A confirmed case of DENV fever was defined as a patient with clinical symptoms (sudden fever onset >38.5° and duration ranging between 2 and 7 days, with the presence of two or more of the following symptoms: severe cephalalgia and retro-orbital pain, arthralgias, myalgias, Cabozantinib datasheet lumbago, maculopapular rash, and hemorrhagic

episodes) confirmed by laboratory tests (virus isolation; presence of viral RNA by RT-PCR; presence of IgM-specific antibodies in the serum; seroconversion or increase by at least four times of the antibody or presence of virus-specific antibodies, confirmed by neutralization, in single serum sample collected). A case-report form containing information about age, sex, countries visited, travel dates, and date of onset of symptoms was completed for each patient. We also estimated the number of imported infections to municipalities with international airports using data on arrivals in Italy from 2008 to October 2011 (Capstats.com, RDC Aviation Ltd, Nottingham, United Kingdom) and data derived from the surveillance system (January 2008–October 2011) in order to define the degree of underreporting. In our model to calculate the estimated number of imported CHIKV and Roxadustat supplier DENV infections in Italy per 100,000 travelers we use as numerator the number of imported

cases derived from the surveillance system by visited area for each study year and as denominator the extrapolated number of travelers from the same areas as

those visited by notified imported cases each study year. All analyses were done using the STATA 11.2 software (Stata Corporation, College Station, TX, USA). not A total of 130 persons were notified from 10 Italian regions during the study period. The population of the reporting regions represents 72% of the Italian population (60 million). Of the 130 reported CHIKV and DENV cases: 57.7% were male, median age was 39 years (range 11–73 y), and most (79.2%) were Italian. A total of 21 (16.2%) were CHIKV, and 109 (83.8%) were DENV. Of the 21 CHIKV cases, 12 (57.1%) were Italian and 9 (42.9%) of other nationalities; 61.9% were females and 10 (47.6%), 6 (28.6%), and 5 (23.8%) were between 0 to 35, 36 to 50 and >50 years old of age, respectively. Overall, nine (42.8%) had visited the Indian Ocean Islands (Mauritius, Maldives, Bali, and Sri Lanka), nine (42.8%) had visited Asia, one (4.8%) had visited Africa, and for two (9.6%) the travel history was unknown. Of the 109 DENV confirmed cases, 93 (85.3%) were Italian and 16 (14.7%) of other nationalities; 61.5% were males and 44 (40.3%), 38 (34.9%), and 27 (24.8%) were between 0 to 35, 36 to 50, and >50 years old of age, respectively. Overall, 44 (40.4%) had visited Asia, 30 (27.5%) had visited Central-South America and Caribbean Islands, 11 (10.1%) had visited the Indian Ocean Islands (Mauritius, Maldives, Indonesia, and Sri Lanka), 10 (9.2%) had visited Africa, and for 14 (12.

Therefore, a study with a larger sample size is needed to clarify the relationship between anti-TNF therapy and endothelial function in patients with RA. In addition, we only performed FMD examination, and did not examine microvascular endothelial function or induced macrovascular dilation using glyceryl trinitrate, which are well-known global measures of endothelial function. Furthermore, the links between systemic inflammation, and vascular function and morphology in patients with RA are not completely supported, as noted in a recent systematic review.[44] Further studies, involving evaluation of both microvascular and macrovascular endothelial function, with much larger numbers of subjects and longer

follow-up periods are warranted to validate the present findings. In conclusion, the present results demonstrate significant associations between the FMD measurements, disease activity and anti-TNF therapy among randomly selected patients with RA. selleck inhibitor Anti-TNF therapy may influence endothelial function more than conventional DMARD therapy. Prospective longitudinal studies examining whether DMXAA cell line anti-TNF therapy is able to improve endothelial function are required. None declared. No funding. TW conceived and designed the study, collected the data, was responsible for the statistics, and drafted and translated the paper. MT conceived the study.

