bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of a novel protective monoclonal antibody that recognizes an epitope common to Vibrio cholerae Ogawa and Inaba serotypes
Authors: Dharmasena Madushini N. , Krebs Shelly J. , Taylor Ronald K.
Published: June 2009

A novel protective monoclonal antibody (mAb) that recognizes a lipopolysaccharide (LPS) epitope common between serotypes Ogawa and Inaba of the O1 serogroup ofVibrio choleraewas characterized and the potential to develop peptide mimics of this protective LPS epitope was investigated. mAb 72.1 recognizes both Ogawa and Inaba LPS and it is vibriocidal and protective in passive immunization against infection by strains of both serotypes. The cDNA-derived amino acid sequence of mAb 72.1 is closely related to the previously characterized mAb ZAC-3, which is thought to recognize an epitope in the lipid A core region of O1 LPS. In an attempt to develop a peptide mimic-based vaccine againstV. cholerae, phage display libraries were screened with mAb 72.1 and 11 peptide mimics were identified. Remarkably, all of the peptide sequences identified from linear phage display libraries contained two cysteine residues, suggesting that mAb 72.1 preferentially binds to peptides constrained with a disulphide bond. One of the peptide mimics was immunologically characterized. Although immunization of mice with this peptide mimic conjugated to KLH elicited antibodies against the peptide itself, these antibodies did not cross-react with Ogawa or Inaba LPS. Effectiveness of a peptide mimic as a vaccine may depend on how well the peptide can mimic the carbohydrate interactions when binding to the anti-carbohydrate antibody. Thus, investigating how peptides and LPS bind to mAb 72.1 may be useful in improving current peptide mimics or designing more effective peptide mimics. Identification and characterization of novel protective anti-LPS antibodies may be useful in studying protective epitopes of LPS, which may help develop LPS-based therapeutics againstV. cholerae.
SwrAA activates poly-γ-glutamate synthesis in addition to swarming in Bacillus subtilis
Authors: Osera Cecilia , Amati Giuseppe , Calvio Cinzia , Galizzi Alessandro
Published: June 2009

Poly-γ-glutamic acid (γ-PGA) is an extracellular polymer produced by various strains ofBacillus. Ιt was first described as the component of the capsule inBacillus anthracis, where it plays a relevant role in virulence.γ-PGA is also a distinctive component of ‘natto’, a traditional Japanese food consisting of soybean fermented byBacillus subtilis(natto). DomesticatedB.subtilisstrains do not synthesizeγ-PGA although they possess the functional biosyntheticpgsoperon. In the present work we explore the correlation between the genetic determinants,swrAAanddegU, which allow a derivative of the domestic strain JH642 to display a mucoid colony morphology on LB agar plates due to the production ofγ-PGA. Full activation of thepgsoperon requires the co-presence of SwrAA and the phosphorylated form of DegU (DegU∼P). The presence of either DegU∼P or SwrAA alone has only marginal effects onpgsoperon transcription andγ-PGA production. Although SwrAA was identified as necessary for swarming and full swimming motility together with DegU, we show that motility is not involved inγ-PGA production. Activation ofγ-PGA synthesis is therefore a motility-independent phenotype in which SwrAA and DegU∼P display a cooperative effect.
Detection of Mycobacterium tuberculosis complex organisms in the stools of patients with pulmonary tuberculosis
Authors: El Khéchine Amel , Henry Mireille , Raoult Didier , Drancourt Michel
Published: June 2009

The laboratory diagnosis of pulmonary tuberculosis mainly relies on the detection of Mycobacterium tuberculosis complex (MTC) organisms in the sputum. In patients who do not give sputum, alternative respiratory tract specimens can be obtained only by invasive procedures. Based on the known survival of MTC organisms in the gastric fluid, we hypothesized that swallowed MTC organisms would be detectable in stool samples. We compared the presence of MTC organisms in respiratory tract specimens and stool specimens collected in parallel from the same patients. MTC was detected in cultures grown on egg-based medium after appropriate decontamination, by microscopic examination after Ziehl–Neelsen staining and by real-time PCR detection of IS6110 using internal controls. A case of pulmonary tuberculosis was defined by the presence of (i) clinical and radiological signs and symptoms suggestive of pulmonary tuberculosis, and (ii) culture of MTC organisms from at least one respiratory tract specimen or (iii) the presence of acid-fast bacilli in the sputum that were subsequently identified as MTC organisms by real-time PCR. The observation of 134 patients suspected to be suffering pulmonary tuberculosis led to the identification of 24 cases and 110 non-infected control patients. Cases and controls did not significantly differ with respect to sex but cases were significantly younger than controls. The sensitivity/specificity was 37.5 %/100 % for the microscopic examination of stools, 54.2 %/100 % for culturing and 100 %/97.3 % for real-time PCR. The positive predicted value was 100 %, 100 % and 88.9 %, respectively, and the negative predicted value was 88 %, 90.9 % and 100 %, respectively. In four patients, a stool specimen initially yielded the correct diagnosis of pulmonary tuberculosis before evaluation of the respiratory tract specimen confirmed the diagnosis. These data indicate that stools could be used in conjunction with sputum testing or as an alternative specimen upon which to base the diagnosis of pulmonary tuberculosis by molecular identification of acid-fast bacilli and culture. This non-invasive alternative procedure is of particular interest for patients who cannot expectorate.
An iron-regulated LysR-type element mediates antimicrobial peptide resistance and virulence in Yersinia pseudotuberculosis
Authors: Arafah Sonia , Rosso Marie-Laure , Rehaume Linda , Hancock Robert E. W. , Simonet Michel , Marceau Michaël
Published: June 2009

