexus with electroneurography (M-wave stimulation studies).

Results

In the group of supervised patients the active range of movement changed significantly from 26.4° to 101.5° on average for flexion with adduction while flexion with abduction improved from 21° to 95.5°. Pain sensation changed from 6.4 to 3.2. The mean resting electromyogram amplitude decreased to the greatest degree from 80.9μV to 36.8μV in trapezius muscle while maximal effort electromyogram amplitude increased in this muscle from 381.8μV to 790.9μV. The mean values of amplitudes in electroneurographical suprascapular nerve examinations increased from 536.4μV to 1691μV. No significant differences at P=0.05 were found in these parameters recorded in the patients performing uncontrolled exercises.

Conclusion

The supervised exercise therapy is more effective than uncontrolled one after the rotator cuff surgical reconstruction.
Treatment of Septic Shock with Continuous HDF Using 2 PMMA Hemofilters for Enhanced Intensity
Authors: Matsumura Yosuke , Oda Shigeto , Sadahiro Tomohito , Nakamura Masataka , Hirayama Yo , Watanabe Eizo , Abe Ryuzo , Nakada Taka-aki , Tateishi Yoshihisa , Oshima Taku , Shinozaki Koichiro , Hirasawa Hiroyuki
Published: February 2012

Purpose

Cytokines play pivotal roles in the pathophysiology of severe sepsis/septic shock, and continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF) removes cytokines efficiently and continuously, mainly through adsorption to a hemofilter membrane. The aim of this study was to investigate the clinical efficacy of enhanced intensity PMMA-CHDF in treating refractory septic shock.

Methods

Seventy-two septic shock patients admitted to the intensive care unit (ICU) underwent critical care including PMMA-CHDF. We employed enhanced intensity PMMA-CHDF to improve the cytokine removal rate by increasing the hemofilter membrane area in 10 refractory septic shock patients (enhanced intensity group, EI group; 2 extracorporeal CHDF circuits using the hemofilter with a larger membrane area of 2.1 m2). Other patients undergoing conventional PMMA-CHDF and matched for severity with the EI group, comprised a matched conventional group (MC group; using a PMMA membrane hemofilter with a membrane area of 1.0 m2; n=15). The case-control comparison was performed between the 2 groups.

Results

Enhanced intensity PMMA-CHDF significantly increased mean arterial pressure by 23.8% in 1 hour (p=0.037), decreased the blood lactate level by 28.6% in 12 hours (p=0.006), and reduced blood IL-6 level in 24 hours (p=0.005). The ICU survival rate in the EI group was significantly better than that in the MC group (60% vs. 13.3%, p=0.028).

Conclusion

Enhanced intensity PMMA-CHDF may improve hemodynamics and survival rate in patients with refractory septic shock.
Degradation Effect of Diepoxide Fixation on Porcine Endogenous Retrovirus DNA in Heart Valves: Molecular Aspects
Authors: Cyganek-Niemiec Aleksandra , Strzalka-Mrozik Barbara , Pawlus-Lachecka Lucyna , Wszolek Jolanta , Adamska Jolanta , Kudrjavtseva Julia , Zhuravleva Irina , Kimsa Malgorzata , Okla Hubert , Kimsa Magdalena , Gudek Agnieszka , Mazurek Urszula
Published: February 2012

Purpose

Xenotransplantations of porcine cells, tissues, and organs involve a risk of zoonotic viral infections in recipients, including by porcine endogenous retroviruses (PERVs), which are embedded the genome of all pigs. An appropriate preparation of porcine heart valves for transplantation can prevent retroviral infection. Therefore, the present study focuses on the effect of epoxy compounds and glutaraldehyde on the PERV presence in porcine heart valves prepared for clinical use.

Methods

Porcine aortic heart valves were fixed with ethylene glycol diglycidyl ether (EDGE) at 5°C and 25°C as well as with glutaraldehyde (GA) for 4 weeks. Salting out was used to isolate genomic DNA from native as well as EDGE- and GA-fixed fragments of valves every week. Quantification of PERV-A, PERV-B, and PERV-C DNA was performed by real-time quantitative polymerase chain reaction (QPCR).