MS conceived the study and advised the translation of the paper. HM advised the statistical evaluation. MS advised the translation of the paper. KS designed the study. TM designed

the study, and was study adviser. “
“To validate the Thai version of the Health Assessment Questionnaire (HAQ) for patients with psoriatic arthritis (PsA). The Thai version of the HAQ was administered to 47 patients with PsA attending our rheumatology clinic. Clinical assessments included the measures of disease activity, disease severity and functional status. The correlation of the single items and total score of the Thai HAQ with the measures of disease activity, disease severity and functional status was assessed using Pearson’s correlation or Spearman rank correlation, as appropriate. Of 47 patients who fulfilled the Classification Criteria for Psoriatic Arthritis (CASPAR), 21 were male. Their mean age ± standard deviation (SD) and Chloroambucil mean disease duration ± SD were 49 ± 10 years and 6.97 ± 6.17 years, respectively. Spondylitis was the most common manifestation (38%). The mean Thai HAQ score was 0.47. The single items and total score of the Thai HAQ were moderately to highly correlated with several measures of disease activity (r = 0.32–0.81, P < 0.01), except for swollen joint count (r = 0.16). For functional status and disease severity, the Thai HAQ was moderately correlated with grip strength (r = −0.39, P < 0.01), but poorly correlated with the range of spinal movement and the number of damaged joints. (r = −0.01 to 0.17).

A single systemic injection of CBZ (20 mg/kg) induced a significant increase in the power of EEG 5–9-Hz oscillations and spindles. Intracellular recordings of glutamatergic TC neurons revealed 5–9-Hz depolarizing wave–hyperpolarizing wave sequences prolonged Natural Product Library solubility dmso by robust, rhythmic

spindle-frequency hyperpolarizing waves. This hybrid sequence occurred during a slow hyperpolarizing trough, and was at least 10 times more frequent under the CBZ condition than under the control condition. The hyperpolarizing waves reversed at approximately −70 mV, and became depolarizing when recorded with KCl-filled intracellular micropipettes, indicating that they were GABAA receptor-mediated potentials. In neurons of the GABAergic thalamic reticular nucleus, the principal source of TC GABAergic inputs, CBZ augmented both the number and the duration of sequences of rhythmic spindle-frequency bursts of action potentials. This indicates that these GABAergic neurons

are responsible for the generation Protein Tyrosine Kinase inhibitor of at least the spindle-frequency hyperpolarizing waves in TC neurons. In conclusion, CBZ potentiates GABAA receptor-mediated TC spindle oscillations. Furthermore, we propose that CT 5–9-Hz waves can trigger TC spindles. “
“The endogenous cannabinoid (endocannabinoid) system plays a key role in the modulation of aversive and nociceptive behaviour. The components of the endocannabinoid system are expressed throughout the hippocampus, a brain region implicated in both conditioned fear and pain. In light of evidence that pain can impact on the expression of fear-related behaviour, and vice versa, we hypothesised that exogenous administration of

the endocannabinoid 2-arachidonoyl glycerol (2-AG) into the ventral hippocampus (vHip) would differentially regulate fear responding in the absence vs. the presence of formalin-evoked nociceptive tone. Fear-conditioned rats showed significantly Rutecarpine increased freezing and a reduction in formalin-evoked nociceptive behaviour upon re-exposure to a context previously paired with footshock. Bilateral microinjection of 2-AG into the vHip significantly reduced contextually induced freezing in non-formalin-treated rats, and reduced formalin-evoked nociceptive behaviour in non-fear-conditioned rats. In contrast, 2-AG microinjection had no effect on fear responding in formalin-treated rats, and no effect on nociceptive behaviour in fear-conditioned rats. The inhibitory effect of 2-AG on fear-related behaviour, but not pain-related behaviour, was blocked by co-administration of the cannabinoid receptor 1 (CB1) antagonist/inverse agonist rimonabant. Tissue levels of the endocannabinoids N-arachidonoylethanolamide (anandamide, AEA) and 2-AG were similar in the vHip of fear-conditioned rats receiving formalin injection and the vHip of fear-conditioned rats receiving saline injection.