During the course of its infection of the mammalian digestive tract, the entero-invasive, Gram-negative bacteriumYersinia pseudotuberculosismust overcome various hostile living conditions (notably, iron starvation and the presence of antimicrobial compounds producedin situ). We have previously reported thatin vitrobacterial growth during iron deprivation raises resistance to the antimicrobial peptide polymyxin B; here, we show that this phenotype is mediated by a chromosomal gene (YPTB0333) encoding a transcriptional regulator from the LysR family. We determined that the product ofYPTB0333is a pleiotropic regulator which controls (in addition to its own expression) genes encoding the Yfe iron-uptake system and polymyxin B resistance. Lastly, by using a mouse model of oral infection, we demonstrated that YPTB0333 is required for colonization of Peyer's patches and mesenteric lymph nodes byY. pseudotuberculosis.
Surface-associated lipoprotein PpmA of Streptococcus pneumoniae is involved in colonization in a strain-specific manner
Authors: Cron L. E. , Bootsma H. J. , Noske N. , Burghout P. , Hammerschmidt S. , Hermans P. W. M.
Published: June 2009

Streptococcus pneumoniaeproduces two surface-associated lipoproteins that share homology with two distinct families of peptidyl-prolyl isomerases (PPIases), the streptococcal lipoprotein rotamase A (SlrA) and the putative proteinase maturation protein A (PpmA). Previously, we have demonstrated that SlrA has PPIase activity, and that the enzyme plays a role in pneumococcal virulence. Here, we investigated the contribution of PpmA to pneumococcal pathogenesis. Pneumococcal mutants of D39 and TIGR4 lacking the gene encoding PpmA were less capable of persisting in the nasopharynx of mice, demonstrating the contribution of PpmA to pneumococcal colonization. This observation was partially confirmedin vitro, as the pneumococcal mutants NCTC10319ΔppmAand TIGR4ΔcpsΔppmA, but not D39ΔcpsΔppmA, were impaired in adherence to Detroit 562 pharyngeal cells. This suggests that the contribution of PpmA to pneumococcal colonization is not solely the result of its role in adherence to epithelial cells. Deficiency in PpmA did not result in reduced binding to various extracellular matrix and serum proteins. Similar to SlrA, we observed that PpmA was involved in immune evasion. Uptake of PpmA-deficient D39Δcpsand NCTC10319 by human polymorphonuclear leukocytes was significantly enhanced compared to the isogenic wild-types. In addition, ingestion of D39ΔppmA, but not that of either NCTC10319ΔppmAor TIGR4ΔppmA, by murine macrophage cell line J774 was also enhanced, whereas intracellular killing remained unaffected. We conclude that PpmA contributes to the early stages of infection, i.e. colonization. The contribution of PpmA to virulence can be explained by its strain-specific role in adherence to epithelial cells and contribution to the evasion of phagocytosis.
Actinomyces naeslundii in initial dental biofilm formation
Authors: Dige I. , Raarup M. K. , Nyengaard J. R. , Kilian M. , Nyvad B.
Published: June 2009

The combined use of confocal laser scanning microscopy (CLSM) and fluorescentin situhybridization (FISH) offers new opportunities for analysis of the spatial relationships and temporal changes of specific members of the microbiota of intact dental biofilms. The purpose of this study was to analyse the patterns of colonization and population dynamics ofActinomyces naeslundiicompared to streptococci and other bacteria during the initial 48 h of biofilm formation in the oral cavity. Biofilms developed on standardized glass slabs mounted in intra-oral appliances worn by ten individuals for 6, 12, 24 and 48 h. The biofilms were subsequently labelled with probes againstA. naeslundii(ACT476), streptococci (STR405) or all bacteria (EUB338), and were analysed by CLSM. Labelled bacteria were quantified by stereological tools. The results showed a notable increase in the number of streptococci andA. naeslundiiover time, with a tendency towards a slower growth rate forA. naeslundiicompared with streptococci.A. naeslundiiwas located mainly in the inner part of the multilayered biofilm, indicating that it is one of the species that attaches directly to the acquired pellicle. The participation ofA. naeslundiiin the initial stages of dental biofilm formation may have important ecological consequences.
A two-component system is required for colonization of host cells by meningococcus
Authors: Jamet Anne , Rousseau Clotilde , Monfort Jean-Benoît , Frapy Eric , Nassif Xavier , Martin Patricia
Published: June 2009

