bluuebunny/crossref_metadata_2025 huggingface dataset:
Automated analysis of information processing, kinetic independence and modular architecture in biochemical networks using MIDIA
Authors: Bowsher Clive G.
Published: December 2010

Motivation: Understanding the encoding and propagation of information by biochemical reaction networks and the relationship of such information processing properties to modular network structure is of fundamental importance in the study of cell signalling and regulation. However, a rigorous, automated approach for general biochemical networks has not been available, and high-throughput analysis has therefore been out of reach.

Results: Modularization Identification by Dynamic Independence Algorithms (MIDIA) is a user-friendly, extensible R package that performs automated analysis of how information is processed by biochemical networks. An important component is the algorithm's ability to identify exact network decompositions based on both the mass action kinetics and informational properties of the network. These modularizations are visualized using a tree structure from which important dynamic conditional independence properties can be directly read. Only partial stoichiometric information needs to be used as input to MIDIA, and neither simulations nor knowledge of rate parameters are required. When applied to a signalling network, for example, the method identifies the routes and species involved in the sequential propagation of information between its multiple inputs and outputs. These routes correspond to the relevant paths in the tree structure and may be further visualized using the Input–Output Path Matrix tool. MIDIA remains computationally feasible for the largest network reconstructions currently available and is straightforward to use with models written in Systems Biology Markup Language (SBML).

Availability: The package is distributed under the GNU General Public License and is available, together with a link to browsable Supplementary Material, at http://code.google.com/p/midia. Further information is at www.maths.bris.ac.uk/~macgb/Software.html.

Contact:  C.Bowsher@bristol.ac.uk

Supplementary information: The Supplementary Material contains extensive description of the MIDIA package and is available at Bioinformatics online.
Using bioinformatics to predict the functional impact of SNVs
Authors: Cline Melissa S. , Karchin Rachel
Published: December 2010

Motivation: The past decade has seen the introduction of fast and relatively inexpensive methods to detect genetic variation across the genome and exponential growth in the number of known single nucleotide variants (SNVs). There is increasing interest in bioinformatics approaches to identify variants that are functionally important from millions of candidate variants. Here, we describe the essential components of bionformatics tools that predict functional SNVs.

Results: Bioinformatics tools have great potential to identify functional SNVs, but the black box nature of many tools can be a pitfall for researchers. Understanding the underlying methods, assumptions and biases of these tools is essential to their intelligent application.

Contact:  karchin@jhu.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Classification of Sturm–Liouville differential equations with complex coefficients and operator realizations
Authors: Qi Jiangang , Zheng Zhaowen , Sun Huaqing
Published: December 2010

In this paper, a new classification of Sturm–Liouville differential equations with complex coefficients is given. Compared with the corresponding result of Brown
et al
., this classification reveals the great effects of rotation angle and it is independent of the rotation angles. Moreover, the asymptotic behaviours of functions in the maximal domain are presented and
J
-self-adjoint extensions associated with the differential equations are characterized.
Duality of privacy amplification against quantum adversaries and data compression with quantum side information
Authors: Renes Joseph M.
Published: December 2010

Information processing protocols are typically built out of simpler parts, called primitives, and two of the most important such primitives are privacy amplification (PA) and data compression. The former extracts the truly secret part of some classical data, while the latter squeezes it into the smallest possible form. We show these tasks are dual in the setting of quantum information processing. Specifically, the tasks of PA of classical information against quantum adversaries and classical data compression with quantum side information are dual in the sense that the ability to perform one implies the ability to perform the other. The duality arises because the two protocols are connected by complementarity and the uncertainty principle in the quantum setting. Applications include a new uncertainty principle formulated in terms of smooth min- and max-entropies, which are useful in the study of one-shot protocols, as well as new conditions for approximate quantum error correction.
Climate change correlates with rapid delays and advancements in reproductive timing in an amphibian community
Authors: Todd Brian D. , Scott David E. , Pechmann Joseph H. K. , Gibbons J. Whitfield
Published: December 2010

Climate change has had a significant impact globally on the timing of ecological events such as reproduction and migration in many species. Here, we examined the phenology of reproductive migrations in 10 amphibian species at a wetland in South Carolina, USA using a 30 year dataset. We show for the first time that two autumn-breeding amphibians are breeding increasingly later in recent years, coincident with an estimated 1.2°C increase in local overnight air temperatures during the September through February pre-breeding and breeding periods. Additionally, two winter-breeding species in the same community are breeding increasingly earlier. Four of the 10 species studied have shifted their reproductive timing an estimated 15.3 to 76.4 days in the past 30 years. This has resulted in rates of phenological change that range from 5.9 to 37.2 days per decade, providing examples of some of the greatest rates of changing phenology in ecological events reported to date. Owing to the opposing direction of the shifts in reproductive timing, our results suggest an alteration in the degree of temporal niche overlap experienced by amphibian larvae in this community. Reproductive timing can drive community dynamics in larval amphibians and our results identify an important pathway by which climate change may affect amphibian communities.
Bioluminescent signals spatially amplified by wavelength-specific diffusion through the shell of a marine snail
Authors: Deheyn Dimitri D. , Wilson Nerida G.
Published: December 2010