Results

All subtypes of PERVs were detected in native porcine aortic heart valves. The reduction of the PERV-A, PERV-B, and PERV-C DNA copy numbers was observed in the heart valves which were EDGE-fixed at both temperatures, and in GA-fixed ones in the following weeks. After 7 and 14 days of EDGE cross-linking, significant differences between the investigated temperatures were found for the number of PERV-A and PERV-B copies. PERV DNA was completely degraded within the first week of EDGE fixation at 25°C.

Conclusions

EDGE fixation induces complete PERV genetic material degradation in porcine aortic heart valves. This suggests that epoxy compounds may be alternatively used in the preparation of bioprosthetic heart valves in future.
Performing Encapsulation of dsDNA and a Polymerase Chain Reaction (PCR) inside Nanocontainers Using the Inverse Miniemulsion Process
Authors: Baier Grit , Musyanovych Anna , Mailänder Volker , Landfester Katharina
Published: February 2012

We report the encapsulation of dsDNA molecules with a defined number of base pairs (476 bp and 790 bp) and their subsequent amplification by polymerase chain reaction (PCR) inside nanosized polymeric capsules/droplets. In the first set of experiments, the dsDNA template and PCR reagents were encapsulated in crosslinked potato starch using the inverse (water-in-oil) miniemulsion technique. After redispersion of the capsules in a water-surfactant mixture, PCR was performed inside the crosslinked starch nanocapsules. In the second set of experiments, the PCR was performed inside the aqueous nanodroplets before capsule formation, and then each miniemulsion droplet was covered with a polybutylcyanoacrylate (PBCA) shell which was formed through anionic polymerization directly at the droplet interface. The PCR efficiency was quantitatively evaluated by fluorescence spectroscopy, using a DNA-specific dye called SYBR® Green which intercalates between the base pairs of the dsDNA.
Combined Robotic-Assisted Retroperitoneoscopic Partial Nephrectomy and Extraperitoneal Prostatectomy. First Case Reported
Authors: Guttilla Andrea , Crestani Alessandro , Zattoni Fabio , Secco Silvia , Dal Moro Fabrizio , Valotto Claudio , Zattoni Filiberto
Published: February 2012

A 54-year-old man with a history of prostate cancer and clear cell renal cell carcinoma of the left kidney underwent concomitant robot-assisted laparoscopic partial nephrectomy and radical prostatectomy. We report, to our knowledge, the first case of a concomitant retroperitoneal robotic-assisted partial nephrectomy and extraperitoneal radical prostatectomy.
“Prostate Cancer Unit” for an Optimal Management of Prostate Cancer
Authors: Sciarra Alessandro , Salciccia Stefano , Gentilucci Alessandro , Innocenzi Michele , Alfarone Andrea , Cattarino Susanna , Ravaziol Michele , Panebianco Valeria
Published: February 2012

Prostate cancer (PC) is established as one of the most important medical problems affecting the male population. PC is the most common solid neoplasm (214 cases per 1000 men) and the second most common cause of cancer death in men. Its management involves several complex issues for both clinicians and patients. An early diagnosis is necessary to implement well-balanced therapeutic options, and the correct evaluation can reduce the risk of overtreatment with its consequential adverse effects. Breast and Prostate cancers, respectively, are the most common cancers in women and in men, and different similarities have been underlined. The paradigm of the patient consulting a multidisciplinary medical team has been an established standard approach in treating breast cancer. Such multidisciplinary approach can offer the same optional care for men with PC as it does for women with breast cancer. A multidisciplinary team (MDT) comprises healthcare professionals from different disciplines whose goal of providing optimal patient care is achieved through coordination and communication with one another. A Prostate Cancer Unit is a place where men can be cared for by specialists in PC, working together within a multi-professional team. The MTD approach guarantees a higher probability for the PC patient to receive adequate information on the disease and on all possible therapeutic strategies, balancing advantages and related side effects. The future of PC patients relies on a successful multidisciplinary collaboration between experienced physicians, which can lead to important advantages in all the phases and aspects of PC management.
Clean Vesical Intermittent Catheterization: Lubrication of Vesical Catheter through Lidocaine or Gentamicine?
Authors: Liotta Raimondo Fausto , Tarantino Maria Lucia
Published: February 2012