In order to adapt to changing environments, bacteria have evolved two-component systems (TCSs) that are able to sense and respond to environmental stimuli. The signal perception relies on a sensor protein whose activation allows rapid adaptation through transcriptional regulation achieved by the regulatory protein. The ability to adhere to and grow on the surface of human host cells is an absolute requirement for many pathogens, including Neisseria meningitidis, in order to colonize new hosts and to disseminate inside their host. Among the four TCSs encoded in the meningococcus genome, only the PhoQ (MisS)/PhoP (MisR) system has been shown to constitute a functional signal transduction circuit. To investigate the involvement of this TCS in the adaptation process requisite for host cell colonization, we have tested the ability to grow on host cells of a mutant inactivated for the sensor of the TCS. Our results demonstrate the involvement of the TCS in the adaptation of the meningococcus to growth on host cells. We show that the expression of the PhoQ (MisS)/PhoP (MisR) TCS is cell-contact controlled. Furthermore, this TCS controls the regulation of a group of genes, the REP2 regulon, previously shown to be cell-contact regulated and to encode functions crucial for the adaptation of the bacterium to host cell colonization. Thus, we provide evidence that one of the four TCSs existing in N. meningitidis contributes to the adaptation of the pathogen to growth on host cells.
Identification of novel Ralstonia solanacearum type III effector proteins through translocation analysis of hrpB-regulated gene products
Authors: Mukaihara Takafumi , Tamura Naoyuki
Published: June 2009

The Hrp type III secretion system (TTSS) is essential for the pathogenicity of Ralstonia solanacearum on host plants. Hrp TTSS is a specialized secretion system that injects virulence proteins, the so-called type III effector proteins, into plant cells. In R. solanacearum, the expression of Hrp TTSS-related genes is regulated by an AraC-type transcriptional activator, HrpB. We have identified 30 hrpB-regulated hpx (
hrpB-dependent expression) genes and three well-known hrpB-regulated genes, popA, popB and popC, as candidate effector genes in R. solanacearum strain RS1000. In this study, we newly cloned 11 additional candidate effector genes that share homology with known hpx genes from R. solanacearum RS1000. Using a Cya reporter system, we investigated the translocation of these 44 gene products into plant cells via the Hrp TTSS and identified 34 effector proteins. These include three effector families composed of more than four members, namely the Hpx4, Hpx30 and GALA families. The Hpx30 family effectors are 2200–2500 aa in size and appear to be the largest class of effector proteins among animal- and plant-pathogenic bacteria. Members of this family contain 12–18 tandem repeats of a novel 42 aa motif, designated SKWP repeats.
Inactivation of the Lactococcus lactis high-affinity phosphate transporter confers oxygen and thiol resistance and alters metal homeostasis
Authors: Cesselin Bénédicte , Ali Djae , Gratadoux Jean-Jacques , Gaudu Philippe , Duwat Patrick , Gruss Alexandra , El Karoui Meriem
Published: June 2009

Numerous strategies allowing bacteria to detect and respond to oxidative conditions depend on the cell redox state. Here we examined the ability ofLactococcus lactisto survive aerobically in the presence of the reducing agent dithiothreitol (DTT), which would be expected to modify the cell redox state and disable the oxidative stress response. DTT inhibitedL. lactisgrowth at 37 °C in aerobic conditions, but not in anaerobiosis. Mutants selected as DTT resistant all mapped to thepstFEDCBAlocus, encoding a high-affinity phosphate transporter. Transcription ofpstFEDCBAand a downstream putative regulator of stress response,phoU, was deregulated in apstAstrain, but amounts of major oxidative stress proteins were unchanged. As metals participate in oxygen radical formation, we compared metal sensitivity of wild-type andpstAstrains. ThepstAmutant showed approximately 100-fold increased resistance to copper and zinc. Furthermore, copper or zinc addition exacerbated the sensitivity of a wild-typeL. lactisstrain to DTT. Inactivation ofpstAconferred a more general resistance to oxidative stress, alleviating the oxygen- and thermo-sensitivity of aclpPmutant. This study establishes a role for thepstlocus in metal homeostasis, suggesting thatpstinactivation lowers intracellular reactivity of copper and zinc, which would limit bacterial sensitivity to oxygen.
Role of Vfr in regulating exotoxin A production by Pseudomonas aeruginosa
Authors: Davinic Marko , Carty Nancy L. , Colmer-Hamood Jane A. , San Francisco Michael , Hamood Abdul N.
Published: June 2009

Pseudomonas aeruginosaexotoxin A (ETA) production depends on the virulence-factor regulator Vfr. Recent evidence indicates that theP. aeruginosairon-starvation sigma factor PvdS also enhances ETA production through the ETA-regulatory generegA. Mutants defective invfr,regAandpvdS, plasmids that overexpress these genes individually andlacZtranscriptional/translational fusion plasmids were utilized to examine the relationship betweenvfr,regAandpvdSin regulatingP. aeruginosaETA production. ETA concentration andregAexpression were reduced significantly in PAOΔvfr, butpvdSexpression was not affected. Overexpression of Vfr produced a limited increase in ETA production in PAOΔpvdS, but not PAOΔregA. Additionally, overexpression of either RegA or PvdS did not enhance ETA production in PAOΔvfr. RT-PCR analysis showed that iron did not affect the accumulation ofvfrmRNA in PAO1. These results suggest that: (i) Vfr enhancestoxAexpression in PAO1 both directly and indirectly throughregA, but not throughpvdS; (ii)vfrexpression is not regulated by iron; and (iii) both Vfr and PvdS cooperate in the presence of RegA to achieve a maximum level oftoxAexpression.
Sequence variations in RepMP2/3 and RepMP4 elements reveal intragenomic homologous DNA recombination events in Mycoplasma pneumoniae
Authors: Spuesens Emiel B. M. , Oduber Minoushka , Hoogenboezem Theo , Sluijter Marcel , Hartwig Nico G. , van Rossum Annemarie M. C. , Vink Cornelis
Published: June 2009