Some living organisms produce visible light (bioluminescence) for intra- or interspecific visual communication. Here, we describe a remarkable bioluminescent adaptation in the marine snailHinea brasiliana. This species produces a luminous display in response to mechanical stimulation caused by encounters with other motile organisms. The light is produced from discrete areas on the snail's body beneath the snail's shell, and must thus overcome this structural barrier to be viewed by an external receiver. The diffusion and transmission efficiency of the shell is greater than a commercial diffuser reference material. Most strikingly, the shell, although opaque and pigmented, selectively diffuses the blue-green wavelength of the species bioluminescence. This diffusion generates a luminous display that is enlarged relative to the original light source. This unusual shell thus allows spatially amplified outward transmission of light communication signals from the snail, while allowing the animal to remain safely inside its hard protective shell.
Dramatic colour changes in a bird of paradise caused by uniquely structured breast feather barbules
Authors: Stavenga Doekele G. , Leertouwer Hein L. , Marshall N. Justin , Osorio Daniel
Published: December 2010

The breast-plate plumage of male Lawes' parotia (Parotia lawesii) produces dramatic colour changes when this bird of paradise displays on its forest-floor lek. We show that this effect is achieved not solely by the iridescence—that is an angular-dependent spectral shift of the reflected light—which is inherent in structural coloration, but is based on a unique anatomical modification of the breast-feather barbule. The barbules have a segmental structure, and in common with many other iridescent feathers, they contain stacked melanin rodlets surrounded by a keratin film. The unique property of the parotia barbules is their boomerang-like cross section. This allows each barbule to work as three coloured mirrors: a yellow-orange reflector in the plane of the feather, and two symmetrically positioned bluish reflectors at respective angles of about 30°. Movement during the parotia's courtship displays thereby achieves much larger and more abrupt colour changes than is possible with ordinary iridescent plumage. To our knowledge, this is the first example of multiple thin film or multi-layer reflectors incorporated in a single structure (engineered or biological). It nicely illustrates how subtle modification of the basic feather structure can achieve novel visual effects. The fact that the parotia's breast feathers seem to be specifically adapted to give much stronger colour changes than normal structural coloration implies that colour change is important in their courtship display.
The ‘spiteful’ origins of human cooperation
Authors: Marlowe Frank W. , Berbesque J. Colette , Barrett Clark , Bolyanatz Alexander , Gurven Michael , Tracer David
Published: December 2010

We analyse generosity, second-party (‘spiteful’) punishment (2PP), and third-party (‘altruistic’) punishment (3PP) in a cross-cultural experimental economics project. We show that smaller societies are less generous in the Dictator Game but no less prone to 2PP in the Ultimatum Game. We might assume people everywhere would be more willing to punish someone who hurt them directly (2PP) than someone who hurt an anonymous third person (3PP). While this is true of small societies, people in large societies are actually more likely to engage in 3PP than 2PP. Strong reciprocity, including generous offers and 3PP, exists mostly in large, complex societies that face numerous challenging collective action problems. We argue that ‘spiteful’ 2PP, motivated by the basic emotion of anger, is more universal than 3PP and sufficient to explain the origins of human cooperation.
An evaluation of the proposed DSM‐5 alcohol use disorder criteria using Australian national data
Authors: Mewton Louise , Slade Tim , McBride Orla , Grove Rachel , Teesson Maree
Published: December 2010

Aims  To evaluate the proposed revisions to the DSM‐IV alcohol use disorder criteria using epidemiological data.

Design, setting and participants  Data came from the 1997 Australian National Survey of Mental Health and Well‐Being. The sample consisted of 10 641 participants aged 18 years and over.

Measurements  Alcohol use disorders were assessed using a revised version of the CIDI version 2.0. Alcohol use disorders were assessed in all respondents who indicated that they had used alcohol more than 12 times in the previous 12 months (n = 7746).

Findings  The proposed introduction of a single alcohol use disorder was supported by confirmatory factor analysis (CFA). DSM‐5 criteria were all indicators of a single underlying disorder. Under DSM‐5, the prevalence of alcohol use disorders would increase by 61.7% when compared with those diagnosed under DSM‐IV. When investigating the most appropriate diagnostic threshold, the 3+ threshold maximized agreement between DSM‐IV and DSM‐5 diagnoses, and produced similar prevalence estimates to those yielded by DSM‐IV. Item response theory (IRT) analyses supported the removal of the legal criterion while provided equivocal results for the craving criterion.

Conclusions  Under the proposed DSM‐IV revisions for alcohol use disorders, estimates of the prevalence in the general population would increase substantially. Whereas evidence supports some of the revisions such as a single underlying disorder, others such as the 2+ threshold for diagnosis of alcohol use disorder and the inclusion of a ‘craving’ criterion may be problematic.
The clinical impact of combining intermittent preventive treatment with home management of malaria in children aged below 5 years: cluster randomised trial
Authors: Tagbor Harry , Cairns Matthew , Nakwa Emmanuel , Browne Edmund , Sarkodie Badu , Counihan Helen , Meek Sylvia , Chandramohan Daniel
Published: December 2010

Objective  To investigate the impact of seasonal intermittent preventive treatment (IPTc) on malaria‐related morbidity in children <5 years of age who already had access to home‐based management of malaria (HMM) for presumptive treatment of fevers.

Method  Thirty community‐based drug distributors (CDDs) from all 13 communities of a rural subdistrict in Ghana were trained to provide prompt treatment for presumptive malaria using artesunate‐amodiaquine (AS+AQ) to all children under 5 years of age. Six communities were randomised to also receive bimonthly courses of seasonal IPTc with AS+AQ in May, July and September of 2007. The primary outcome was the incidence rate of febrile episodes diagnosed presumptively as malaria by the CDDs in the communities in each intervention group. Cross‐sectional surveys were conducted to determine the prevalence of parasitaemia and anaemia among the study children.

