bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide identification of specific oligonucleotides using artificial neural network and computational genomic analysis
Authors: Liu Chun-Chi , Lin Chin-Chung , Li Ker-Chau , Chen Wen-Shyen E , Chen Jiun-Ching , Yang Ming-Te , Yang Pan-Chyr , Chang Pei-Chun , Chen Jeremy JW
Published: May 2007

Background

Genome-wide identification of specific oligonucleotides (oligos) is a computationally-intensive task and is a requirement for designing microarray probes, primers, and siRNAs. An artificial neural network (ANN) is a machine learning technique that can effectively process complex and high noise data. Here, ANNs are applied to process the unique subsequence distribution for prediction of specific oligos.

Results

We present a novel and efficient algorithm, named the integration of ANN and BLAST (IAB) algorithm, to identify specific oligos. We establish the unique marker database for human and rat gene index databases using the hash table algorithm. We then create the input vectors, via the unique marker database, to train and test the ANN. The trained ANN predicted the specific oligos with high efficiency, and these oligos were subsequently verified by BLAST. To improve the prediction performance, the ANN over-fitting issue was avoided by early stopping with the best observed error and a k-fold validation was also applied. The performance of the IAB algorithm was about 5.2, 7.1, and 6.7 times faster than the BLAST search without ANN for experimental results of 70-mer, 50-mer, and 25-mer specific oligos, respectively. In addition, the results of polymerase chain reactions showed that the primers predicted by the IAB algorithm could specifically amplify the corresponding genes. The IAB algorithm has been integrated into a previously published comprehensive web server to support microarray analysis and genome-wide iterative enrichment analysis, through which users can identify a group of desired genes and then discover the specific oligos of these genes.

Conclusion

The IAB algorithm has been developed to construct SpecificDB, a web server that provides a specific and valid oligo database of the probe, siRNA, and primer design for the human genome. We also demonstrate the ability of the IAB algorithm to predict specific oligos through polymerase chain reaction experiments. SpecificDB provides comprehensive information and a user-friendly interface.
Hinge Atlas: relating protein sequence to sites of structural flexibility
Authors: Flores Samuel C , Lu Long J , Yang Julie , Carriero Nicholas , Gerstein Mark B
Published: May 2007

Background

Relating features of protein sequences to structural hinges is important for identifying domain boundaries, understanding structure-function relationships, and designing flexibility into proteins. Efforts in this field have been hampered by the lack of a proper dataset for studying characteristics of hinges.

Results

Using the Molecular Motions Database we have created a Hinge Atlas of manually annotated hinges and a statistical formalism for calculating the enrichment of various types of residues in these hinges.

Conclusion

We found various correlations between hinges and sequence features. Some of these are expected; for instance, we found that hinges tend to occur on the surface and in coils and turns and to be enriched with small and hydrophilic residues. Others are less obvious and intuitive. In particular, we found that hinges tend to coincide with active sites, but unlike the latter they are not at all conserved in evolution. We evaluate the potential for hinge prediction based on sequence.

Motions play an important role in catalysis and protein-ligand interactions. Hinge bending motions comprise the largest class of known motions. Therefore it is important to relate the hinge location to sequence features such as residue type, physicochemical class, secondary structure, solvent exposure, evolutionary conservation, and proximity to active sites. To do this, we first generated the Hinge Atlas, a set of protein motions with the hinge locations manually annotated, and then studied the coincidence of these features with the hinge location. We found that all of the features have bearing on the hinge location. Most interestingly, we found that hinges tend to occur at or near active sites and yet unlike the latter are not conserved. Less surprisingly, we found that hinge residues tend to be small, not hydrophobic or aliphatic, and occur in turns and random coils on the surface. A functional sequence based hinge predictor was made which uses some of the data generated in this study. The Hinge Atlas is made available to the community for further flexibility studies.
A feature selection approach for identification of signature genes from SAGE data
Authors: Barrera Junior , Cesar Roberto M , Humes Carlos , Martins David C , Patrão Diogo FC , Silva Paulo JS , Brentani Helena
Published: May 2007

Background

One goal of gene expression profiling is to identify signature genes that robustly distinguish different types or grades of tumors. Several tumor classifiers based on expression profiling have been proposed using microarray technique. Due to important differences in the probabilistic models of microarray and SAGE technologies, it is important to develop suitable techniques to select specific genes from SAGE measurements.

Results

A new framework to select specific genes that distinguish different biological states based on the analysis of SAGE data is proposed. The new framework applies the bolstered error for the identification of strong genes that separate the biological states in a feature space defined by the gene expression of a training set. Credibility intervals defined from a probabilistic model of SAGE measurements are used to identify the genes that distinguish the different states with more reliability among all gene groups selected by the strong genes method. A score taking into account the credibility and the bolstered error values in order to rank the groups of considered genes is proposed. Results obtained using SAGE data from gliomas are presented, thus corroborating the introduced methodology.