Introduction

The patients who undergo intermittent catheterization are at high risk of urinary tract infection. A prophylaxis method for this infection can be represented by the lubrication of urethral catheters with 0.1% gentamycin cream. This study compared the lubrication of urethral catheters with 0.1% gentamycin cream and 2% lidocaine jelly in relation to the quantitative results of the urine culture and incidence of symptomatic urinary tract infection and asymptomatic bacteriuria.

Material and Methods

Sixteen patients, divided in groups A and B, were studied. Patients in Group A were directed to lubricate the urethral catheter with 0.1% gentamicin cream, whereas in Group B with 2% lidocaine jelly. Urine cultures and urine analysis were carried out every three weeks, for four months, for a total of 5 samples. The presence or absence of bacteria or fungi, the number of colonies and the isolated types, and the leukocyturia were evaluated.

Results

No significant differences in the presence of significant bacteriuria, symptomatic urinary tract infection and asymptomatic bacteriuria were found between the two groups. Escherichia coli was the most common isolated bacterium in both groups.

Conclusions

The results of this study, in line with previous works, showed that the lubrication of urethral catheters with 0.1% gentamicin cream is not an effective alternative to reduce significant bacteriuria and prevent urinary infection in patients who undergo clean intermittent catheterization.
Semen Parameters and Hormaone Profile of Men Investigated for Infertility at Midland Fertility Centre, Ilorin, Nigeria
Authors: Jimoh A.A.G. , Olawuyi T.S. , Omotoso G.O. , Oyewopo A.O. , Dare J.K.
Published: February 2012

This study aimed at comparing the semen parameters and pattern of endocrine abnormalities in patients investigated for male infertility in our fertility centre. Hormonal assays and semen analysis were carried out, from February 2008 to April 2010. Three hundred and sixteen (316) men were evaluated out of which forty-five (45) underwent hormonal assessment, because of the abnormalities in their sperm count. Sixteen (35.6%; 16 out of 45) of the subjects were azoospermic; twenty-three (23 out of 45; 51.1%) were oligospermic with sperm count less than 20 million sperm cell/ ml; and six (n=6; 13.3%) of the subjects were normospermic, with sperm count greater than 20 million sperm cell/ ml. The mean values of the hormonal assays for azoospermia were: 21.84±1.94 (luteinizing hormone), 14.14±4.4 (follicle-stimulating hormone), 23.95±17.43 (testosterone), and 15.03±2.91 for prolactin. Hormonal assays for patients having oligospermia were as follow: luteinizing hormone (LH) 12.56±3.90, follicle-stimulating hormone (FSH) 5.96±1.17, testosterone 10.13±2.40 and prolactin 13.42±2.43, while normospermic patients had the following hormone levels: LH: 7.72±3.90, FSH: 2.93±.74, testosterone: 17.00±3.36 and, prolactin: 12.45±2.16. We conclude that infertile men with low sperm count may not always present with abnormal hormone profiles; and, male factor, in this environment, contributes a high percentage to infertility.
Current Status and Distribution of Reptiles of Sindh
Authors: Khan Muhammad Zaheer , Ghalib Syed Ali , Siddiqui Saima , Siddiqui Tanveer Fatima , Farooq Rehana Yasmeen , Yasmeen Ghazala , Abbas Darakhshan , Zehra Afsheen
Published: February 2012