Results  During the 6 months in which IPTc was delivered, incidence of fevers in communities given HMM+IPTc was lower than in communities given HMM alone, but this difference was not statistically significant (protective efficacy: 37.0%(95% CI: −9.7 to 63.8; P = 0.14). However, incidence of presumptive malaria was significantly lower in IPTc communities when only children who received all three courses of IPTc were included in the analysis: protective efficacy 61.5% (95% CI:31.2–78.5; P = 0.018). Protection with IPTc was not followed by rebound morbidity in the following year. At the end of the intervention period, prevalence of asymptomatic parasitaemia was lower in communities that had received IPTc, but there were no differences in anaemia or haemoglobin concentration.

Conclusion  In this study area, incidence of fevers was lower in communities given three courses of IPTc during the time of peak transmission than in communities that received only HMM. However, high levels of coverage for IPTc will be necessary for maximum impact.
Disturbed energy metabolism after lung and heart transplantation
Authors: Forli Liv , Bollerslev Jens , Simonsen Svein , Isaksen Gunhild A. , Godang Kristin , Pripp Are H. , Bjortuft Oystein
Published: December 2010

Forli L, Bollerslev J, Simonsen S, Isaksen GA, Godang K, Pripp AH, Bjortuft O. Disturbed energy metabolism after lung and heart transplantation.  Clin Transplant 2011: 25: E136–E143. © 2010 John Wiley & Sons A/S.

Abstract:  Overweight, in combination with other cardiovascular risk factors, reduces survival after transplantation. The aim of this prospective study was to observe leptin, adiponectin, and energy intake as predictors of body mass index (BMI) and body composition and as risk factors associated with metabolic syndrome after lung and heart transplantation. After pre‐operative baseline investigations, 35 lung and 59 heart recipients were followed and re‐investigated two, six, and 12 months after transplantation. Linear regressions were performed to predict BMI and body composition. The lung recipients had a substantial weight gain after transplantation. Leptin increased, especially in the lung recipients and positively predicted BMI. Energy intake predicted BMI before and at two months after transplantation, but not after 12 months. Percentage trunk fat increased and lean mass decreased. Before transplantation, the dominant determinant of lean mass was adiponectin (positively associated), while after it was leptin (negatively associated), controlled for possible confounding variables (including prednisolone). Metabolic syndrome 12 months after transplantation was associated with higher leptin, greater weight gain without increased energy intake. After transplantation, a disturbed energy metabolism is indicated, where adiponectin and especially leptin are involved and a disadvantageous body composition is favored with increased body fat and decreased lean mass.
Host plant effects on morphometric characteristics of Liriomyza huidobrensis, L. sativae and L. trifolii (Diptera: Agromyzidae)
Authors: Musundire R. , Chabi‐Olaye A. , Krüger K.
Published: December 2010

Body size of herbivorous insects may be directly related to host plant characteristics (e.g. nutrition, chemical composition) and positively linked to performance of the herbivore and its parasitoids. Differences in adult body size of Liriomyza huidobrensis, L. sativae and L. trifolii reared on Pisum sativum, Phaseolus vulgaris, Vicia faba and Solanum lycopersicum were assessed to determine the effect of host plants on adult size. Furthermore, morphometric wing and hind tibia measurements were used to determine suitability as proxy measures for adult size. Based on canonical and linear discriminant analyses, two distinct Liriomyza morphospecies groups were recognized across all plant species. The first cluster represented L. huidobrensis and the second L. sativae and L. trifolii. The overall degree of correct classification of the three species across all plants tested (correct observation) with cross validation was estimated at 85%. Liriomyza huidobrensis, the largest species, showed no differences in the variables measured when reared on the four plant species. However, different plant species seem to influence wing and hind tibia measurements in L. trifolii to a greater extent than in L. huidobrensis and L. sativae. The first two canonical variates could not separate the populations of L. huidobrensis and L. sativae reared on different plant species, but showed separation of L. trifolii populations into two clusters: firstly, insects reared on V. faba and secondly, insects reared on P. vulgaris and S. lycopersicum. Hind tibia length strongly correlated with wing length. Both can be used to determine adult size of the three Liriomyza species. This study provides some new evidence for the existence of differential preferences by Liriomyza species for the four host plant species. This, therefore, warrants larger scale field studies to test for positive preference‐performance of Liriomyza species on these plant species and to determine possible consequences at the third tritrophic level.
Species distribution models for the alien invasive Asian Harlequin ladybird (Harmonia axyridis)
Authors: Bidinger K. , Lötters S. , Rödder D. , Veith M.
Published: December 2010

The Asian Harlequin ladybird (Harmonia axyridis) is a globally invasive alien species. We developed species distribution models (SDMs) aiming at an explanation of the observed native and invasive distributions and the prediction of the species’ potential distribution. SDMs were built based on bioclim parameters with Maxent (i) on known native occurrence only (SDMnat), (ii) on known European invasive occurrence only (SDMinv) and (iii) by combining both previous approaches (SDMall). Results indicate that SDMinvmatch the observed European invasive range better than SDMnator SDMall. The origin of Asian founders in Europe remains unknown. SDMinvhighlighted a restricted area in China which may represent the region of origin of the European Harlequin ladybird, leaving the possibility of within‐species climate niche variation. As a result, when targeting the worldwide potential of invasiveness ofH. axyridis, SDMallmay reveal maximum results uncovering the species’ potential distribution. These results have to be seen in the framework of conceptual problems and pitfalls when generating SDMs including niche definition, niche shift, sampling bias, biological importance of predictors and model transferability uncertainties.
Genetic architecture of plant height in winter rye introgression libraries
Authors: Miedaner T. , Müller B. U. , Piepho H.‐P. , Falke K. C.
Published: December 2010