Conclusion

The model representing counting data, such as SAGE, provides additional statistical information that allows a more robust analysis. The additional statistical information provided by the probabilistic model is incorporated in the methodology described in the paper. The introduced method is suitable to identify signature genes that lead to a good separation of the biological states using SAGE and may be adapted for other counting methods such as Massive Parallel Signature Sequencing (MPSS) or the recent Sequencing-By-Synthesis (SBS) technique. Some of such genes identified by the proposed method may be useful to generate classifiers.
Gene function prediction based on genomic context clustering and discriminative learning: an application to bacteriophages
Authors: Li Jason , Halgamuge Saman K , Kells Christopher I , Tang Sen-Lin
Published: May 2007

Background

Existing methods for whole-genome comparisons require prior knowledge of related species and provide little automation in the function prediction process. Bacteriophage genomes are an example that cannot be easily analyzed by these methods. This work addresses these shortcomings and aims to provide an automated prediction system of gene function.

Results

We have developed a novel system called SynFPS to perform gene function prediction over completed genomes. The prediction system is initialized by clustering a large collection of weakly related genomes into groups based on their resemblance in gene distribution. From each individual group, data are then extracted and used to train a Support Vector Machine that makes gene function predictions. Experiments were conducted with 9 different gene functions over 296 bacteriophage genomes. Cross validation results gave an average prediction accuracy of ~80%, which is comparable to other genomic-context based prediction methods. Functional predictions are also made on 3 uncharacterized genes and 12 genes that cannot be identified by sequence alignment. The software is publicly available at http://www.synteny.net/.

Conclusion

The proposed system employs genomic context to predict gene function and detect gene correspondence in whole-genome comparisons. Although our experimental focus is on bacteriophages, the method may be extended to other microbial genomes as they share a number of similar characteristics with phage genomes such as gene order conservation.
Mutation accumulation and fitness effects in hybridogenetic populations: a comparison to sexual and asexual systems
Authors: Som Christian , Bagheri Homayoun C , Reyer Heinz-Ulrich
Published: May 2007

Background

Female only unisexual vertebrates that reproduce by hybridogenesis show an unusual genetic composition. They are of hybrid origin but show no recombination between the genomes of their parental species. Instead, the paternal genome is discarded from the germline prior to meiosis, and gametes (eggs only) contain solely unrecombined maternal genomes. Hence hybridogens only transmit maternally inherited mutations. Hybridity is restored each generation by backcrossing with males of the sexual parental species whose genome was eliminated. In contrast, recombining sexual species propagate an intermixed pool of mutations derived from the maternal and paternal parts of the genome. If mutation rates are lower in female gametes than males, it raises the possibility for lower mutation accumulation in a hybridogenetic population, and consequently, higher population fitness than its sexual counterpart.

Results

We show through Monte-Carlo simulations that at higher male to female mutation ratios, and sufficiently large population sizes, hybridogenetic populations can carry a lower mutation load than sexual species. This effect is more pronounced with synergistic forms of epistasis. Mutations accumulate faster on the sexual part of the genome, and with the purifying effects of epistasis, it makes it more difficult for mutations to be transmitted on the clonal part of the genome. In smaller populations, the same mechanism reduces the speed of Muller's Ratchet and the number of fixed mutations compared to similar asexual species.

Conclusion

Since mutation accumulation can be less pronounced in hybridogenetic populations, the question arises why hybridogenetic organisms are so scarce compared to sexual species. In considering this, it is likely that comparison of population fitnesses is not sufficient. Despite competition with the sexual parental species, hybrid populations are dependent on the maintenance of – and contact with – their sexual counterpart. Other problems may involve too little genetic diversity to respond to changing environments and problems in becoming hybridogenetic (e.g. disruption of meiosis and subsequent infertility or sterility). Yet, lower mutation accumulation in hybridogenetic populations opens the possibility that hybridogenetic species can develop into new sexual species once recombination is re-established and reproductive isolation from sexual ancestors has occurred.
Toxin production in a rare and genetically remote cluster of strains of the Bacillus cereus group
Authors: Fagerlund Annette , Brillard Julien , Fürst Rainer , Guinebretière Marie-Hélène , Granum Per Einar
Published: May 2007

Background

Three enterotoxins are implicated in diarrhoeal food poisoning due to Bacillus cereus: Haemolysin BL (Hbl), Non-haemolytic enterotoxin (Nhe), and Cytotoxin K (CytK). Toxin gene profiling and assays for detection of toxin-producing stains have been used in attempts to evaluate the enterotoxic potential of B. cereus group strains. B. cereus strain NVH 391/98, isolated from a case of fatal enteritis, was genetically remote from other B. cereus group strains. This strain lacked the genes encoding Hbl and Nhe, but contains CytK-1. The high virulence of this strain is thought to be due to the greater cytotoxic activity of CytK-1 compared to CytK-2, and to a high level of cytK expression. To date, only three strains containing cytK-1 have been identified; B. cereus strains NVH 391/98, NVH 883/00, and INRA AF2.

Results

A novel gene variant encoding Nhe was identified in these three strains, which had an average of 80% identity in protein sequence with previously identified Nhe toxins. While culture supernatants containing CytK and Nhe from NVH 391/98 and INRA AF2 were highly cytotoxic, NVH 883/00 expressed little or no CytK and Nhe and was non-cytotoxic. Comparative sequence and expression studies indicated that neither the PlcR/PapR quorum sensing system, nor theYvrGH and YvfTU two-component systems, were responsible for the observed difference in toxin production. Additionally, phylogenetic analysis of 13 genes showed that NVH 391/98, NVH 883/00, and INRA AF2 comprise a novel cluster of strains genetically distant from other B. cereus group strains.