In Sindh province, total 103 species of reptiles comprising of 42 Lizards, 45 Snakes, 14 Turtles, 1 species each of Tortoise, Crocodile and Gavial has been recorded. 13 key areas for the reptiles have been identified in Sindh along with three important sites viz. Karachi coast, Deh Akro Wildlife Sanctuary and Nara Wetland Complex. Some reptiles are under threat due to large scale exploitation for skin, medicinal use and as food item. Marine Turtles are threatened mainly due to habitat degradation. The common species include Indian Fringe-toad Lizard, Indian Sand Swimmer, Indian Garden Lizard, Sindh Sand Gecko, Desert Monitor and Saw-scaled Viper. Eight species are threatened and 16 species are of special conservation interest and need to be conserved.
Anti-hyperlipidemic Activity of Carissa carandas (Auct.) Leaves Extract in Egg Yolk Induced Hyperlipidemic Rats
Authors: Sumbul S. , Ahmed S. I.
Published: February 2012

The  Purpose  of  this  study  was  to  examine  the  lipid  lowering  activity  of  aqueous:  ethanol  (1:1)  extract  of Carissa  carandas  in  Egg  yolk  induced  hyperlipidemic  rats.  A  highly  significant  increase  in  the  weight  of  group C (High cholesterol  diet)  rats  was  observed  when  compared  with  control  group N (P<0.01).  The  extract  caused  a  significant reduction  in  body  weight,  Cholesterol,  Triglycerides,  HDL  and  LDL  in  hyperlipidemic  rats.  Histopathological  changes induced by  high cholesterol diet were  also significantly reduced by the  extract. The  activity of  ethanol  and water extract of C. carandas was comparable to that of atorvastatin.
Mechanisms of Cytochrome P450‐Mediated Reactions
Authors: Guengerich F. Peter
Published: February 2012

Cytochrome P450 (P450) oxidations are the most common reactions involved in the metabolism of drugs. P450 oxidations consist of two phases, oxygen activation and substrate oxidation. The latter phase has a general inherent chemistry. However, owing to rearrangements during and after oxidation, the reactions catalyze diverse processes including carbon hydroxylation, heteroatom oxygenation and dealkylation, epoxidation, and a variety of other transformations. The course of reactions is considered not to be due to inherent chemistry associated with individual P450s but due to the juxtaposition of substrates within active sites.
Cytochrome P450 Polymorphisms
Authors: Zanger Ulrich M.
Published: February 2012

The human genome comprises 57 putatively functional, protein‐coding cytochrome P450 (CYP) genes that are grouped according to their sequence similarity into 18 families and 44 subfamilies. Approximately one dozen CYP isozymes of families 1, 2, and 3 are mainly responsible for the metabolism of drugs and other xenobiotics. Large interindividual variability of these enzymes, to which both genetic and nongenetic factors contribute, is an important determinant of drug pharmacokinetics and drug response. This chapter summarizes the functional, clinical, and toxicological relevance of human P450 genetic polymorphism, which affects all drug‐metabolizing CYPs, but to a very different extent.
Flavin‐Containing Monooxygenase: The Role of Flavin‐Containing Monooxgenase in Lead Design and Selection
Authors: Cashman John R.
Published: February 2012

The flavin‐containing monooxygenase (FMO) is a drug‐metabolizing enzyme that oxygenates sulfur‐, nitrogen‐, phosphorous‐ and selenium‐containing compounds. Amines and sulfides are very prevalent in drugs and drug candidates, and FMO could play an important role in drug discovery. Generally, FMO‐mediated metabolism converts compounds to more polar, readily excreted metabolites, and this constitutes a detoxication process. However, sometimes, FMO produces electrophilic metabolites that inhibit other enzyme systems because FMO is quite recalcitrant to inhibition. Because FMO is not readily inhibited or induced, most of its functional variability is not due to environmental factors but due to genetic polymorphisms. Compared with cytochrome P450, drugs and drug candidates that are metabolized by FMO possess less potential for toxicity and adverse drug–drug interactions. Nucleophilic drugs and drug candidates are oxygenated by FMO, and some of these oxygenated metabolites can be readily retroreduced to the parent compound quite efficiently. One class of highly nucleophilic agent that is not oxygenated by FMO includes endogenous physiological nucleophiles such as glutathione or cysteine. The lack of S‐oxygenation of these physiological nucleophiles probably spares the cell from unnecessary consumption of NADPH reductive equivalents as well as from the loss of thiaphile cytoprotective agents such as glutathione. With regard to drug or drug candidate metabolism, introducing a functional group into drug candidates that are metabolized by FMO may be beneficial in drug development and might distribute the metabolism of the drug candidate over a wider set of enzymes as well as potentially provide FMO metabolites that are generally polar, nontoxic, and readily excreted. By avoiding metabolism (and bioactivation) by cytochrome P450, the prospects for increasing druglike properties and decreasing adverse drug–drug interactions of a drug candidate are likely increased. Distributing the metabolism of drugs over a wide range of metabolic processes including FMO might decrease reliance on one metabolic pathway and decrease toxicity and adverse drug–drug interactions.
UDP‐Glucuronosyltransferases: Pharmacogenetics, Functional Characterization, and Clinical Relevance
Authors: Foti Robert S. , Fisher Michael B.
Published: February 2012