The gene encoding major adhesin protein P1 of Mycoplasma pneumoniae, MPN141, contains two DNA sequence stretches, designated RepMP2/3 and RepMP4, which display variation among strains. This variation allows strains to be differentiated into two major P1 genotypes (1 and 2) and several variants. Interestingly, multiple versions of the RepMP2/3 and RepMP4 elements exist at other sites within the bacterial genome. Because these versions are closely related in sequence, but not identical, it has been hypothesized that they have the capacity to recombine with their counterparts within MPN141, and thereby serve as a source of sequence variation of the P1 protein. In order to determine the variation within the RepMP2/3 and RepMP4 elements, both within the bacterial genome and among strains, we analysed the DNA sequences of all RepMP2/3 and RepMP4 elements within the genomes of 23 M. pneumoniae strains. Our data demonstrate that: (i) recombination is likely to have occurred between two RepMP2/3 elements in four of the strains, and (ii) all previously described P1 genotypes can be explained by inter-RepMP recombination events. Moreover, the difference between the two major P1 genotypes was reflected in all RepMP elements, such that subtype 1 and 2 strains can be differentiated on the basis of sequence variation in each RepMP element. This implies that subtype 1 and subtype 2 strains represent evolutionarily diverged strain lineages. Finally, a classification scheme is proposed in which the P1 genotype of M. pneumoniae isolates can be described in a sequence-based, universal fashion.
The DNA static curvature has a role in the regulation of the ompS1 porin gene in Salmonella enterica serovar Typhi
Authors: De la Cruz Miguel Ángel , Merino Enrique , Oropeza Ricardo , Téllez Juan , Calva Edmundo
Published: June 2009

The DNA static curvature has been described to play a key role as a regulatory element in the transcription process of several bacterial genes. Here, the role of DNA curvature in the expression of the ompS1 porin gene in Salmonella enterica serovar Typhi is described. The web server mutacurve was used to predict mutations that diminished or restored the extent of DNA curvature in the 5′ regulatory region of ompS1. Using these predictions, curvature was diminished by site-directed mutagenesis of only two residues, and curvature was restored by further mutagenesis of the same two residues. Lowering the extent of DNA curvature resulted in an increase in ompS1 expression and in the diminution of the affinity of the silencer proteins H-NS and StpA for the ompS1 5′ regulatory region. These mutations were in a region shown not to contain the H-NS nucleation site, consistent with the notion that the effect on expression was due to changes in DNA structural topology.
DHPG activation of group 1 mGluRs in BLA enhances fear conditioning
Authors: Rudy Jerry W. , Matus-Amat Patricia
Published: June 2009

Group 1 metabotropic glutamate receptors are known to play an important role in both synaptic plasticity and memory. We show that activating these receptors prior to fear conditioning by infusing the group 1 mGluR agonist, (R.S.)-3,5-dihydroxyphenylglycine (DHPG), into the basolateral region of the amygdala (BLA) of adult Sprague–Dawley rats enhances freezing normally supported by a weak footshock. This effect of DHPG was blocked when it was co-infused with either the general group 1 mGluR1 antagonist, (R,S)-1-aminoindan-1,5 dicarboxylic acid (AIDA), or with the selective mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). These results support previous findings by Rodrigues and colleagues that mGluR5s in the lateral region of the amygdala make an import contribution to fear conditioning. More importantly, they support the general ideas embedded in the concept of metaplasticity, as per Abraham, and the synaptic-tagging hypothesis per Frey and Morris—that the processes that specify the content of experience can be experimentally separated from those needed to acquire the memory.
New hippocampal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning
Authors: Jaholkowski Piotr , Kiryk Anna , Jedynak Paulina , Ben Abdallah Nada M. , Knapska Ewelina , Kowalczyk Anna , Piechal Agnieszka , Blecharz-Klin Kamilla , Figiel Izabela , Lioudyno Victoria , Widy-Tyszkiewicz Ewa , Wilczynski Grzegorz M. , Lipp Hans-Peter , Kaczmarek Leszek , Filipkowski Robert K.
Published: June 2009

The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs known for their side effects and the results obtained vary greatly. We used a novel approach, cyclin D2 knockout mice (D2 KO mice), specifically lacking adult brain neurogenesis to verify its importance in learning and memory. D2 KO mice and their wild-type siblings were tested in several behavioral paradigms, including those in which the role of adult neurogenesis has been postulated. D2 KO mice showed no impairment in sensorimotor tests, with only sensory impairment in an olfaction-dependent task. However, D2 KO mice showed proper procedural learning as well as learning in context (including remote memory), cue, and trace fear conditioning, Morris water maze, novel object recognition test, and in a multifunctional behavioral system—IntelliCages. D2 KO mice also demonstrated correct reversal learning. Our results suggest that adult brain neurogenesis is not obligatory in learning, including the kinds of learning where the role of adult neurogenesis has previously been strongly suggested.
Systematic review: standard‐ and double‐dose proton pump inhibitors for the healing of severe erosive oesophagitis – a mixed treatment comparison of randomized controlled trials
Authors: EDWARDS S. J. , LIND T. , LUNDELL L. , DAS R.
Published: June 2009

Background  No randomized controlled trial (RCT) has compared all European‐licensed standard‐ and double‐dose PPIs for the healing of severe erosive oesophagitis.