With 4 figures and 1 table

Plant height is an important trait for breeding and as fitness criterion in natural populations of rye (Secale cereale L.). Our objectives were to investigate the inheritance of plant height in rye introgression libraries and estimate the covariation between per se and testcross performance. Two introgression libraries containing each of 40 BC2S3 candidate introgression lines (pre‐ILs) were tested at five locations in two years for per se and testcross performance. Donor population was the Iranian primitive rye accession Altevogt 14160. Plant height of the donor population was 145 ± 3.6 cm as population and 152 ± 2.9 and 132 ± 2.8 cm when crossed to the two testers, respectively. Pre‐ILs were much closer to the recurrent parent, but still most of them exceeded the recurrent parent in per se performance. Estimates of the genotypic variance were significant (P = 0.01) for both per se and testcross performance. Entry‐mean heritabilities were high in both libraries (0.97 and 0.94, respectively). Donor chromosome segments (DCS) of 59 of 72 pre‐ILs had a significant (P = 0.05) effect on plant height compared to the recurrent parent. For the testcrosses, 10 pre‐ILs still contributed DCS with significantly (P = 0.05) taller effects. Genotypic correlations between pre‐ILs per se and as testcrosses were moderate for the two testers. In conclusion, plant height per se has a complex inheritance with many loci spread across the entire genome. Hybrid breeding, however, facilitates the use of genetic resources because the tallness is less pronounced in the testcrosses.
Development and characterization of genomic microsatellite markers in safflower (Carthamus tinctorius L.)
Authors: Hamdan Y. A. S. , García‐Moreno M. J. , Redondo‐Nevado J. , Velasco L. , Pérez‐Vich B.
Published: December 2010

With 2 tables

Specific and robust marker resources available for safflower breeding are scarce. The present research was aimed at developing a collection of genomic microsatellite (SSR) markers and to assess their informativeness. A genomic library enriched for AC‐ and AG‐ repeats was constructed from safflower DNA. Around 35% of the 768 clones that were isolated and sequenced contained SSR sequences. From these, 108 unique primer pairs were designed. The majority of the SSRs contained simple di‐nucleotide motifs (77 of 108), most of them being perfect repeats (63 of 77). Reference allele length ranged from 95 to 414 bp, averaging 241.2 bp. The 108 SSRs were amplified in a set of ten safflower lines. From 88 SSR markers that amplified successfully, 64 of them detected polymorphism among the ten safflower lines genotyped. The number of alleles per locus ranged from 2 to 8 (mean value of 3.2), whereas heterozygosity ranged from 0.18 to 0.86 (mean value of 0.52). These genomic SSR markers will contribute to advance in safflower molecular breeding.
Molecular characterization and expression analysis of ADAM12 during chicken embryonic development
Authors: Lin Juntang , Luo Jiankai , Redies Christoph
Published: December 2010

ADAM12 is a member of the disintegrin and metalloprotease (ADAM) family of molecules, which consist of multiple domains. ADAM12 is involved in different physiological and pathological processes. In the present study, full‐length sequences of two chicken ADAM12 isoforms were cloned and identified by reverse transcription–polymerase chain reaction (RT–PCR), rapid amplification of cDNA ends methods and bioinformatics analysis. The long isoform consists of all domains characteristic for ADAMs and is strongly expressed in different tissues, whereas the short isoform lacks large parts of the metalloprotease and disintegrin domains and is only expressed weakly. Results from semi‐quantitative RT–PCR show that the complete ADAM12 is stably expressed throughout chicken embryonic development, while the short isoform is only regionally detectable in the lung and brain. Results from in situ hybridization show that chicken ADAM12 is expressed exclusively in tissues and organs derived from the neural tube, the neural crest or the mesoderm, with a highly regulated spatiotemporal expression pattern. Our data confirm and extend studies of ADAM12 in other species, and suggest that ADAM12 may play a role in the development of several organs, including the formation of feather buds.
Role of preoperative platelet level in clinical and pathological outcomes after surgery for renal cortical malignancies
Authors: Wosnitzer Matthew , Polland Allison , Hai Qiong , Hruby Gregory , McKiernan James
Published: December 2010

Study Type – Therapy (case series)  Level of Evidence 4

What's known on the subject? and What does the study add?

Preoperative platelet count (PLT), which reflects the systemic inflammatory response, has been previously identified in several small studies as useful prognostic factor in a number of cancers including renal cell carcinoma. This study is the largest study to our knowledge to investigate the relationship between platelets and surgical outcomes in patients with renal cell carcinoma. Thrombocytosis (PLT > 400) was associated with and was an independent predictor of decreased overall and disease‐specific survival in patients undergoing extirpative renal surgery, and was associated with larger tumour size, and higher TNM stage at surgery.

OBJECTIVE • To investigate preoperative platelet level (PLT) as a prognostic factor for pathologic and clinical outcomes following surgery for renal cortical malignancy.

PATIENTS AND METHODS • 1422 patients underwent radical or partial nephrectomy at our institution from 1988–2009 for renal cortical lesions.