Conclusion

Due to its divergent sequence, the novel nhe operon had previously not been detected in NVH 391/98 using PCR and several monoclonal antibodies. Thus, toxigenic profiling based on the original nhe sequence will fail to detect the toxin in this group of strains. The observation that strain NVH 883/00 carries cytK-1 but is non-cytotoxic indicates that the detection of this gene variant is not a sufficient criterion for identification of highly cytotoxic strains. The presence of the novel nhe operon and the cytK-1 gene variant in this cluster of strains reflect their phylogenetically remote relationship towards other B. cereus group strains.
Quantification of malaria parasite release from infected erythrocytes: inhibition by protein-free media
Authors: Glushakova Svetlana , Yin Dan , Gartner Nicole , Zimmerberg Joshua
Published: May 2007

Background

Intracellular malaria parasites leave their host erythrocytes to infect neighbouring cells after each cycle of asexual replication. No method is currently available for the direct quantification of parasite release.

Method and results

To quantify parasite release process, human erythrocytes infected with Plasmodium falciparum were injected into sealed chambers at optimal density, where they progressed through the end of the erythrocyte cycle. Each event of parasite release inside the chamber at the site of erythrocyte rupture leaves on the chamber wall a footprint, composed of 1) separated parasites, 2) a digestive vacuole with haemozoin, and 3) fragments of the ruptured membranes. These footprints are stable for hours, allowing precise identification using differential interference contrast (DIC) microscopy. The relative rate of parasite release is defined as the percent of such footprints out of all schizonts injected and incubated into chamber at 37°C for two hours. The method is highly reproducible, easy to perform, and does not require expensive equipment. Additionally, this method allows one to analyse cell and release site morphology, which adds information about the release process and the quality of the culture. The method is used here to show that swelling of schizonts caused by protein-free media inhibits parasite release.

Conclusion

In this study, a novel method is described to count sites of parasite release by microscopy. Besides the direct estimation of parasite release from infected erythrocytes, this method provides a morphological evaluation of normal infected cells approaching the end of the plasmodial life cycle, or pathological forms accumulated as the result of experimental intervention in the parasite release process. One may now accurately estimate the relative parasite release rate at the time of cycle transition, without any obligatory coupling to parasite invasion.
Serum procalcitonin measurement as diagnostic and prognostic marker in febrile adult patients presenting to the emergency department
Authors: Hausfater Pierre , Juillien Gaëlle , Madonna-Py Beatrice , Haroche Julien , Bernard Maguy , Riou Bruno
Published: May 2007

Introduction

Identification of bacterial infections is crucial if treatment is to be initiated early and antibiotics used rationally. The primary objective of this study was to test the efficiency of procalcitonin (PCT) in identifying bacterial/parasitic episodes among febrile adult patients presenting to an emergency department. Secondary objectives were to identify clinical or biological variables associated with either bacterial/parasitic infection or critical illness.

Methods

This was a prospective, single centre, non-interventional study, conducted in the adult emergency department of an academic tertiary care hospital. We included patients with body temperature of 38.5°C or greater. A serum sample for measurement of PCT was collected in the emergency room. Patients were followed up until day 30. After reviewing the medical files, two independent experts, who were blind to the PCT results, classified each of the patients as having a bacterial/parasitic infection, viral infection, or another diagnosis.

Results

Among 243 patients included in the study, 167 had bacterial/parasitic infections, 35 had viral infections and 41 had other diagnoses. The PCT assay, with a 0.2 μg/l cutoff value, had a sensitivity of 0.77 and a specificity of 0.59 in diagnosing bacterial/parasitic infection. Of the patients with PCT 5 μg/l or greater, 51% had critical illness (death or intensive care unit admission) as compared with 13% of patients with lower PCT values.

Conclusion

Bearing in mind the limitations of an observational study design, the judgements of the emergency department physicians were reasonably accurate in determining the pretest probability of bacterial/parasitic infection. PCT may provide additional, valuable information on the aetiology and prognosis of infection in the emergency department.
Monitoring of gene knockouts: genome-wide profiling of conditionally essential genes
Authors: Smith Lisa K , Gomez Maria J , Shatalin Konstantin Y , Lee Hyunwoo , Neyfakh Alexander A
Published: May 2007

We have developed a new microarray-based genetic technique, named MGK (Monitoring of Gene Knockouts), for genome-wide identification of conditionally essential genes. MGK identified bacterial genes that are critical for fitness in the absence of aromatic amino acids, and was further applied to identify genes whose inactivation causes bacterial cell death upon exposure to the bacteriostatic antibiotic chloramphenicol. Our findings suggest that MGK can serve as a robust tool in functional genomics studies.
GSMN-TB: a web-based genome-scale network model of Mycobacterium tuberculosismetabolism
Authors: Beste Dany JV , Hooper Tracy , Stewart Graham , Bonde Bhushan , Avignone-Rossa Claudio , Bushell Michael E , Wheeler Paul , Klamt Steffen , Kierzek Andrzej M , McFadden Johnjoe
Published: May 2007

Background

An impediment to the rational development of novel drugs against tuberculosis (TB) is a general paucity of knowledge concerning the metabolism of Mycobacterium tuberculosis, particularly during infection. Constraint-based modeling provides a novel approach to investigating microbial metabolism but has not yet been applied to genome-scale modeling of M. tuberculosis.

