A scale to measure pain in non-verbally communicating older patients: the EPCA-2 Study of its psychometric properties

We have constructed and validated the Elderly Pain Caring Assessment 2 (EPCA-2) an 8 items behavioural scale to rate the intensity of pain in non-verbally communicating older (age 65 years) patients (NVC-OP). It was postulated that the assessed pain had two dimensions (signs outside and during caregiving). The first version of the scale was constructed on the basis of the results of a survey among 48 experienced nurses and caregivers and of a review of the literature. After testing of three intermediate versions, the psychometrics properties of the final version were studied on 340 NVC-OP. The face and content validities were good. Convergent validity: the total score was well correlated both with a pain global clinical score given by two highly experienced observers (r(s)=0.846) and with the opioid dose prescribed in a sub-group of patients (r(s)=0.698). The discriminant and divergent validities were satisfactory. After factor analysis, the internal structure of the scale was consistent with the postulated two-dimensional structure of the construct. The inter-rater reliability was very good (ICC=0.877) and is always equally good irrespective of the status (doctor, nurse and caregiver) of the raters. The internal consistency was highly satisfactory (alpha=0.79). The responsiveness evaluated in 4 ways was always very good. EPCA-2 may provided nurses, caregivers and doctors with a validated instrument for pain assessment in NVC-OP.     

Impairment of the Growth of Plasmodium Falciparum in HbEE Erythrocytes

HbE is a β-chain mutant frequently found among inhabitants of Southeast Asia and surrounding territories. We find that Plasmodium falciparum multiplies more slowly in erythrocytes from individuals homozygous for HbE than in cells from HbA individuals. In contrast, this parasite grows normally in erythrocytes heterozygous for HbE. This is the first direct evidence that suggests what has been suspected on the basis of circumstantial data, that HbE-containing erythrocytes might be advantageous to the carrier in regions with endemic malaria.     

Reduced azole susceptibility in genotype 3 Candida dubliniensis isolates associated with increased CdCDR1 and CdCDR2 expression

Candida dubliniensis is a recently identified yeast species primarily associated with oral carriage and infection in individuals infected with the human immunodeficiency virus. The species can be divided into at least four genotypes on the basis of the nucleotide sequence of the internal transcribed spacer region of the rRNA operon. Previous studies have shown that a small number of clinical isolates belonging to genotype 1 are resistant to the commonly used antifungal drug fluconazole. The aim of the present study was to investigate the molecular mechanisms responsible for reduced susceptibility to azole drugs in C. dubliniensis genotype 3 isolates obtained from a patient with fluconazole-recalcitrant oral candidiasis. Four isolates from a single clinical sample, one susceptible, the other three exhibiting reduced susceptibilities to fluconazole, itraconazole, ketoconazole, voriconazole, and posaconazole, were examined. Results showed that reduced susceptibility to azole drugs was associated with an increase in the expression of the multidrug transporters CdCDR1 and CdCDR2 which correlated with reduced intracellular accumulation of radiolabeled fluconazole and an increase in the activity of energy-dependent efflux mechanisms. In contrast to observations made in previous studies, overexpression of the multidrug transporter CdMDR1 was not observed. Despite a thorough investigation of all commonly encountered mechanisms of azole resistance, no other mechanism could be associated with reduced susceptibility to azole drugs in the clinical isolates studied. This is the first report of CdCDR2 involvement in azole resistance in C. dubliniensis.     