• The cohort with available PLT values was divided into group 1 (PLT ≤ 400 × 109) and (PLT > 400 × 109) based on institutional laboratory upper threshold (400 × 109 cells/liter).

RESULTS • 961 patients were divided into groups 1 (n = 870) and 2 (n = 91), with mean age at surgery of 61 and 60 years, 70.6% and 50.6% males (P ≤ 0.0001), 56% undergoing radical nephrectomy in each group, 39.1% vs. 22% undergoing partial nephrectomy (P = 0.001) respectively.

• Groups differed significantly inmedian tumour size (5.06 vs. 7.28 cm) (P ≤ 0.001), pathologic T stage (P = 0.002), and metastases (P ≤ 0.0001). No significant difference existed regarding histologic findings at surgery.

• With median follow‐up of 24 months, PLT > 400 × 109 cells/liter was associated with decreased overall (OS) and disease‐specific survival (DSS) using log rank test (P ≤ 0.0001).

• On multivariate analysis, controlling for TNM stage, histology, and tumour diameter, PLT > 400 × 109cells/liter independently predicted decreased OS (HR 1.67, P = 0.007) and DSS (HR 2.39, P = 0.001). As a continuous variable, PLT predicted OS (HR 1.002, P = 0.005) and DSS (HR 1.003, P =  0.004).

• With metastatic patients excluded, PLT was significantly associated with OS and DSS, but was not an independent predictor.

CONCLUSION • PLT is a clinically significant independent predictor of OS and DSS in continuous and categorical analyses in patients undergoing renal cortical malignancy surgery. PLT may be clinically useful for risk stratifying patients undergoing surgery for renal cancer, especially for prognosis assessment of patients with renal cortical malignancy and micrometastatic disease at surgery.
The risk profiles of three clinical types of carcinoma in situ of the bladder
Authors: Meijer Richard P. , van Onna Ilze E.W. , Kok Esther T. , Bosch Ruud
Published: December 2010

Study Type – Therapy (individual cohort)

Level of Evidence 2b

What’s known on the subject? and What does the study add?

Although it has been reported that patients with primary carcinoma in situ of the bladder (CIS) have a better prognosis than patients with concomitant or secondary CIS, the risk profiles of these three clinical types of CIS have not yet been fully clarified.

The current study was performed to give further insight into the risk profiles of these three clinical types of CIS. In clinical practice it would be helpful to be able to discriminate ‘high‐risk’ from ‘low‐risk’ CIS before the start of intravesical therapy and as such to tailor the treatment and follow‐up to this risk‐profile.

OBJECTIVE

• To further clarify the risk profiles of three clinical types of carcinoma in situ (CIS) of the bladder.

MATERIALS AND METHODS

• Population‐based data from the Comprehensive Cancer Centre Middle Netherlands, as part of the nationwide Netherlands Cancer Registry, were used for patients presenting with CIS in the period from 1987 to 2009.

• Patients with muscle‐invasive bladder cancer on primary diagnosis were excluded. The patients were divided into three groups according to their ‘clinical type’, being primary, concomitant or secondary CIS.

RESULTS

• Overall, 90 patients with CIS were identified with a mean age of 63.4 years, predominantly men (91.1%). Primary CIS (P‐CIS) was found in 43 patients (47.8%), concomitant CIS (C‐CIS) in 21 patients (23.3%) and secondary CIS (S‐CIS) in 26 patients (28.9%). Mean follow up was 81.3 months (range 8–222 months). Recurrence of disease was observed in 68.9% of patients, with significantly more recurrences in the S‐CIS group (88.5%).

• Progression to muscle‐invasive disease was seen in 17 patients (18.9%): eight patients (18.7%) with P‐CIS, four (19.0%) with C‐CIS and five (19.2%) with S‐CIS. Overall, 29 patients underwent a cystectomy, equally distributed over the three groups. The duration of bladder preservation was worse in the C‐CIS group but did not differ significantly between the groups.

• Overall survival at 5 years was 79.6% for the total group, with poorer results for the C‐CIS group, although the difference was not significant.

CONCLUSIONS

• Carcinoma in situ is clearly an entity that requires meticulous treatment and thorough follow up because of its high recurrence rate (68.9%) and high rate of progression to muscle‐invasive bladder cancer (18.9%).

• The C‐CIS group appears to have a poorer prognosis with a shorter duration of bladder preservation and a worse overall survival.
Vasoactive intestinal polypeptide, an erectile neurotransmitter, improves erectile function more significantly in castrated rats than in normal rats
Authors: Zhang Min‐Guang , Shen Zhou‐Jun , Zhang Cun‐Ming , Wu Wei , Gao Ping‐Jin , Chen Shan‐Wen , Zhou Wen‐Long
Published: December 2010

What’s known on the subject? and What does the study add?

Vasoactive intestinal polypeptide (VIP) is an important erectile neurotransmitter, and our previous study found that the mRNA expression of VIP was independent of androgens.

The present study further investigated the vivo effect of VIP on erection. We found that not only the expression of VIP was independent of androgens, but also the effect of VIP on erection was independent of androgens. In fact, we found that VIP played a more significant role on erection in castrated rats than in normal rats.

OBJECTIVE

To investigate the regulatory role of androgen in VIP‐mediated erectile effect. Androgen is essential for physiological erection. Vasoactive intestinal polypeptide (VIP) is an important erectile neurotransmitter. While previous studies demonstrated that VIP expression in the penis was androgen‐independent, it remains controversial whether androgen has any effect on VIP‐mediated erection.