Results

GSMN-TB, a genome-scale metabolic model of M. tuberculosis, was constructed, consisting of 849 unique reactions and 739 metabolites, and involving 726 genes. The model was calibrated by growing Mycobacterium bovis bacille Calmette Guérin in continuous culture and steady-state growth parameters were measured. Flux balance analysis was used to calculate substrate consumption rates, which were shown to correspond closely to experimentally determined values. Predictions of gene essentiality were also made by flux balance analysis simulation and were compared with global mutagenesis data for M. tuberculosis grown in vitro. A prediction accuracy of 78% was achieved. Known drug targets were predicted to be essential by the model. The model demonstrated a potential role for the enzyme isocitrate lyase during the slow growth of mycobacteria, and this hypothesis was experimentally verified. An interactive web-based version of the model is available.

Conclusion

The GSMN-TB model successfully simulated many of the growth properties of M. tuberculosis. The model provides a means to examine the metabolic flexibility of bacteria and predict the phenotype of mutants, and it highlights previously unexplored features of M. tuberculosis metabolism.
A systematic comparative and structural analysis of protein phosphorylation sites based on the mtcPTM database
Authors: Jiménez José L , Hegemann Björn , Hutchins James RA , Peters Jan-Michael , Durbin Richard
Published: May 2007

mtcPTM is an online repository of human and mouse phosphosites in which data are hierarchically organized to preserve biologically relevant experimental information, thus allowing straightforward comparisons of phosphorylation patterns found under different conditions. The database also contains the largest available collection of atomic models of phosphorylatable proteins. Detailed analysis of this structural dataset reveals that phosphorylation sites are found in a heterogeneous range of structural and sequence contexts. mtcPTM is available on the web http://www.mitocheck.org/cgi-bin/mtcPTM/search.
Multicenter Phase II Trial of Neoadjuvant Therapy With Trastuzumab, Docetaxel, and Carboplatin for Human Epidermal Growth Factor Receptor-2–Overexpressing Stage II or III Breast Cancer: Results of the GETN(A)-1 Trial
Authors: Coudert Bruno P. , Largillier Remy , Arnould Laurent , Chollet Philippe , Campone Mario , Coeffic David , Priou Frank , Gligorov Joseph , Martin Xavier , Trillet-Lenoir Véronique , Weber Béatrice , Bleuse Jean Pierre , Vasseur Berangère , Serin Daniel , Namer Moïse
Published: May 2007

Purpose

Trastuzumab plus chemotherapy has become the standard of care for human epidermal growth factor receptor-2 (HER-2) –positive breast cancer. Trastuzumab-based preoperative systemic therapy (PST; neoadjuvant therapy) also appears promising, warranting further investigation.

Patients and Methods

Patients with HER-2-positive, stage II/III, noninflammatory, operable breast cancer requiring a mastectomy (but who wanted to conserve the breast) received trastuzumab 4 mg/kg (day 1), followed by 2 mg/kg weekly, plus docetaxel 75 mg/m2 every 3 weeks, and carboplatin (area under curve, 6) for six cycles before surgery. The primary end point was pathologic complete response (pCR) rate, determined from surgical specimens.

Results

Seventy patients were enrolled. Most patients had clinical T2/T3 tumors (100%) or clinical N1/2 nodes (53%). Sixty-seven patients (96%) completed six cycles of therapy, one patient withdrew due to progressive disease, and two patients withdrew for toxicity. A complete or partial objective clinical response occurred in 95% of patients (85% and 10%, respectively). Surgery was breast conservative in 45 (64%) of 70 patients. In an intent-to-treat analysis, tumor and nodal pCR were seen in 27 (39%) of 70 patients. Centralized retrospective analysis of HER-2 status demonstrated a 43% pCR rate in the 24 of 56 confirmed HER-2-overexpressing (3+) and/or fluorescence in situ hybridization–positive tumors. Treatment was generally well tolerated. Grade 3/4 neutropenia and febrile neutropenia were uncommon (2%). Two patients withdrew prematurely due to a transient, asymptomatic decrease in left ventricular ejection fraction. No symptomatic cardiac dysfunction occurred.