UDP‐glucuronosyltransferase (UGT)‐catalyzed conjugation reactions play an important role in the metabolism of both xenobiotics and endogenous compounds. The frequency of UGT involvement in xenobiotic drug metabolism has increased as the ability to design out other routes of metabolism (i.e., cytochrome P450) has improved. To this end, the primary goal of this chapter is to serve as a compendium for the significant amount of information surrounding UGTs that has been compiled to date. Where relevant, the chapter covers expression, regulation and polymorphisms, substrates and inhibitors, active site characterization, and finally, clinical relevance of the various UGT isoforms.
ABCDrug Transporters and Their Impact on Drug Disposition/Drug Sensitivity and Resistance
Authors: Wolf Steven J. , Lee Caroline G.
Published: February 2012

The “ATP‐binding cassette” superfamily of proteins comprises 49 members, each possessing evolutionarily conserved sequence motifs that lie in the proteins nucleotide (ATP) binding domain. Each member is further classified into seven subclasses (A–G). Most ABC proteins function as membrane‐bound efflux pumps, transporting various small‐molecule substrates from the cytoplasm to the extracellular space; however, there are some exceptions (ABCE and ABCF). A vast array of drugs used in the treatment of diseases such as cancer, HIV, and epilepsy are known substrates of one or more ABC transport pumps. Consequently, the impact of the ABC transport pumps on drug efficacy and resistance has been widely assessed and is explored in this chapter from various perspectives. A focus on cancer drug resistance and the influence of the key ABC proteins ABCB1, ABCC1, ABCC2, and ABCG2 is presented along with a look into the contributions of these proteins to adverse reactions. The chapter concludes with a look into the genetics of the ABC transport pumps, including the genetic regulation of these proteins. The influence of single nucleotide polymorphisms identified within theABCgenes on the efficacy of drugs is discussed in depth. Lastly, the chapter assesses disease states that arise from abnormalities in ABC genes.
Physiologically Based Pharmacokinetic (PBPK) Modeling: Usefulness and Applications
Authors: Maeng Han‐Joo , Chow Edwin C. Y. , Fan Jianghong , Pang K. Sandy
Published: February 2012

Physiologically based pharmacokinetic (PBPK) models are increasingly being used to describe and define more meaningful parameters that relate to physiology, anatomy, and biochemistry in the prediction of pharmacokinetic (PK) profiles and tissue concentration–time profiles of the parent drug and metabolites and to provide mechanistic insight into drug dynamics. Physiological data (blood flow rates and tissue volumes), physical data (protein binding and tissue partition coefficients), and biochemical data (Michaelis–Menten parameters for transporters and enzymes,Vmax/Km) are the information required for building a PBPK model. The whole‐body PBPK model approach is extremely useful to understand sequential metabolism, the kinetics of metabolites, and examine effects of the transporter and enzyme interplay on the blood and target organ exposures of the drug and its metabolites. The application of PBPK models allows one to make predictions of the exposure in target sites, pharmacological activity, or toxicity and the effects of age, pregnancy, disease states, and drug–drug interactions (DDIs). In this chapter, many cases for the application and usefulness of PBPK models are summarized.
ADME of Herbal Dietary Supplements
Authors: PaiBir Sheela , Rahavendran Sadayappan V.
Published: February 2012