Finding a direct relationship between measures of modulation of cortico-spinal excitability,

e.g. changes in MEPs, and measures of modulation of cortical excitability extracted from the EEG is challenging. Paus et al. (2001) found a correlation between MEP amplitude and N100, the negative TEP recorded 100 ms after a single-pulse of TMS. However, this correlation was not found in other studies (e.g. Bender et al., SCH727965 2005). Bonato et al. (2006) also failed to find a correlation between MEPs and N10, N18 or P30. Rather than trying to correlate MEPs with single TEPs, one might be more successful with a combination of TEPs (i.e. the sum and subtraction of weighted TEP values). For example, Maki & Ilmoniemi (2010) found a non-linear correlation between peak-to-peak N15–P30 and MEPs at the single trial level. this website The absence of any strong correlation between

natural fluctuations of MEPs and TEPs is not surprising. Indeed, the variability in MEPs may not only be related to the variability in cortical excitability, but also to the variability in the excitability of the spinal moto-neuron pools recruited by the cortical efferent volley induced by TMS. More successful correlation could thus be expected when comparing EEG and MEPs before and after an induction of plasticity at the cortical level (e.g. with rTMS, including the cTBS protocol presented here, or paired associative stimulation). Low-frequency rTMS over M1 has been shown to induce a reduction of the N45 (Van Der Werf & Paus, 2006) but no consistent

change in MEP could be found. High-frequency rTMS over M1 has been shown to increase both MEPs and global field power measures 15–55 ms after single pulse TMS (Esser et al., 2006). Finally, a decrease or increase of MEPs after LTD-like or long-term potentiation (LTP)-like plasticity (paired-associative stimulation) has also been shown to correlate with global induced brain response in different areas (Huber et al., 2008). To our knowledge, the effects of TBS on TMS-evoked components recorded on the EEG have not been previously reported. This study shows that cTBS-induced modulation of MEPs cannot Carnitine palmitoyltransferase II be explained by the modulation of a single TEP. However, considering a combination of TEPs it is possible to account for a substantial amount of the cTBS-induced modulation of MEPs. The generators of the different TEPs after stimulation of M1 are unclear. Previous studies have shown that the P30 is distributed centrally (Paus et al., 2001) or shows major activation in the contralateral hemisphere, probably reflecting a spreading of brain activity via subcortical pathways (Bonato et al., 2006). The N40 (Bonato et al., 2006) or N45 (Paus et al., 2001; Komssi et al., 2004) forms a dipole centered over the stimulation site and might be caused by a resetting of ongoing rhythmic oscillations (Paus et al., 2001; Van Der Werf & Paus, 2006). The P55 (Komssi et al., 2004) or P60 (Bonato et al., 2006) is generally recorded over the stimulation site.

Determining robust and discriminant questions is a difficult task, but the Royal College Federation has drafted a repository of such questions through an established process and with expert input from specialist diabetologists trained in examination

question methodology. Although the Federation recommends that preparation for the examination should derive from reading up-to-date postgraduate textbooks and specialty journals, as well as through clinical experience, it is evident that a primary focus is placed on national guidelines of good clinical practice and its supportive evidence base, particularly those determined by NICE. Some diabetologists of more mature age may find that certain ‘correct’ answers are RG7420 not entirely concordant with their own judgement, but the remit is clear – adhere to national recommended guidelines! Possibly, the specialty

AZD1208 molecular weight of Diabetes & Endocrinology is more subject to these vicissitudes which may, in part, explain the relatively low pass rates so far attained in the examination, lower than with most other specialty topics. Not surprisingly, this has caused some concern among trainees and a recognition of need for preparatory material targeted specifically at the examination. Although the College curriculum is accessible on the MRCP website, demand for an additional practice resource of questions has been clearly identified from the body of young diabetologists in training. With this need HSP90 in mind we are pleased

to announce within this issue (page 10) a new CPD learning initiative, developed in partnership between the Young Diabetologists Forum (YDF) and Practical Diabetes International, and supported by an unrestricted educational grant from Boehringer Ingelheim. We believe this will prove of useful benefit for SpR/StR trainees in Diabetes & Endocrinology (the latter being a parallel professional requirement combined with diabetes) and should prove of more than passing interest to established consultants and no doubt to other disciplines as well. We are building a bank of peer-reviewed questions in current examination format, and we should be pleased to receive readers’ submissions for future questions and answers. By providing this CPD opportunity for those working towards the College SCE, it is our hope that a greater measure of success in the examination pass rate will be achieved and that trainees will feel that much better prepared for the test ahead.