Aim  To compare the effectiveness of licensed doses of PPIs for healing severe erosive oesophagitis (i.e. esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg and 40 mg, pantoprazole 40 mg and rabeprazole 20 mg).

Methods  Systematic review of CENTRAL, EMBASE and MEDLINE for RCTs in patients with erosive oesophagitis (completed October 2008). Endoscopically verified healing rates at 4 and 8 weeks were extracted and re‐calculated if not analysed by intention‐to‐treat. A mixed treatment comparison was used to combine direct treatment comparisons with indirect trial evidence while maintaining randomization. Odds ratios (OR) are reported compared to omeprazole 20 mg.

Results  A total of 3021 papers were identified in the literature search; 12 were of sufficient quality to be included in the analysis. Insufficient data were available to included rabeprazole. Esomeprazole 40 mg was found to provide significantly higher healing rates at 4 weeks [OR 1.84, 95% Credible Interval (95% CrI): 1.50 to 2.22] and 8 weeks (OR 1.91, 95% CrI: 1.13 to 2.88). No other PPI investigated had significantly higher healing rates than omeprazole 20 mg.

Conclusion  Esomeprazole 40 mg consistently demonstrates higher healing rates compared with licensed standard‐ and double‐dose PPIs.
Development and content validity of a gastroparesis cardinal symptom index daily diary
Authors: REVICKI D. A. , CAMILLERI M. , KUO B. , NORTON N. J. , MURRAY L. , PALSGROVE A. , PARKMAN H. P.
Published: June 2009

Background  The Gastroparesis Cardinal Symptom Index (GCSI) is a patient‐reported outcome for gastroparesis using a two‐week recall period. To minimize potential patient recall effects, a daily diary version of the GCSI (GCSI‐DD) was developed.

Aims  To evaluate the content validity of GCSI‐DD for the symptoms in patients with documented gastroparesis, to capture symptom variability over time and to compare responses of this GCSI‐DD to the original GCSI.

Methods  In gastroparesis adults with delayed gastric emptying, cognitive debriefing interviews were conducted to elicit their perspective on relevant symptoms of gastroparesis and relevant recall periods and to evaluate patient understanding of GCSI‐DD. Patients completed the GCSI‐DD daily over a 2‐week period and completed the GCSI at baseline and the 2‐week follow‐up visit.

Results  Twelve gastroparesis patients, of whom five were diabetic and nine women, reported nausea (100%), vomiting (100%), stomach fullness (75%), bloating (58%) and loss of appetite (50%) were important symptoms. All patients understood diary instructions and item content and reported that the diary captured their gastroparesis symptom experience; 83% considered response scales adequate. There was significant daily variability in GCSI‐DD scores. Mean GCSI‐DD subscale and total scores over 2 weeks correlated strongly (all r > 0.90) with GCSI scores at 2‐week follow‐up.

Conclusions  The GCSI‐DD includes symptoms relevant to patients with gastroparesis, captures daily variability of those symptoms and has psychometric properties consistent with a good patient‐reported outcome endpoint for gastroparesis clinical trials.
Medication errors in elderly people: contributing factors and future perspectives
Authors: Fialová Daniela , Onder Graziano
Published: June 2009

1. Older people have substantial interindividual variability in health, disability, age‐related changes, polymorbidity, and associated polypharmacy, making generalization of prescribing recommendations difficult.

2. Medication use in older adults is often inappropriate and erroneous, partly because of the complexities of prescribing and partly because of many patient, provider, and health system factors that substantially influence the therapeutic value of medications in aged people.

3. A high prevalence of medication errors in older adults results on the one hand from accumulation of factors that contribute to medication errors in all age groups, such as polypharmacy, polymorbidity, enrolment in several disease‐management programmes, and fragmentation of care. On the other hand, specific geriatric aspects play a role in these medication errors; these include age‐related pharmacological changes, lack of specific evidence on the efficacy and safety of medications, underuse of comprehensive geriatric assessment, less availability of drug formulations offering geriatric doses, and inadequate harmonization of geriatric recommendations across Europe.

4. The dearth of geriatric clinical pharmacology and clinical pharmacy services compounds the difficulties.

5. There are gaps in research and clinical practice that lead to frequent medication errors in older adults, which must be solved by future studies and by regulatory measures in order to support errorless and appropriate use medications in these people.
Medication errors: the role of the patient
Authors: Britten Nicky
Published: June 2009

1. Patients and their carers will usually be the first to notice any observable problems resulting from medication errors. They will probably be unable to distinguish between medication errors, adverse drug reactions, or ‘side effects’.

2. Little is known about how patients understand drug related problems or how they make attributions of adverse effects. Some research suggests that patients' cognitive models of adverse drug reactions bear a close relationship to models of illness perception.

3. Attributions of adverse drug reactions are related to people's previous experiences and to their level of education. The evidence suggests that on the whole patients' reports of adverse drug reactions are accurate. However, patients do not report all the problems they perceive and are more likely to report those that they do perceive as severe. Patients may not report problems attributed to their medications if they are fearful of doctors' reactions. Doctors may respond inappropriately to patients' concerns, for example by ignoring them. Some authors have proposed the use of a symptom checklist to elicit patients' reports of suspected adverse drug reactions.