MATERIALS AND METHODS

Male SD rats were divided into a control group, a castration group, and a castration‐with‐testosterone‐replacement group. Four weeks later, each group was subdivided into low and high‐dose VIP subgroups and subjected to intracavernous injection of 0.5 and 2 µg VIP, respectively.

Erectile function was tested by recording intracavernosal pressure (ICP) and mean arterial blood pressure (MAP) before and after VIP injection.

The expressions of the VIP‐receptor (VPAC2), G‐protein stimulatory and inhibitory alpha subunits (Gs‐α, Gi‐α), and PDE3A in rat corpus cavernosum (CC) was qualified by real‐time PCR and Western blot analysis.

RESULTS

Castration reduced erectile function while testosterone restored it. VIP improved erectile function in a dose‐dependent manner.

High‐dose VIP significantly enhanced erectile function in castrated rats and there was no difference of ICP/MAP among three groups after injection of high‐dose VIP.

Low‐dose VIP also resulted in a higher improvement of erectile function in castrated rats, although the ICP/MAP was lower in these rats than in the other two groups. VPAC2 and Gs‐α were up‐regulated while Gi‐α and PDE3A were down‐regulated in CC of castrated rats.

CONCLUSION

VIP improves erectile function much more significantly in hypogonadal condition, mainly due to the higher expression of VPAC2, Gs‐α, and lower expression of Gi‐α and PDE3A in CC of castrated rats. Androgen may negatively regulate the erectile effect of VIP.
Cost‐effectiveness analysis of sacral neuromodulation and botulinum toxin A treatment for patients with idiopathic overactive bladder
Authors: Leong Randall K. , de Wachter Stephan G.G. , Joore Manuela A. , van Kerrebroeck Philip E.V.
Published: December 2010

Study Type – Therapy (economic analysis)

Level of Evidence 1b

OBJECTIVE

To assess and compare the costs and effects value of either starting with sacral neuromodulation (SNM) or botulinum toxin A (BTX) treatment in patients with refractory idiopathic overactive bladder from a societal perspective.

MATERIALS AND METHODS

An economic model comparing SNM with BTX was developed. A clinical relevant effect (i.e. success) was defined as 50% or greater reduction in incontinence episodes or urgency frequency symptoms. Information on the clinical effectiveness of the two treatments and on the course of the disease with the two treatments were based primarily on published literature and, when required, on expert opinion. Both treatments were assumed to be performed under general anaesthesia and, for SNM treatment, first‐stage tined lead test was used. All costs were based on national data from the year 2008. Analyses from the societal perspective were conducted for a 5‐year duration. Costs were discounted at 4% and effects at 1.5%. In addition, different modelling scenarios were used to see determine any changes in the results obtained.

RESULTS

Starting with SNM resulted in a higher quality adjusted life year (QALY) gain (differenceof 0.23) and a higher cost (difference of €6428) compared to starting with BTX. The corresponding incremental cost‐effectiveness ratio was €27 991/QALY. The probability of this ratio being cost effective (e.g. under €40 000/QALY) is 88%. SNM starts to be cost‐effective after 4 years. SNM was not cost‐effective in some other scenarios, such as when BTX was conducted under local anaesthesia or when peripheral nerve evaluation or bilateral testing was used for SNM.

CONCLUSIONS

Starting with SNM, treatment is cost‐effective after 5 years compared to BTX. However, in some scenarios, such as the use of local anaesthesia for BTX treatment and SNM peripheral nerve evaluation or bilateral test, SNM was not cost‐effective.
Improved cancer specific‐survival in patients with carcinoma invading bladder muscle expressing cyclo‐oxygenase‐2
Authors: Aziz Anis , Lessard Annie , Moore Katherine , Hovington Hélène , Latulippe Eva , Larue Hélène , Fradet Yves , Lacombe Louis
Published: December 2010

Study Type – Prognosis (case series)

Level of Evidence 4

OBJECTIVE

To determine whether the expression of cyclo‐oxygenase (COX)‐2 has an influence on survival and on the response to chemotherapy in invasive bladder cancer.

PATIENTS AND METHODS

A population of 266 patients from a tertiary university centre with carcinoma invading bladder muscle without evidence of metastasis at time of cystectomy was analyzed retrospectively. COX‐2 expression was evaluated immunohistochemically with a monoclonal anti‐COX‐2 antibody. All pertinent clinical and pathological parameters were reviewed and correlated with risk factors influencing outcome, including disease‐specific and overall survival, as well as COX‐2 expression. Immunoreactivity was categorized as positive if COX‐2 staining was present in >5% tumour cells.

RESULTS

The expression of COX‐2 was not influenced by tumour stage, grade or nodal status, nor any other parameters. The risk factors that influenced disease‐specific survival in carcinoma invading bladder muscle on multivariate analysis were lymph node status (hazards ratio, HR = 2.46 for N1, P= 0.001, HR = 2.90 for N2, P < 0.001, HR = 5.19 for N3, P= 0.012), use of neoadjuvant chemotherapy (HR = 3.54; P= 0.004) or adjuvant chemotherapy (HR = 0.57, P= 0.014) and COX‐2 expression (HR = 0.64 if >5% cells had positive expression; P= 0.025). Kaplan–Meier analysis showed an increased disease‐specific survival (P= 0.0063), as well as longer recurrence‐free survival (P= 0.003), in patients with muscle‐invasive bladder tumours expressing COX‐2 in >5% of the cells. A tendency was also observed in a subgroup with positive nodes treated with adjuvant chemotherapy (P= 0.093).