Categorical variables were expressed as numbers (percentages)

and continuous variables as medians (Q1–Q3). Continuous variables were log-transformed to improve their normal distribution. Categorical variables were compared using the χ2 test or Fisher’s exact test, as appropriate. Student’s t-test or the Mann–Whitney test, if applicable, was used to compare continuous variables. The Kruskal–Wallis test was used to compare continuous variables among three or more PCI32765 groups. Variables with a level of significance <0.2 in the univariate analysis were included in multivariate logistic regression models to determine the independent predictors of F≥2 and F4. The logistic regression equation was tested as a predictive

model. The diagnostic value of the model was evaluated by measuring the areas under the receiver operating characteristic curves (AUROCs). Cut-off values were selected from the AUROCs to maximize the PPV and NPV. The diagnostic accuracy was calculated on the basis of sensitivity, specificity, PPV Veliparib ic50 and NPV, considering F≥2 and F4 as disease. The statistical analysis was carried out using the spss 15 statistical software package (SPSS, Chicago, IL, USA). The study was performed according to the Helsinki declaration and was approved by the Ethics Committee of Hospital Universitario de Valme. Ninety HIV/HCV-coinfected patients met the inclusion criteria Ergoloid for the study. The characteristics of the patients are summarized in Table 1. Fifty-nine patients (66%) had F≥2 and 16 (18%) had cirrhosis according to the liver biopsy. Eighty-three patients (92%) were on antiretroviral therapy, and 68 (76%) of them had undetectable HIV viral load at the time of the liver biopsy. The median (Q1–Q3) serum levels were 141.6 (126.4–171) ng/mL for TIMP-1 and 303.8 (255.5–369.9) ng/mL for MMP-2. The serum levels of TIMP-1 and MMP-2 by fibrosis stage are shown in Figure 1. Only the serum levels of MMP-2 were associated with liver fibrosis.

The AUROC [95% confidence interval (CI)] for TIMP-1 serum levels was 0.57 (0.44–0.69) and that for MMP-2 serum levels was 0.64 (0.52–0.75) for the diagnosis of F≥2. The AUROC (95% confidence interval) for TIMP-1 serum levels was 0.64 (0.47–0.81) and that for MMP-2 serum levels was 0.79 (0.67–0.93) for the diagnosis of F4. The AUROC for TIMP-1 to diagnose either F≥2 or F4 was not significantly different from 0.5. The best MMP-2 cut-off value for diagnosis of F≥2 was ≥344 ng/mL. Twenty-eight patients (31%) were classified as having F≥2 using this cut-off. Four (14%) of them showed F1 in the liver biopsy. The cut-off of MMP-2≥344 ng/mL yielded a PPV of 86%. The best MMP-2 cut-off value to detect cirrhosis was ≥500 ng/mL. Eight patients (9%) were classified as having cirrhosis using this cut-off. Three (38%) of them were misclassified: two showed F2 and one F3. This cut-off yielded a PPV of 63% and an NPV of 87%.

Virtually as a one-man show, he conducted phase II Selleck CHIR99021 and phase III studies on the efficacy of a P. aeruginosa flagella vaccine and lately he strongly pursued the concept of using nitric oxide (NO) inhalation therapy in CF patients, to help disperse P. aeruginosa biofilms in the lung. Gerd Döring was the President of the European Cystic Fibrosis Society from 1998 to 2006, and thereafter until his death, the Editor-in-Chief of the Journal of Cystic Fibrosis. During these fifteen years, Gerd organized European Consensus Conferences that resulted in guidelines for the early intervention and prevention of lung disease, clinical trials, and the management of nutrition and infections. The first

consensus paper was published in 2000 on the antibiotic therapy against P. aeruginosa in CF. Gerd Döring was a very creative and inspiring scientist with a distinct sense of humor and a knack for nonconformity, which did not always facilitate his own academic career in Germany, but greatly helped him with international networking. Many of his publications are the fruit of international collaborations that he initiated. In discussions, Gerd could reach high-flying objectives and conclusions, often leaving his own ground staff puzzled. But when he was grounded

again, with his hard-working attitude, he got do-able things done and this is amply reflected by his list of over 200 scientific publications. Apart from science, the company of Gerd was always enjoyable as he was fond of good wines and food, classical music, and his vintage car, a Citroën 15 familiale, GW-572016 concentration which he used on special