4. Many patients want information about adverse drug effects, and the challenge for the professional is to judge how much information to provide and the best way of doing so. Professionals' inappropriate emphasis on adherence may be dangerous when a medication error has occurred.

5. Recent NICE guidelines recommend that professionals should ask patients if they have any concerns about their medicines, and this approach is likely to yield information conducive to the identification of medication errors.
Prevention of medication errors: detection and audit
Authors: Montesi Germana , Lechi Alessandro
Published: June 2009

1. Medication errors have important implications for patient safety, and their identification is a main target in improving clinical practice errors, in order to prevent adverse events.

2. Error detection is the first crucial step. Approaches to this are likely to be different in research and routine care, and the most suitable must be chosen according to the setting.

3. The major methods for detecting medication errors and associated adverse drug‐related events are chart review, computerized monitoring, administrative databases, and claims data, using direct observation, incident reporting, and patient monitoring. All of these methods have both advantages and limitations.

4. Reporting discloses medication errors, can trigger warnings, and encourages the diffusion of a culture of safe practice. Combining and comparing data from various and encourages the diffusion of a culture of safe practice sources increases the reliability of the system.

5. Error prevention can be planned by means of retroactive and proactive tools, such as audit and Failure Mode, Effect, and Criticality Analysis (FMECA). Audit is also an educational activity, which promotes high‐quality care; it should be carried out regularly. In an audit cycle we can compare what is actually done against reference standards and put in place corrective actions to improve the performances of individuals and systems.

6. Patient safety must be the first aim in every setting, in order to build safer systems, learning from errors and reducing the human and fiscal costs.
Prevention of medication errors: teaching and training
Authors: Likic Robert , Maxwell Simon R. J.
Published: June 2009

1. Poor prescribing is probably the most common cause of preventable medication errors in hospitals, and many of these events involve junior doctors who have recently graduated. Prescribing is a complex skill that depends on a sound knowledge of medicines, an understanding of the principles of clinical pharmacology, the ability to make judgements concerning risks and benefits, and ideally experience. It is not surprising that errors occur.

2. The challenge of being a prescriber is probably greater now than ever before. Medical education has changed radically in the last 20 years, reflecting concerns about an overburdened curriculum and lack of focus on social sciences. In the UK, these changes have resulted in less teaching in clinical pharmacology and practical prescribing as guaranteed features of undergraduate training and assessment. There has been growing concern, not least from students, that medical school training is not sufficient to prepare them for the pressures of becoming prescribers. Similar concerns are being expressed in other countries. While irrefutable evidence that these changes are related to medication errors identified in practice, there is circumstantial evidence that this is so.

3. Systems analysis of errors suggests that knowledge and training are relevant factors in causation and that focused education improves prescribing performance. We believe that there is already sufficient evidence to support a careful review of how students are trained to become prescribers and how these skills are fostered in the postgraduate years. We provide a list of guiding principles on which training might be based.
Medication errors: the importance of an accurate drug history
Authors: FitzGerald Richard J.
Published: June 2009

1. Medication histories are important in preventing prescription errors and consequent risks to patients. Apart from preventing prescription errors, accurate medication histories are also useful in detecting drug‐related pathology or changes in clinical signs that may be the result of drug therapy. A good medication history should encompass all currently and recently prescribed drugs, previous adverse drug reactions including hypersensitivity reactions, any over‐the counter medications, including herbal or alternative medicines, and adherence to therapy.

2. Medication history errors, such as omitting drugs erroneously, are common and often have the potential to harm the patient. Hypersensitivity reactions are often poorly documented or not explored in detail, which may lead to unnecessary avoidance of a drug. Accurate documentation of concomitant herbal or alternative therapies is rare, despite the importance they may have in causing adverse effects or drug‐drug interactions. Polypharmacy, specific drugs, and clinical specialty can affect the risk of medication history errors.

3. There are various strategies to reduce medication history errors. Pharmacists are better at taking an accurate medication history than many physicians or nurses. In the context of acute hospital admissions they reduce error, the risks of adverse drug reactions, and prescription costs. Electronic prescribing may reduce transcription errors, but it can facilitate other errors and still depends on an accurate medication history.

4. Education of prescribers, both in clinical pharmacology and in taking accurate medication histories is vitally important in reducing errors.
Endonasal transsphenoidal surgery and multimodality treatment for giant pituitary adenomas
Authors: De Paiva Neto Manoel Antonio , Vandergrift Alexander , Fatemi Nasrin , Gorgulho Alessandra A. , DeSalles Antonio A. , Cohan Pejman , Wang Christina , Swerdloff Ronald , Kelly Daniel F.
Published: June 2009

Objective  Giant pituitary adenomas (≥40 mm) pose a major management challenge. We describe the experience of a single surgeon and a dedicated neuro‐endocrine team with multimodality treatment of these tumours in three specialized institutions.

Design  Retrospective data set analyses.

Patients  Fifty‐one consecutive patients with a giant adenoma (39 endocrine‐inactive, 12 endocrine‐active; mean tumour diameter 45 mm) treated over 10 years by an endonasal transsphenoidal approach were included. All patients had surgical resection followed by radiotherapy and/or medical therapy as judged necessary.