CONCLUSIONS

The overexpression of COX‐2 is associated with a better recurrence‐free and disease‐specific survival in a large cohort of 266 patients with carcinoma invading bladder muscle treated by cystectomy. A trend for increased disease‐specific survival was also observed for patients with COX‐2 overexpression and positive nodes who received adjuvant chemotherapy. Potential of COX‐2 as a prognostic marker in bladder cancer should be considered.
Higher levels of cell apoptosis and abnormal E‐cadherin expression in the urothelium are associated with inflammation in patients with interstitial cystitis/painful bladder syndrome
Authors: Shie Jia‐Heng , Kuo Hann‐Chorng
Published: December 2010

What’s known on the subject? and What does the study add?

Interstitial cystitis/painful bladder syndrome (IC/PBS) is considered to result from long‐standing inflammation of the bladder. Urothelial dysfunction and increased urothelial permeability are known to result in clinical symptoms such as pain and urgency, however the actual pathophysiology remains unclear.

This study demonstrated increased cell apoptosis, decreased cell proliferation, increased mast cell activation, and impaired expression of E‐cadherin were significant in IC/PBS bladders. There was a significant correlation between mast cell activation and urothelial cell apoptosis and the reduced E‐cadherin expression was significantly correlated with clinical pain VAS scale, suggesting the barrier defect of the bladder wall may lead to increasing bladder sensitivity and pain.

OBJECTIVE

• To investigate the relationships between suburothelial inflammation and urothelial dysfunction in interstitial cystitis/painful bladder syndrome (IC/PBlS).

MATERIALS AND METHODS

• Immunofluorescence staining of ki‐67 (to assess cell proliferation), junction protein E‐cadherin, tryptase (to assess mast cell activation) and TUNEL (to assess urothelial apoptosis) were performed in bladder tissues from 20 patients with IC/PBlS and from 6 control patients.

• The fluorescence intensity of E‐cadherin was measured using the ImageJ method.

• The percentage of apoptotic cells, proliferated cells and activated mast cells were measured and quantified as positive cells (±SD) per area unit (4 µm2).

RESULTS

• The ratio of ki‐67‐positive cells in the bladder tissue of the patients with IC/PBlS was significantly down‐regulated compared with that of the control patients (0.559 ± 0.658 vs. 1.23 ± 1.28, P= 0.001).

• TUNEL staining revealed a significantly higher number of apoptotic cells in the IC/PBlS bladder tissue compared with control bladder tissue (2.26 ± 2.04 v 0.051 ± 0.124, P= 0.000).

• The tryptase signal was significantly stronger in the IC/PBlS bladder tissue compared with that of control patients (6.16 ± 4.35 v 1.15 ± 0.436, P= 0.000).

• The apoptotic cell number in IC/PBlS bladder tissue correlated significantly with mast cell activation (P= 0.021).

• Immunofluorescence also showed a significantly lower distribution of E‐cadherin in IC/PBlS bladder tissue compared with that of control patients (8.50 ± 6.83 v 17.2 ± 11.9, P= 0.000).

• Lower expression of E‐cadherin in IC/PBlS bladder tissue was significantly correlated with higher visual analogue pain scores in patients with IC/PBlS (P= 0.008).

CONCLUSIONS

• The results of the present study suggest that urothelial homeostasis in IC/PBlS bladders was impaired, and abnormal urothelial function was significantly associated with chronic inflammation.

• The junctions between urothelial cells in IC/PBlS bladders were abnormal, which was associated with the patient’s self‐report pain scales.
Contemporary outcomes of 2287 patients with bladder cancer who were treated with radical cystectomy: a Canadian multicentre experience
Authors: Yafi Faysal A. , Aprikian Armen G. , Chin Joseph L. , Fradet Yves , Izawa Jonathan , Estey Eric , Fairey Adrian , Rendon Ricardo , Cagiannos Ilias , Lacombe Louis , Lattouf Jean‐Baptiste , Bell David , Drachenberg Darrel , Kassouf Wassim
Published: December 2010

Study Type – Therapy (case series)

Level of Evidence 4

OBJECTIVE

To evaluate data obtained from a large, multi‐institutional, contemporary series of patients who underwent radical cystectomy (RC) in a universal healthcare system aiming to assess outcome and identify novel prognostic variables.

MATERIALS AND METHODS

Data were collected and pooled from 2287 patients treated with RC between 1998 and 2008 by urological oncologists from eight Canadian academic centres. Collected variables included various clinicopathological parameters, recurrence and death. Survival and prognostic variables were analyzed using the Kaplan‐Meier method and Cox regression analysis.

RESULTS

The median age of patients was 68 years with a mean (median) follow‐up time of 35 (29) months. The 30, 60 and 90‐day postoperative mortality rates were 1.3%, 2.6% and 3.2%, respectively. The 5‐year overall, recurrence‐free and cancer‐specific survival was 57%, 48% and 67%, respectively, with a local recurrence rate of 6%. Pathological stage distribution was <pT2N0, n= 498 (23%); pT2N0, n= 365 (17%); pT3N0, n= 463 (21%); pT4N0, n= 170 (8%); and pTxN+, n= 507 (23%). Only 3.1% of patients received neoadjuvant chemotherapy and 19.4% received adjuvant chemotherapy. On multivariate analysis, lower pathological stage, negative surgical margins, receipt of adjuvant chemotherapy, performance of pelvic lymphadenectomy and an absence of smoking were associated with prolonged disease‐specific and overall survival.