Conclusion

PST with trastuzumab plus docetaxel and carboplatin achieved promising efficacy, with a good pCR rate and favorable tolerability in stage II or III HER-2-positive breast cancer.
Gonadal Function in Males After Chemotherapy for Early-Stage Hodgkin's Lymphoma Treated in Four Subsequent Trials by the European Organisation for Research and Treatment of Cancer: EORTC Lymphoma Group and the Groupe d'Étude des Lymphomes de l'Adulte
Authors: van der Kaaij Marleen A.E. , Heutte Natacha , Le Stang Nolwenn , Raemaekers John M.M. , Simons Arnold H.M. , Carde Patrice , Noordijk Evert M. , Fermé Christophe , Thomas José , Eghbali Houchingue , Kluin-Nelemans Hanneke C. , Henry-Amar Michel
Published: May 2007

Purpose

To analyze fertility in male patients treated with various combinations of radiotherapy and chemotherapy, with or without alkylating agents, or with radiotherapy alone for Hodgkin's lymphoma.

Patients and Methods

Follicle-stimulating hormone (FSH) levels were measured in patients with early-stage upper-diaphragmatic disease enrolled in four European Organisation for Research and Treatment of Cancer (EORTC) trials (H6-H9). Median follow-up after therapy was 32 months. Patients with FSH measurement at least 12 months after end of treatment (n = 355) were selected to assess post-treatment fertility. Patients with FSH measurement 0 to 9 months after therapy (n = 349) were selected to analyze fertility recovery; of these, patients with elevated FSH (> 10 U/L; n = 101) were followed until recovery. Factors predictive for therapy-related infertility were assessed by logistic regression.

Results

The proportion of elevated FSH was 3% and 8% in patients treated with radiotherapy only or with nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD], epirubicin, bleomycin, vinblastine, prednisone [EBVP]); it was 60% (P < .001) after chemotherapy containing alkylating agents (mechlorethamine, vincristine, procarbazine, prednisone [MOPP], MOPP/doxorubicin, bleomycin, vinblastine [ABV], bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone [BEACOPP]). After a median time of 19 months, recovery of fertility occurred in 82% of patients treated without alkylating chemotherapy. This proportion was 30%, statistically (P < .001) lower in those treated with alkylating chemotherapy, and median time to recovery was 27 months. The post-treatment proportion of elevated FSH increased significantly (P < .001) with the dose of alkylating chemotherapy administered, and recovery was less frequent and slower after higher doses. Age more than 50 years and stage II disease also contributed to poor outcome.

Conclusion

Fertility can be secured after nonalkylating chemotherapy for Hodgkin's lymphoma. In contrast, alkylating chemotherapy has a dismal effect, even after a limited number of cycles.
Poor Outcome of Hormone Receptor–Positive Breast Cancer at Very Young Age Is Due to Tamoxifen Resistance: Nationwide Survival Data in Korea—A Report From the Korean Breast Cancer Society
Authors: Ahn Sei Hyun , Son Byung Ho , Kim Seok Won , Kim Seung Il , Jeong Joon , Ko Seung-Sang , Han Wonshik
Published: May 2007

Purpose

Breast cancer in very young women (age < 35 years) is uncommon and poorly understood. We sought to evaluate the prognosis and treatment response of these patients compared with women ages 35 to 50 years.

Patients and Methods

We analyzed data from 9,885 breast cancer patients age ≤ 50 years who were part of the Korean Breast Cancer Society registration program between 1992 and 2001. The overall survival (OS) and breast cancer-specific survival (BCSS) were compared between age groups.

Results

One thousand four hundred forty-four patients (14.6%) were younger than age 35 and 8,441 (85.4%) patients were between 35 and 50 years of age. Younger patients had significantly higher T-stage and higher lymph node positivity and lower hormone receptor expression than older patients. Younger patients had a greater probability of death than older patients, regardless of tumor size or lymph node status. The survival difference was significant for patients with positive or unknown hormone receptor status (P < .0001), but not for patients with negative hormone receptor status. In a multivariate analysis, the interaction term of young age and hormone receptor positivity was significant for OS and BCSS with a hazard ratio for OS of 2.13 (95% CI, 1.52 to 2.98). The significant survival benefit from adjuvant hormone therapy after chemotherapy observed in older patients (hazard ratio for OS, 0.61; 95% CI, 0.47 to 0.79; P = .001) could not be seen in younger patients (P > .05).

Conclusion

Younger patients (age < 35) showed worse prognosis than older patients (age, 35 to 50 years) only in the hormone receptor–unknown or hormone receptor–positive subgroups. Adjuvant tamoxifen therapy might provide less survival benefit when added to chemotherapy in very young breast cancer patients.
American Society of Clinical Oncology 2007 Clinical Practice Guideline Update on the Role of Bisphosphonates in Multiple Myeloma
Authors: Kyle Robert A. , Yee Gary C. , Somerfield Mark R. , Flynn Patrick J. , Halabi Susan , Jagannath Sundar , Orlowski Robert Z. , Roodman David G. , Twilde Patricia , Anderson Kenneth
Published: May 2007

Purpose

To update the recommendations for the use of bisphosphonates in the prevention and treatment of bone disease in multiple myeloma. The Update Committee expanded the guideline to include a discussion of osteonecrosis of the jaw (ONJ).

Methods

For the 2007 update, an Update Committee composed of members from the full panel completed a review and analysis of data published since 2002. Searches of Medline and the Cochrane Collaboration Library databases were performed.