Measurements  Hormonal and visual status, extent of resection, tumour control rates, complications and use of medical and radiotherapy were evaluated.

Results  Surgery resulted in gross total, near total and subtotal removal in21 (41%), 10 (20%) and 20 (39%) patients respectively. Complete tumour removal was associated with absence of cavernous sinus invasion (P < 0·001). Long‐term endocrine function improved in 49% of patients and new endocrinopathy occurred in 14·6%; 76% required long‐term hormone replacement therapy. Vision improved in 81·5% of the patients and there was no visual worsening. At the last follow up (median 30 months), tumour control was achieved in 96% of patients: 59% with surgery alone, 20% with surgery plus focussed radiotherapy, 18% with surgery and medical therapy and two with all three modalities.

Conclusions  Endonasal surgery provides effective initial treatment for patients with giant adenomas. Multimodality therapy was needed in almost 50% of patients and this rate will likely increase with longer follow up. Close collaboration of neurosurgeons with endocrinologists and radiation oncologists is essential for optimal treatment of patients with these challenging tumours.
Neurofibromatosis type 1: should we screen for other genetic syndromes? A case report of co‐existence with multiple endocrine neoplasia 2A
Authors: Gkaliagkousi E. , Erlic Z. , Petidis K. , Semertzidis P. , Doumas M. , Zamboulis C. , Neumann H. P. H. , Douma S.
Published: June 2009

Background  NF 1 is a genetic disorder with an autosomal dominant pattern of inheritence. It is associated with neoplastic disorders mainly derived from the neural seath. However, the co‐existence of NF1 with the full spectrum of MEN 2A has rarely been reported. The aim of the study was to investigate the presence of secondary neoplasias in a patient with diagnosed NF1, and in particular the presence of hyperparathyroidism and the possible co‐existence with another pheochromocytoma‐related syndrome.

Methods  We report a case of a 70 years old female patient who had NF1. The patient was referred to our center and was diagnosed with an isolated pheochromocytoma of the right adrenal gland for which she underwent right adrenalectomy. We further investigated for the presence of another pheochromocytoma‐related syndrome and in particular for the presence of hyperparathyroidism and medullary thyroid cancer. Molecular screening for germline mutations of the genes NF1, RET and VHL has also been performed.

Results  The patient was further diagnosed with hyperparathyroidism and medullary thyroid cancer, having the full spectrum of the clinical picture of the MEN2A syndrome. The genetic testing revealed the germline mutation for NF1 but not for the RET proto‐oncogene which is generally found in MEN2A cases.

Conclusion  To our knowledge this is a rare case of co‐existence of two pheochromocytoma‐related genetic syndromes, and generates the question of whether all patients with these syndromes should undergo a thorough clinical and laboratory investigation for the possibility of another co‐existing pheochromocytoma‐related genetic syndrome.
Nitrogen and phosphorus allocation in leaves, twigs, and fine roots across 49 temperate, subtropical and tropical tree species: a hierarchical pattern
Authors: Li Ang , Guo Dali , Wang Zhengquan , Liu Hongyan
Published: June 2009

1. Hierarchical branching is a fundamental feature of trees. Understanding how tree architecture is linked to tissue nutrient concentrations, metabolic rates, and life cycles is important for predicting ecosystem processes such as respiration, module turnover, and organic matter decomposition.

2. Here, we examined branch order–nutrient relationships in above‐ and belowground tree branching systems by analysing nitrogen (N), phosphorus (P), and N : P ratio in leaves, the first three orders of twigs, and the first five orders of roots in 49 tree species, including 21 temperate angiosperm species, six temperate gymnosperm species, and 22 subtropical‐tropical angiosperm species.

3. Tissue [N] and [P] declined linearly with increasing twig and root orders across all species. The slope of the linear regression between root order and root [N] was the same between temperate and subtropical‐tropical angiosperms, but steeper in angiosperms than gymnosperms. In contrast, root order–[P] relationship differed between biomes but not between phylogenetic groups, probably due to the significantly lower P availability in subtropical‐tropical soils. Additionally, the magnitude of change in tissue [N] and [P] between successive shoot and root branch orders was not constant across branching levels. Among all fine root orders, first order root tips had [N], [P], and N : P ratio most similar to those of leaves.

4. These results demonstrate that there is a general inverse order–nutrient relationship in above‐ and belowground modules, though specific patterns of this relationship differed between N and P, and between species groups. Moreover, among all root orders within the fine root guild, root tips are the best parallels of leaves in nutrient concentrations. The order–nutrient relationships presented here advances our understanding of functional module construction in trees, and provide a basis for modelling tissue chemistry‐regulated processes such as respiration and decomposition in forest ecosystems.
Follow‐ups of the Cardiovascular Risk in Young Finns Study in 2001 and 2007: Levels and 6‐year changes in risk factors
Authors: Raiko J. R. H. , Viikari J. S. A. , Ilmanen A. , Hutri‐Kähönen N. , Taittonen L. , Jokinen E. , Pietikäinen M. , Jula A. , Loo B.‐M. , Marniemi J. , Lehtimäki T. , Kähönen M. , Rönnemaa T. , Raitakari O. T. , Juonala M.
Published: June 2009

Abstract.  Raiko JRH, Viikari JSA, Ilmanen A, Hutri‐Kähönen N, Taittonen L, Jokinen E, Pietikäinen M, Jula A, Loo B.‐M, Marniemi J, Lehtimäki T, Kähönen M, Rönnemaa T, Raitakari OT, Juonala M (University of Turku; University of Tampere and Tampere University Hospital, Tampere; University of Oulu, Oulu; Vaasa Central Hospital, Vaasa; University of Helsinki, Helsinki; and Center of Social and Health Services, Kuopio; Finland). Follow‐ups of the Cardiovascular Risk in Young Finns Study in 2001 and 2007: Levels and 6‐year changes in risk factors. J Intern Med 2010; 267: 370–384.