In spite of modern medical advances, herbal dietary supplements continue to be widely used for health maintenance, disease prevention, and even disease treatment. The ADME mechanisms for the known herb–drug interactions involve, in most cases, inhibition or induction of hepatic and intestinal drug‐metabolizing enzymes of the cytochrome P450 family, and/or drug transporters. This chapter provides a review of the potential for herb–drug interactions based on literature reports for those herbs that are most popularly used in the United States. Relevant clinical and humanin vitrostudies that have evaluated metabolism‐based or absorption‐based mechanisms to understand the interactions between these herbs and commonly used drugs are also reviewed.
Safety Testing of Drug Metabolites: A Practical Approach for the Implementation of the
MIST
Guidance in
PKDM
Authors: Subramanian Raju , Slatter J. Greg
Published: February 2012

The FDA Safety Testing of Drug Metabolites Guidance and the ICH Requirements for Registration of Pharmaceuticals for Human Use (ICH M3) guidance defined threshholds for metabolite exposure in humans and preclinical species, which (ICH M3) would indicate that preclinical species were exposed adequately to quantitatively significant human metabolites. Proactive, data‐driven, best practices were developed by consensus with key development partners. Nontraditional metabolism approaches such as nonradiometric high resolution‐mass spectrometry (HR‐MS) profiling of plasma metabolites across species were developed to enable timely drug development decision making.
Proteomics in Drug Discovery and Development
Authors: Wang Mu , Witzmann Frank A.
Published: February 2012

Aided by major technological advances, the field of proteomics has become extremely active in the identification of drug targets that can guide drug development and treatment decisions and ultimately improve treatment outcomes. Proteomics has provided a means for molecular profiling that will assist in the development of tailored therapies. Although the implementation of genomic and proteomic testing in clinical practice is still in its infancy, the rapid development of new technologies and platforms provides hope for personalized medicine. This chapter describes these technologies and platforms, presenting many of their technical aspects along with examples of how they have been implemented in pharmaceutical applications.
Idiosyncratic Drug Reactions
Authors: Wojcinski Zbigniew W. , Uetrecht Jack P.
Published: February 2012

Idiosyncratic drug reactions (IDRs) are adverse drug reactions that are not related to the known pharmacological properties of the drug occur in only a small percentage of the population and do not show any apparent dose–response relationship. The unpredictable nature of IDRs together with the often serious adverse effects encountered pose a major health concern in the development and clinical usage of pharmaceuticals. The mechanism of IDRs is not clearly understood, and although several theories have been proposed, IDRs can be generally categorized mechanistically as either immune mediated or non‐immune‐mediated. There is circumstantial evidence that suggests that most idiosyncratic reactions are hypersensitivity reactions initiated by the formation of chemically reactive metabolites that bind to proteins and induce an immune‐mediated response. Investigations in animal models have had limited success owing to the unpredictability of IDRs in animals, which is similar to the situation in humans. However, IDRs in animals do share some similar characteristics and mechanisms observed in humans supporting the need for further study of animal models.
Gas‐Phase Ion Mobility‐Mass Spectrometry (IM‐MS) and TandemIM‐MS/MSStrategies for Metabolism Studies and Metabolomics
Authors: May Jody C. , Goodwin Cody R. , McLean John A.
Published: February 2012

This chapter describes the current and potential impact of ion mobility‐mass spectrometry (IM‐MS) for addressing the challenges of sample complexity, dynamic range, and throughput for metabolomics experiments. The four primary ion mobility techniques are described with regard to their defining analytical figures‐of‐merit. Tandem MS methods are reviewed, and novel tandem experiments made possible from multi stage activation in IM‐MS instrumentation are discussed in light of the additional information, such experiments provide for the analysis of metabolites.
Analytical Method Development and Validation in Accordance to the Regulatory Guidelines
Authors: Unger Steve E.
Published: February 2012