occasions. Gerd was sorry that he had to leave so early – his wife Cornelia, his two sons, his friends, and his work and projects – but found comfort in looking those back on a life well spent and on a scientific oeuvre fully recognized by his peers. “
“The aim of this study was to examine the filament formation and differential gene expression of Listeria monocytogenes 08-5923 grown on refrigerated vacuum-packaged ham products with various NaCl concentrations. Filament formation of L. monocytogenes was observed on ham products with 1.35% and 2.35% NaCl, which was monitored using flow cytometry by measuring forward light scatter. Quantitative real-time PCR was used to study the differential expression of genes in filamented cells of L. monocytogenes grown on hams following 2 or 3 months of storage at 4 °C. The genes involved in cell division (ftsX/lmo2506), cell wall synthesis (murZ/lmo2552), and NADPH production (gnd/lmo1376) were significantly downregulated in filamented cells of L. monocytogenes grown on ham with 2.35% NaCl stored at 4 °C. To our knowledge, this study reports the first evidence of filament formation of Listeria grown on meat products, which could impact the food safety risk and tolerance levels of L. monocytogenes set by regulatory agencies.

Nevertheless, some reports revealed that massive amplification

of antibiotic biosynthesis gene cluster is often one of the outcomes of empirical strain improvement programs. The kanamycin-overproducing strain, Streptomyces kanamyceticus 12-6 generated by classical mutagenesis possesses tandem amplification of the entire kanamycin (Km) biosynthetic gene cluster and the level of Km production is linearly www.selleckchem.com/products/GDC-0941.html co-related with the copy number of the Km biosynthetic gene cluster (Yanai et al., 2006). A penicillin-overproducing strain of Penicillium chrysogenum contains a large number of copies of penicillin biosynthetic genes (pcbAB, pcbC, and penDE) in tandem on a c. 57.9-kb DNA fragment (Fierro et al., 1995). In the industrial strain Streptomyces lincolnensis 78-11; the non-adjacent gene clusters for the production of lincomycin and melanin are duplicated (Peschke et al., 1995). These examples imply that introduction of extra copies of biosynthetic gene clusters into a wild-type strain might be an effective approach to improve the yield of the corresponding product. However, most of the antibiotic biosynthetic genes often cluster in a contiguous region containing tens of thousands of nucleotide base pairs in the chromosome. They are consequently almost impossible to manipulate via restriction endonucleases

and DNA ligases due to the frequent occurrence of cleavage sites. Reports focusing on overexpressing these biosynthetic gene clusters in parental strain through directed genetic approaches are few. The Red/ET recombination Smad inhibitor technology provides a convenient and simple method for engineering large DNA fragments in Escherichia coli. The recombineering is mediated by homologous recombination, which occurs between two DNA molecules and requires only short homology regions (c. 40–50 bp) for efficient recombination (Zhang et al., 2000). The myxochromide S (mchS, c. 30 kb) and myxothiazol (mta, c. 60 kb) gene clusters from the myxobacteria

Stigmatella aurantiaca, the epothilone (epo, c. 60 kb) gene cluster from myxobacteria Sorangium cellulosum have all been successfully engineered for heterologous expression by different strategies based on Red/ET technology (Wenzel et al., 2005; Perlova et al., 2006). The S. spinosa CCTCC M206084 isolated by our laboratory has a low capability for spinosyn production. We thus attempted Leukotriene-A4 hydrolase to improve its spinosyn productivity through duplication of the spinosyn biosynthetic genes. It is difficult to obtain the c. 74-kb gene cluster on one single vector by one step and therefore we first directly cloned part of the spinosyn biosynthetic gene cluster (c. 18 kb) which encoded the enzymes for cross-bridging of the cyclized polyketide, for deoxysugar biosynthesis, attachment and methylation from the genomic DNA of S. spinosa CCTCC M206084 with the assistance of Red/ET recombination instead of constructing a genomic library. The resultant plasmid pUCAmT-spn was then introduced into S. spinosa CCTCC M206084 through conjugal transfer.