Recommendations

For multiple myeloma patients who have, on plain radiograph(s) or imaging studies, lytic destruction of bone or spine compression fracture from osteopenia, intravenous pamidronate 90 mg delivered over at least 2 hours or zoledronic acid 4 mg delivered over at least 15 minutes every 3 to 4 weeks is recommended. Clodronate is an alternative bisphosphonate approved worldwide, except in the United States, for oral or intravenous administration. New dosing guidelines for patients with pre-existing renal impairment were added to the zoledronic acid package insert. Although no similar dosing guidelines are available for pamidronate, the Update Committee recommends that clinicians consider reducing the initial pamidronate dose in patients with pre-existing renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended in this setting. The Update Committee suggests that bisphosphonate treatment continue for a period of 2 years. At 2 years, physicians should seriously consider discontinuing bisphosphonates in patients with responsive or stable disease, but further use is at the discretion of the treating physician. The Update Committee also discusses measures regarding ONJ.
Germline CDKN1B/p27Kip1 Mutation in Multiple Endocrine Neoplasia
Authors: Georgitsi Marianthi , Raitila Anniina , Karhu Auli , van der Luijt Rob B. , Aalfs Cora M. , Sane Timo , Vierimaa Outi , Mäkinen Markus J. , Tuppurainen Karoliina , Paschke Ralph , Gimm Oliver , Koch Christian A. , Gündogdu Sadi , Lucassen Anneke , Tischkowitz Marc , Izatt Louise , Aylwin Simon , Bano Gul , Hodgson Shirley , De Menis Ernesto , Launonen Virpi , Vahteristo Pia , Aaltonen Lauri A.
Published: May 2007

Context: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20–25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27Kip1, was reported in one suspected MEN1 family with two acromegalic patients.

Objective: Our objective was to evaluate the role of CDKN1B/p27Kip1 in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.

Design: Genomic DNA was analyzed for germline mutations in the CDKN1B/p27Kip1 gene by PCR amplification and direct sequencing.

Setting: The study was conducted at nonprofit academic research and medical centers.

Patients: Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.

Main Outcome Measures: We analyzed germline CDKN1B/p27Kip1 mutations in individuals with pituitary adenoma and MEN1-like features.

Results: A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.

Conclusions: Our results support the previous finding that germline CDKN1B/p27Kip1 mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.
Transport characteristics of zolmitriptan in a human intestinal epithelial cell line Caco-2
Authors: Yu Lushan , Zeng Su
Published: May 2007

The intestinal absorption characteristics and the efflux mechanisms of zolmitriptan, a new generation and highly selective 5-HT1B/1D receptor agonist used in the acute oral treatment of migraine, were investigated. A human intestinal cell line, Caco-2, was used as an in-vitro model of the intestinal mucosa to assess transepithelial transport of zolmitriptan. In the Caco-2 cells, the absorptive transport of zolmitriptan was pH dependent and the transport was enhanced at weakly alkali pH on the apical side. No concentration dependence and saturation were observed for the apical-to-basolateral and basolateral-to-apical transport of zolmitriptan at a concentration of 0.1–10 mM. The permeability ratio value was about 1.5-2.6 at a concentration of 0.1–2.0 mM. Inhibition experiments using verapamil, nifedipine and nimodipine as inhibitors were studied and indicated that P-glycoprotein participated in the transport of zolmitriptan. Inhibition of the Na+-H+ exchanger with amiloride resulted in a significant increase in absorption and a slight inhibition in secretion. This suggests that the Na+-H+ exchanger may be involved in the transport of zolmitriptan. The results indicated that the transport of zolmitriptan was mediated by both passive diffusion and active transport. A series of drug-drug interaction experiments were carried out between zolmitriptan and some drugs that may be co-administrated with zolmitriptan in the clinic. The results indicated that flunarizine, cetirizine, propranolol and atenolol potently decreased both the apical-to-basolateral and basolateral-to-apical transport rate of zolmitriptan. Cimetidine and aspirin slightly inhibited the apical-to-basolateral transport of zolmitriptan, but significantly decreased the basolateral-to-apical transport of zolmitriptan. Thus, the absorption drug-drug interactions should be considered when these drugs are co-administrated with zolmitriptan in the clinic.
Topical anti-inflammatory activity of extracts and compounds from Hypericum perforatum L.
Authors: Sosa Silvio , Pace Roberto , Bornanciny Anna , Morazzoni Paolo , Riva Antonella , Tubaro Aurelia , Loggia Roberto Della
Published: May 2007