Best practices and detailed requirements to perform LCMS bioanalysis for submission to regulatory agencies are defined in this chapter. The rationale for regulations is discussed, along with recommendations on achieving compliance. Novel drug candidates, new technology, and innovative processes continue to change LCMS bioanalysis. The evolution of global regulatory guidance is also shaping bioanalysis to test assays in a more consistent and thorough manner. Common procedures are now in place for validation and sample analysis of both large and small molecules, allowing consistent review of new drug applications. Influence from GMPs is seen in incurred sample reanalysis and associated out‐of‐specification investigations in bioanalysis. The nature of regulated bioanalysis is ever changing as new methodology and guidance challenges past practices.
Role and Clinical Consequences of HumanUDP‐Glucuronosyltransferases
Authors: Dalvie Deepak K. , Loi Cho‐Ming
Published: February 2012

Uridine 5′‐diphosphate‐glucuronosyltransferases (UGT) are a family of enzymes that catalyze the conjugation of various drugs and endogenous substances. UGTs contribute to multiple important physiologic functions in the body and serve as an important detoxification pathway for certain drugs. In addition to their abundance in the liver and kidneys, UGTs are also expressed in several other organs including the GI tract. Given their importance in the disposition of drugs and their ubiquitous nature, they have the potential to influence the pharmacokinetics and biological effects of drugs. In addition to detoxification, UGTs are also responsible in metabolically activating compounds to reactive metabolites such as the acyl glucuronides that have the potential to covalently bind to macromolecules and elicit deleterious effects. As the cytochrome P450s (CYPs), UGTs are also subject to genetic polymorphisms and drug‐drug interactions (DDIs), which can impact the clinical development of drugs. This chapter presents an overview of the role and clinical consequences of metabolism of drugs by UGT.
Herb–Drug and Food–Drug Interactions
Authors: Lennard Martin S.
Published: February 2012

Medication with plants and herbs has been practiced for thousands of years, and a substantial proportion of the world's population is thought to use herbal medicines. Herbal medicines are likely to be taken with prescribed drugs, leading to the risk of herb–drug interactions. Herbal consumption can not only diminish the therapeutic effect of drugs but also give rise to adverse reactions and toxicity. These clinical effects are caused by changes in (i) pharmacokinetics, particularly through inhibition or induction of the cytochrome P450 drug‐metabolizing enzymes, and (ii) drug receptor sensitivity. There are many instances where food itself and its constituents have been shown to influence the pharmacokinetics of and response to drugs, sometimes causing substantially diminished therapeutic effects or adverse reactions. Much of the published evidence on herb–drug and food–drug interactions is based on case reports or on pharmacokinetic data alone, and these require substantiation by studies measuring the clinical effects of drugs.
An inherited disorder with splenomegaly, cytopenias, and vision loss
Authors: Tantravahi Srinivas K. , Williams Lloyd B. , Digre Kathleen B. , Creel Donnell J. , Smock Kristi J. , DeAngelis Margaret M. , Clayton Frederic C. , Vitale Albert T. , Rodgers George M.
Published: February 2012

We describe a novel inherited disorder consisting of idiopathic massive splenomegaly, cytopenias, anhidrosis, chronic optic nerve edema, and vision loss. This disorder involves three affected patients in a single non‐consanguineous Caucasian family, a mother and two daughters, who are half‐sisters. All three patients have had splenectomies; histopathology revealed congestion of the red pulp, but otherwise no abnormalities. Electron microscopic studies of splenic tissue showed no evidence for a storage disorder or other ultrastructural abnormality. Two of the three patients had bone marrow examinations that were non‐diagnostic. All three patients developed progressive vision loss such that the two oldest patients are now blind, possibly due to a cone‐rod dystrophy. Characteristics of vision loss in this family include early chronic optic nerve edema, and progressive vision loss, particularly central and color vision. Despite numerous medical and ophthalmic evaluations, no diagnosis has been discovered. © 2012 Wiley Periodicals, Inc.
Niedermolekulare Stabilisatoren von Protein‐Protein‐Wechselwirkungen: ein unterschätztes Konzept in der Wirkstoffentwicklung?
Authors: Thiel Philipp , Kaiser Markus , Ottmann Christian
Published: February 2012