“
“We recorded brain activity when 21 subjects judged the beauty (aesthetic or affective judgment) and brightness (perceptual or cognitive judgment) of simultaneously presented paintings. Aesthetic judgments engaged medial and lateral subdivisions of the orbitofrontal cortex as well as subcortical

stations associated with affective motor planning (globus pallidus, putamen–claustrum, amygdala, and cerebellar vermis), whereas the motor, premotor and supplementary motor areas, as well as the anterior insula and the dorsolateral prefrontal cortex, were engaged 17-AAG chemical structure by both kinds of judgment. The results lead us to conclude: (i) that there is a functional specialization for judgment, with aesthetic judgments engaging distinct systems, in addition to those that they share with perceptual judgments; (ii) that the systems

engaged by affective judgments are those in which activity correlates with polar experiences (e.g. love–hate, beauty–ugliness, and attraction–repulsion); and (iii) that there is also a functional specialization in the motor pathways, with aesthetic judgments engaging motor systems not engaged by perceptual judgments, in addition to www.selleckchem.com/products/gsk1120212-jtp-74057.html those engaged by both kinds of judgment. “
“Most early human immunodeficiency virus type 1 (HIV-1) strains are macrophage (M)-tropic HIV variants and use the chemokine receptor CCR5 for infection. Neuronal loss and dementia are less severe among individuals infected with M-tropic strains. However, after several years, the T-cell (T)-tropic HIV strain, which uses the CXCR4 variant, can emerge in conjunction with brain abnormalities, suggesting strain-specific differences in neuropathogenicity. The molecular and cellular mechanisms of such diversity remain under investigation. We have previously demonstrated that HIV envelope protein gp120IIIB, PDK4 which binds to CXCR4, causes neuronal apoptosis in rodents.

Thus, we have used a similar experimental model to examine the neurotoxic effects of M-tropic gp120BaL. gp120BaL was microinjected in the rat striatum and neuronal apoptosis was examined in the striatum, as well as in anatomically connected areas, such as the somatosensory cortex and the substantia nigra. gp120BaL promoted neuronal apoptosis and tissue loss that were confined to the striatum. Apoptosis was associated with microglial activation and increased levels of interleukin-1β. Intriguingly, gp120BaL increased brain-derived neurotrophic factor in the striatum. Overall, our data show that gp120BaL demonstrates a different neuropathological profile than gp120IIIB. A better understanding of the pathogenic mechanisms mediating HIV neurotoxicity is vital for developing effective neuroprotective therapies against AIDS-associated dementia complex.

We report the results from further analyses investigating the frequency, time distribution and severity of AEs

and laboratory abnormalities of interest for etravirine, performed using the week 96 data set from the DUET trials. For these analyses, AEs of interest were selected based on their relevance in the target population (i.e. treatment-experienced, HIV-1-infected patients), their known association with other antiretrovirals and their potential importance based on preclinical or earlier clinical data. We also present the frequency of AEs and laboratory abnormalities per 100 patient-years of exposure for all AEs and laboratory abnormalities of interest to account OSI-744 research buy for the difference in extent of exposure between the etravirine and placebo groups. DUET-1 (NCT00254046) and DUET-2 (NCT00255099) were randomized, double-blind, placebo-controlled, phase III trials of 48 weeks’ duration, with an optional open-label 48-week extension period. Patients were randomized to receive etravirine 200 mg twice daily (bid) or placebo, both in combination with a background regimen of darunavir/ritonavir 600/100 mg bid, investigator-selected nucleoside

reverse transcriptase inhibitors and optional BTK inhibitor order enfuvirtide. The DUET trial design and methodology have been previously reported in detail [3, 6, 7]. Treatment-experienced, HIV-1-infected patients with plasma viral load > 5000 HIV-1 RNA copies/mL were enrolled if they had been on stable therapy for ≥ 8 weeks, had at least one NNRTI resistance-associated mutation (RAM) and at least three primary Cediranib (AZD2171) protease inhibitor mutations at screening or in documented historical genotype. The trial protocols were reviewed and approved by the relevant Independent Ethics Committees or Institutional Review Boards,

and written informed consent was obtained from all participants prior to any trial-related procedures. The trials were conducted according to the principles of good clinical practice, the Declaration of Helsinki and the European Union Clinical Trials Directive. The week 96 pooled analysis of DUET-1 and DUET-2 was pre-specified. Safety assessments were carried out every 8 weeks between week 48 and week 96. For the purposes of this analysis, AEs of interest (and preferred terms) were: nervous system AEs (e.g. headache, dizziness, somnolence, memory impairment, amnesia, disturbance in attention, balance disorder, and restless legs syndrome); psychiatric AEs (e.g. depression, insomnia, anxiety, sleep disorder, libido decreased, abnormal dreams, stress, confusional state, nightmare and panic attack); rash-related AEs (e.g.