Three preparations of Hypericum perforatum L. (a hydroalcoholic extract, a lipophilic extract and an ethylacetic fraction) and the pure compounds hypericin, adhyperforin, amentoflavone, hyperoside, isoquercitrin, hyperforin dicyclohexylammonium (DHCA) salt and dicyclohexylamine were evaluated for their topical anti-inflammatory activity. H. perforatum preparations provoked a dose-dependent reduction of Croton-oil-induced ear oedema in mice, showing the following rank order of activity: lipophilic extract > ethylacetic fraction > hydroalcoholic extract (ID50 (dose that inhibited oedema by 50%) 220, 267 and >1000 μg cm−2, respectively). Amentoflavone (ID50 0.16μmol cm−2), hypericin (ID50 0.25μmol cm−2), hyperforin DHCA salt (ID50 0.25μmol cm−2) and adhyperofrin (ID50 0.30μmol cm−2) had anti-inflammatory activity that was more potent or comparable to that of indometacin (ID50 0.26 μmol cm−2), whereas isoquercitrin and hyperoside were less active (ID50 about 1μmol cm−2). As dicyclohexylamine alone was inactive, the effect of hyperforin DHCA salt can be attributed completely to the phloroglucinol moiety. The pharmacological activity and phytochemical profile of the tested extracts and fraction suggest that different constituents are involved in the topical antiphlogistic property of H. perforatum in-vivo.
Red wine polyphenolic compounds inhibit tracheal smooth muscle contraction during allergen-induced hyperreactivity of the airways
Authors: Franova Sona , Nosalova Gabriela , Pechanova Olga , Sutovska Martina
Published: May 2007

The aims of the study were to investigate the short and long-term effects of Provinol (red wine polyphenolic compounds) on tracheal smooth muscle reactivity using an in-vitro model of ovalbumin-induced airway inflammation in guinea-pig trachea, and to evaluate the role of nitric oxide (NO) in the bronchodilatory effect of Provinol.

The amplitude of tracheal smooth muscle contraction in response to mediators of bronchoconstriction —histamine (10 nM-1 mM), acetylcholine (10 nM-1 mM) and to allergen (ovalbumin 10−5-10−3 g mL−1) was used as a parameter of tracheal smooth muscle reactivity. To test the short-term effects of Provinol, isolated tracheal strips were pre-treated for 30 min with Provinol (10−4mg mL−1) alone or in combination with Nω-nitro-L-arginine methyl ester (L-NAME; 10−6mol L−1). To test the long-term effects of Provinol, isolated tracheal strips were prepared from guinea pigs that had been treated for 14 days with Provinol (20mg kg−1 per day) alone or in combination with L-NAME (40 mg kg−1 per day).

Incubation of tracheal smooth muscle with Provinol decreased the amplitude of contraction in response to ovalbumin, histamine and acetylcholine. The non-selective NO synthase inhibitor L-NAME partially abolished the effect of Provinol on acetylcholine and ovalbumin-induced but not histamine-induced bronchoconstriction. A similar profile was observed after 14 days' oral administration of Provinol.

In conclusion, Provinol inhibited the allergen- and spasmogen-induced contraction of tracheal smooth muscle in ovalbumin-sensitized guinea pigs via a mechanism that was mediated at least partially through the metabolism of NO.
Distributing State Children's Health Insurance Program Funds: A Critical Review of the Design and Implementation of the Funding Formula
Authors: Blewett Lynn A. , Davern Michael
Published: May 2007

The development of formulas to distribute federal funds to states based on demographic data continues to challenge data and policy analysts. Analysts must forward the best objective statistical analysis and data inputs to formula specifications while acknowledging the politics of the legislative process that authorizes federal funding formulas. This article evaluates the federal funding formula for the State Children's Health Insurance Program (SCHIP) using key formula components of need, effort, capacity, and performance. We also examine the operationalization and measure of the target population in the SCHIP funding formula. Legislative decisions on formulas are, by nature, based on compromises that balance competing policy objectives. The analyst's role is to continually review current research standards, data quality, and relevant formula inputs and make recommendations to refine federal funding formulas to better target resources to their intended populations.
Different Countries, Different Needs: The Role of Private Health Insurance in Developing Countries
Authors: Drechsler Denis , Jütting Johannes
Published: May 2007

This article discusses the role of private health insurance (PHI) in developing countries. Three broad regional clusters are identified that share similar characteristics and policy challenges for the effective integration of private insurance into national health care systems: (1) Latin America and Eastern Europe, where there are already developed insurance industries facing important market and policy failures; (2) the Middle East/North Africa region and East Asia, where there is a projected strong growth of PHI that needs to be accompanied by efficient regulation; and finally, (3) South Asia and Sub-Saharan Africa, where PHI will only play a marginal role in the foreseeable future while the scaling up of small-scale, nonprofit insurance schemes appears to be of critical importance. Overall, this survey shows that the role of private insurance varies depending on the economic, social, and institutional settings in a country or region. Private health insurance schemes can be valuable tools to complement existing health-financing options only if they are carefully managed and adapted to local needs and preferences.
Cdk1 phosphorylation sites on Cdc27 are required for correct chromosomal localisation and APC/C function in syncytial Drosophila embryos
Authors: Huang Jun-Yong , Morley Gary , Li Deyu , Whitaker Michael
Published: May 2007