Die Modulation von Protein‐Protein‐Wechselwirkungen (PPIs) galt lange Zeit als eine der größten Herausforderungen der Wirkstoffentwicklung. Jedoch hat sich die Ansicht, dass deren zielgerichtete Entwicklung unmöglich ist, in den letzten Jahren grundlegend geändert, und erste Wirkstoffkandidaten befinden sich bereits in klinischer Prüfung. Zurzeit handelt es sich bei der überwiegenden Mehrheit dieser PPI‐Modulatoren um Wechselwirkungsinhibitoren. Allerdings wäre in vielen biologischen Zusammenhängen eine verlängerte Lebensdauer von PPIs wünschenswert, sodass der komplementäre Ansatz – die Stabilisierung von PPIs – zunehmend in den Brennpunkt rückt. Interessanterweise liefert die Natur bereits eindrucksvolle Beispiele für diesen Ansatz, von denen einige schon als Medikamente zugelassen sind. Darüber hinaus konnte kürzlich erstmals gezeigt werden, dass auch eine zielgerichtete Entwicklung niedermolekularer PPI‐Stabilisatoren möglich ist. Somit ist es an der Zeit, die konstruktive Seite der Modulation von PPIs genauer in den Blick zu nehmen.
Small‐Molecule Stabilization of Protein–Protein Interactions: An Underestimated Concept in Drug Discovery?
Authors: Thiel Philipp , Kaiser Markus , Ottmann Christian
Published: February 2012

The modulation of protein–protein interactions (PPIs) has been recognized as one of the most challenging tasks in drug discovery. While their systematic development has long been considered as intractable, this view has changed over the last years, with the first drug candidates undergoing clinical studies. To date, the vast majority of PPI modulators are interaction inhibitors. However, in many biological contexts a prolonged lifespan of a PPI might be desirable, calling for the complementary approach of PPI stabilization. In fact, nature offers impressive examples of this concept and some PPI‐stabilizing natural products have already found application as important drugs. Moreover, directed small‐molecule stabilization has recently been demonstrated. Therefore, it is time to take a closer look at the constructive side of modulating PPIs.
Allenes in Molecular Materials
Authors: Rivera‐Fuentes Pablo , Diederich François
Published: February 2012

This Minireview provides a critical account of the development of allene‐containing advanced functional materials, starting with the design and synthesis of stable and enantiopure building blocks. A variety of systems, including shape‐persistent macrocycles, foldamers, polymers, charge‐transfer chromophores, dendrimers, liquid crystals, and redox‐switchable chiral chromophores are discussed from the viewpoint of their syntheses, properties, and potential applications. The goal of this Minireview is to inspire new uses of enantiopure allenes for the rational design of advanced materials.
Synthesis and characterization of polysulfone/clay nanocomposite membranes for fuel cell application
Authors: Unnikrishnan Lakshmi , Mohanty Smita , Nayak Sanjay K. , Singh Nishant
Published: February 2012

In the present investigation, polysulfone (PSu) nanocomposites were successfully prepared by solvent casting method. Layered silicates, viz., sodium montmorillonite (NaMMT), Cloisite 93A, and Cloisite 30B were dispersed in PSu to obtain nanocomposite membranes. PSu nanocomposite membranes were tested for mechanical performance, water uptake, thermal properties, X‐ray diffraction, and scanning electron microscopy (SEM). The nanocomposite membranes showed an increment in tensile properties, whereas a reduction was observed in water uptake. X‐ray diffraction studies confirmed the intercalation of PSu within the silicate galleries. SEM analysis confirmed an increase in the porosity of the membrane with the incorporation of nanoclays. Thermo gravimetric analysis (TGA) thermograms indicated an increase in the thermal stability of PSu nanocomposites. Evaluation of conductivity characteristics and single cell performance revealed improved output for organomodified clay nanocomposites. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012