CONCLUSIONS

RC performed at academic centres provides excellent local control of disease and an acceptable clinical outcome with low perioperative mortality in patients who are treated within a universal healthcare system. Smoking, pelvic lymphadenectomy and receipt of adjuvant chemotherapy are independent prognostic factors for survival. Neoadjuvant chemotherapy continues to be under‐utilized in Canada.
Pilot study of salvage laparoscopic prostatectomy for the treatment of recurrent prostate cancer
Authors: Ahallal Youness , Shariat Shahrokh F. , Chade Daher C. , Mazzola Clarisse , Reuter Victor E. , Sandhu Jaspreet S. , Laudone Vincent P. , Touijer Karim A. , Guillonneau Bertrand D.
Published: December 2010

Study Type – Therapy (case series)

Level of Evidence 4

What’s known on the subject? and What does the study add?

After primary radiation therapy or cryotherapy for prostate cancer, a biochemical‐only recurrence poses a diagnostic and therapeutic dilemma for clinicians and patients alike. Open radical prostatectomy (ORP) represents the most effective curative treatment option for these patients.

Salvage laparoscopic radical prostatectomy seems to offer a safe therapeutic alternative for patients failing primary radiation or cryotherapy.

OBJECTIVE

• To evaluate feasibility, safety and oncological efficacy of salvage laparoscopic radical prostatectomy for pathology‐proven biochemical recurrence after primary radiation therapy or cryotherapy for prostate cancer.

MATERIALS AND METHODS

• This retrospective pilot study examined 15 patients from 2004 to 2010 with biochemical recurrence after external beam radiation therapy (N= 8), brachytherapy (N= 6) or cryotherapy (N= 1).

• Patients were treated with salvage laparoscopic radical prostatectomy (11 conventional, four robotic‐assisted) with bilateral pelvic dissection.

RESULTS

• Median duration of surgery was 235 min. None of the following occurred: conversion to open surgery, transfusion, urethrovesical stenosis or perioperative or postoperative mortality. One patient presented with a rectal injury, repaired using uninterrupted sutures and a colostomy. One patient had anastomotic leak treated with prolonged Foley catheterization.

• Pathological stage was pT2a in three, pT2b in three, pT3a in four, pT3b in three and pT4 in two patients; two patients had nodal metastasis. Within an 8‐month median follow‐up, 11 patients were disease‐free and three had persistent postoperative prostate‐specific antigen (PSA) elevation; the remaining patient experienced PSA recurrence after 21 months.

• Seven patients achieved continence (no pads) by 8.4 months (median), one patient manifested severe incontinence corrected by implanting an artificial sphincter, and seven patients with a 12.6‐month mean follow‐up continued to need one or two pads per day.

• Erectile dysfunction was present in five patients before surgery and in 14 patients after surgery.

CONCLUSION

• Salvage laparoscopic radical prostatectomy seems to offer a safe therapeutic alternative for patients failing primary radiation or cryotherapy. However, larger studies with longer‐term data are required.
A phase I study of personalized peptide vaccination for advanced urothelial carcinoma patients who failed treatment with methotrexate, vinblastine, adriamycin and cisplatin
Authors: Matsumoto Kazumasa , Noguchi Masanori , Satoh Takefumi , Tabata Ken‐Ichi , Fujita Tetsuo , Iwamura Masatsugu , Yamada Akira , Komatsu Nobukazu , Baba Shiro , Itoh Kyogo
Published: December 2010

Study Type – Therapy (case series)

Level of Evidence 4

What’s known on the subject? and What does the study add?

This phase I study showed the safety and boosted immune responses of personalized peptide vaccination for advanced urotherial carcinoma.

This study showed feasibility of personalized peptide vaccination as a new therapeutic modality for advanced urotherial carcinoma patients who failed cisplatin‐based chemotherapy.

OBJECTIVE

• To investigate the safety and immune responses of 12 consecutive weeks of once‐weekly personalized peptide vaccine (PPV) administration in patients with advanced urothelial carcinoma (UC) for whom therapy with methotrexate, vinblastine, adriamycin and cisplatin (MVAC) has failed.

PATIENTS AND METHODS

• A phase I trial was designed. Ten patients with MVAC‐refractory advanced or metastatic UC were treated with weekly personalized peptide vaccine 12 times using positive peptides chosen from 14 and 16 peptides in patients with human leucocyte antigens A24 and A2, respectively.

• Peptide‐specific cytotoxic T lymphocyte precursor analysis by interferon‐γ production and peptide‐reactive immunoglobulin G (IgG) using an enzyme‐linked immunosorbent assay was monitored during the treatment.

RESULTS

• The peptide vaccination was safe and well tolerated with no major adverse effects. Increased cytotoxic T lymphocyte response and the anti‐peptide IgG titre were revealed by the post‐vaccination sera in eight patients.

• Clinical responses were as follows: one complete response, one partial response, two stable disease and six progressive disease.

• Median progression‐free survival and overall survival were 3.0 and 8.9 months, respectively. In the four responders, median progression‐free survival and overall survival were 21 and 24 months, respectively.

CONCLUSIONS

• This phase I study showed the safety of and boosted immune responses in response to PPV for advanced UC.

• The potential efficacy of 12 consecutive weekly vaccinations with PPV in patients with advanced UC merits further investigation based on these findings.