Anaphase-promoting complex or cyclosome (APC/C) controls the metaphase-to-anaphase transition and mitosis exit by triggering the degradation of key cell cycle regulators such as securin and B-type cyclins. However, little is known about the functions of individual APC/C subunits and how they might regulate APC/C activity in space and time. Here, we report that two potential Cdk1 kinase phosphorylation sites are required for the chromosomal localisation of GFP::Cdc27 during mitosis. Either or both of the highly conserved proline residues in the Cdk1 phosphorylation consensus sequence motifs were mutated to alanine (Cdc27 P304A or P456A). The singly mutated fusion proteins, GFP::Cdc27P304A and GFP::Cdc27P456A, can still localise to mitotic chromosomes in a manner identical to wild-type GFP::Cdc27 and are functional in that they can rescue the phenotype of the cdc27L7123 mutant in vivo. However, when both of the Cdk1 phosphorylation sequence motifs were mutated, the resulting GFP::Cdc27P304A,P456A construct was not localised to the chromosomes during mitosis and was no longer functional, as it failed to rescue mutant phenotypes of the cdc27L7123 gene. High levels of cyclin B and cyclin A were detected in mutant third instar larvae brain samples compared with its wild-type control. These results show for the first time that the two potential Cdk1 phosphorylation sites on Drosophila Cdc27 are required for its chromosomal localisation during mitosis and imply that these localisations specific to Cdc27 are crucial for APC/C functions.
Partner referral tools and techniques for the clinician diagnosing a sexually transmitted infection
Authors: Potterat John J
Published: May 2007

Public health agencies have insufficient resources to trace and refer to medical evaluation the sexual partners of patients with sexually transmitted infections (STI). Only a minority of such patients receives formal sex partner referral services. Hence this responsibility rests, by default, with the diagnosing clinician or with the infected patient. Unfortunately, clinicians do not sufficiently appreciate this public health lacuna, and patients with STI usually perform poorly at notifying partners. Clinician and patient obstacles to successful partner referral are discussed, and brief counselling techniques are suggested. Use of patient-delivered therapy, via medication or prescription (dispensed with appropriate warnings), probably serves to emphasize the urgency and importance of notifying partners. Successful referral to medical attention has been shown to help prevent re-infection of the index patient and to curtail community transmission.
Reducing follow-ups: an opportunity to increase the capacity of genitourinary medicine services across the UK
Authors: Ahmed-Jushuf I , Griffiths V ,   The Six Sigma study group
Published: May 2007

Significant increases in genitourinary (GU) medicine clinic workloads throughout the UK have resulted in an unmet demand for appointments, and increased waiting times. In order to meet the government target of a 48-hour maximum waiting time for all patients, many clinics are modernising current practices to increase capacity and improve access to services. The 'Six Sigma' study group of 12 GU medicine clinics which was formed in 2003 to investigate means of enhancing capacity of GU medicine services, has demonstrated that there is a significant amount of unreleased capacity within UK clinics. In this article, the Six Sigma group present potential actions which other GU medicine clinics in the UK may be able to apply and thereby release additional capacity. Example case studies from the Six Sigma study are also presented, illustrating the applicability of this model throughout the UK. The findings of the Six Sigma project offer GU medicine clinics across the UK the opportunity to increase capacity, without adversely affecting quality of care.
Sexually transmitted disease symptom management behaviours among female sex workers in Tashkent, Uzbekistan
Authors: Alibayeva G , Todd C S , Khakimov M M , Giyasova G M , Botros B A , Carr J K , Bautista C T , Sanchez J L , Earhart K C
Published: May 2007

The objective of this cross-sectional study was to assess prevalence and correlates of self-treatment of sexually transmitted diseases (STD) among female sex workers (FSW) in Tashkent, Uzbekistan. Enrolled FSW completed a self-administered questionnaire, HIV serologic testing and optional pelvic examination. STD diagnosis was based on physical examination and/or microscopic findings. Of 448 women, 337 (75.0%) accepted examination; of these, 316 (93.8%) received at least one STD-related diagnosis. Nearly half (45.4%) reported prior STD self-treatment, which was associated with HIV infection (age-adjusted odds ratio [AOR] = 3.20, 95% confidence interval [CI] = 1.45–7.53) and condom knowledge (AOR = 2.10, 95% CI = 1.16–3.80). For those with history of STD, immediate resumption of sex work before completing treatment was common (87.0%). STD self-treatment is common among FSW in Tashkent, particularly women with HIV infection. Confidential venues for STD care and condom utilization programmes targeted to FSW and their clients are needed to prevent STD in this setting.
Estimating dissemination of Centers for Disease Control and Prevention Sexually Transmitted Disease Treatment Guidelines from a survey of physicians
Authors: Hogben Matthew , Wimberly Yolanda H , Moore Sandra
Published: May 2007

Periodically, the Centers for Disease Control and Prevention (CDC) produce guidelines for the treatment of sexually transmitted diseases (STDs) in the USA. To date, few evaluations of the dissemination of these guidelines exist. A paper and pencil survey was distributed via priority mail to a sample of Atlanta-area physicians, 416 (34%) of whom responded with complete data. Physicians were drawn from private practice, managed-care settings and public settings. In all, 85% of respondents treated STD, with a further 10% referring cases. Of those treating STD, 56% owned a copy of the 2002 CDC Treatment Guidelines, and 26% knew how to access them. The corresponding figures for physicians not treating STD were 25% and 30%. Of the physicians who did have copies, half had accessed the internet for their copies. Acquisition of, or the knowledge of how to acquire, the CDC STD Treatment Guidelines was widespread. The internet may be an effective and cost-saving means of disseminating the guidelines, although the continued need for print distribution should not be discounted.