Objectives.  To examine cardiovascular risk factor levels in 2007 and their 6‐year changes between 2001 and 2007 using the data collected in the follow‐ups of the Cardiovascular Risk in Young Finns Study.

Design.  Population‐based follow‐up study.

Subjects.  A total of 2204 healthy Finnish adults aged 30–45 years (1210 women; 994 men).

Main outcome measures.  Levels in 2007 and changes between 2001 and 2007 of lipids, insulin, glucose, blood pressure, smoking, body mass index, alcohol consumption, waist and hip circumferences.

Results.  The mean serum total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglyceride concentrations in 30‐ to 45‐year‐old adults were 5.05, 3.09, 1.34 and 1.40 mmol L−1, respectively. Significant changes (P < 0.05) between 2001 and 2007 in 30‐ to 39‐year‐old subjects included a decrease in total cholesterol (−6.6% in men, −5.8% in women), LDL‐cholesterol (−10.2% and −11.6%) and an increase in diastolic blood pressure (3.5% and 3.9%). Waist circumference (1.8% and 5.5%) and systolic blood pressure increased in 36–39 year olds (2.3% and 2.3%). HDL‐cholesterol increased in 30‐ to 33‐year‐old women (5.8%) Glucose levels increased in 30‐ to 39‐year‐old women (3.7%) and 36‐ to 39‐year‐old men (3.6%). Smoking prevalence decreased in 36‐ to 39‐year‐old men from 29.8% to 22.2%.

Conclusions.  The 6‐year changes in total cholesterol, LDL‐cholesterol and HDL‐cholesterol in young Finns were favourable between 2001 and 2007. However, waist circumference, glucose and blood pressure levels increased. Therefore, continuous efforts are still needed in fighting against cardiovascular risk factors.
Vaccinate your child and save its grandparents from a heart attack? Current perspectives in antipneumococcal vaccination
Authors: Vila‐Córcoles Angel
Published: June 2009

Streptococcus pneumoniae is an important cause of morbidity and mortality worldwide. There are three established approaches to anti‐pneumococcal vaccination: capsular polysaccharide pneumococcal vaccine (PPV), protein–polysaccharide conjugate pneumococcal vaccine (CPV) and protein‐based pneumococcal vaccine (PBPV). At present, only a 23‐valent PPV for use in adults and a seven‐valent CPV for use in infants are available in clinical practice. This study reviews available data on the efficacy of the available vaccines in different age groups and disease presentations, and the advantages and shortcomings of each type of vaccine, including future perspectives. Special attention is given to controversies regarding the efficacy of PPV against pneumonia in adults and its protective effects against myocardial infarction.
Review: Autophagy in neurodegeneration: firefighter and/or incendiarist?
Authors: Rami A.
Published: June 2009

Autophagy is an intracellular bulk degradation system that is found ubiquitously in eukaryotes. Autophagy is responsible for the degradation of most long‐lived proteins and some organelles. Cytoplasmic constituents, including organelles, are sequestered into double‐membrane autophagosomes, which subsequently fuse with lysosomes where their contents are degraded. This system has been implicated in various physiological processes including protein and organelle turnover, stress response, cellular differentiation, programmed cell death and pathological conditions. Defects in the autophagy machinery might have several consequences, as they have been associated with neurodegenerative disease and different forms of cancer. Thus, autophagy occupies a crucial position within the cell's metabolism, and its modulation may represent an alternative therapeutic strategy in several pathological settings including stroke, Alzheimer's, Huntington's, Parkinson's diseases and cancer. Recently, research has begun to identify some characteristics of neuronal autophagy. The results suggest that autophagy may provide a neuroprotective mechanism. However, there is evidence showing that dysfunction of autophagy in certain pathological situations can trigger and mediate programmed cell death. Autophagy has also been defined as prime suspect cause of non‐apoptotic cellular demise. However, there is now mounting evidence that autophagy and apoptosis share several common regulatory elements that are crucial in any attempt to understand the dual role of autophagy in cell death and cell survival. It will be of fundamental importance to dissect whether autophagy is primarily a strategy for survival or whether autophagy can also be a part of a cell death programme and thus contribute to cell death. Many questions are open. Is autophagy a direct death execution pathway? Is autophagy an innocent bystander? Is autophagy a defence mechanism or just a scavenger or self‐clearance tool in the cell? A profound understanding of the biological effects and the mechanisms underlying autophagy in neurones might be helpful in seeking effective new treatments for neurodegenerative diseases. Here, we review the defining characteristics of autophagy with special attention to its role in neurodegenerative disorders, and recent efforts to delineate the pathway of autophagic protein degradation in neurone.