Mechanisms of azole resistance in petite mutants of Candida glabrata

We previously showed that resistant colonies of Candida glabrata inside the azole inhibition zones had respiratory deficiency due to mutations in mitochondrial DNA. Here, we analyzed the mechanisms of azole resistance in petite mutants of C. glabrata obtained by exposure to fluconazole or induced by ethidium bromide. The respiratory deficiency of these mutants was confirmed by oxygraphy and flow cytometric analysis with rhodamine 123, and its mitochondrial origin was demonstrated by transmission electron microscopy and restriction endonuclease analysis of the mitochondrial DNA. Flow cytometry with rhodamine 6G suggested an increased drug efflux in mutant cells, which was further supported by Northern blot analysis of the expression of the C. glabrata CDR1 (CgCDR1) and CgCDR2 genes, encoding efflux pumps. Conversely, the expression of CgERG11, which encodes the azole target, was not affected by petite mutations, and no differences were seen in the sequence of this gene between parent isolates and mutants. Moreover, sterol analysis showed similar overall amount of sterols in parent and mutant cells, but quantitative modifications were observed in the mutants, with almost undetectable biosynthesis intermediates. Further analysis performed after separation of free sterols from steryl esters revealed a defect in sterol esterification in mutant cells, with free ergosterol representing 92% of the overall sterol content. Thus, resistance or decreased susceptibility to azoles in petite mutants of C. glabrata is associated with increased expression of CgCDR1 and, to a lesser extent, of CgCDR2. In addition, the marked increase in free ergosterol content would explain their increased susceptibility to polyenes.     

Pharmacoscintigraphic comparison of HMR 1031, a VLA-4 antagonist, in healthy volunteers following delivery via a nebulizer and a dry powder inhaler

A pharmacoscintigraphic study was conducted to compare the dose deposition of HMR 1031 from the existing nebulizer formulation and the new Ultrahaler device to help determine the doses for future phase 2 trials. This was a single-dose, open-label, randomized, two-way crossover study in which HMR 1031 (3 mg) was delivered by the Ultrahaler and the Pari LC Star nebulizer to 12 healthy male subjects. For both treatments, the formulations were radiolabeled with technetium-99m pertechnetate such that a maximum of 10 MBq was delivered on each study day. Scintigraphic images were acquired immediately after dosing to estimate the percentage of the dose delivered to the lungs and oropharynx. Serial plasma samples were collected up to 12 hours post-dose on each occasion and analyzed for HMR 1031 by a LC/MS/MS method with a lower limit of quantitation of 10 pg/mL (0.01 ng/mL). Pharmacokinetic parameters were calculated for HMR 1031 using noncompartmental methods. No serious adverse events were reported. The systemic absorption of HMR 1031 following inhalation administration was relatively rapid, with median T(max) values of 0.5 hours and 1.0 hours post-dose after administration via Ultrahaler and nebulizer, respectively. The mean plasma AUC(0-12) (Ultrahaler, 15.8 ng*h/mL; nebulizer, 11.1 ng*h/mL) and C(max) (Ultrahaler, 4.96 ng/mL; nebulizer, 2.28 ng/mL) values were approximately 42% and 118% higher for the Ultrahaler compared with the nebulizer. The mean terminal half-life of HMR 1031 was similar after administration from both devices (2.91 and 3.18 hours). Based on the scintigraphic data, the lung deposition of HMR 1031 after administration by Ultrahaler (24.6% of the administered dose) was approximately 37% higher compared with the lung deposition from the nebulizer (18.0% of the administered dose). This observation was in agreement with the relative difference in the plasma AUC values achieved after administration of the two formulations. The in vivo results based on the scintigraphic data were also comparable with those from in vitro studies for the Ultrahaler. Based on the ratio of the dose delivered by both the formulations, the required doses for the future Ultrahaler formulation can be predicted.     

Detection of sentinel lymph nodes by tilmanocept in oral squamous cell carcinoma

Clinical & Experimental Metastasis -     

Prospective analysis of discordant results between biochemical markers and biopsy in patients with chronic hepatitis C

BACKGROUND: The FibroTest and ActiTest are noninvasive biochemical markers of liver injury that are intended for use as alternatives to liver biopsy in patients with chronic hepatitis C. The aims of this study were to assess the quality of biopsy and the prevalence of discordances between biopsy and markers, to identify factors associated with discordances, and to attribute these discordances to either markers or biopsy failure. METHODS: Fibrosis stage and activity grade were prospectively assessed on the same day by a liver biopsy and by markers. On the basis of risk factors for failure and independent endpoints, discordance was classified as being attributable to biopsy or to markers. RESULTS: Only 74 of 537 patients (14%) had a biopsy size > or =25 mm. Discordance was observed in 154 of 537 patients (29%), including 16% for fibrosis staging and 17% for activity grading. Steatosis, an inflammatory profile, and biopsy size were associated with discordance. Discordance was attributable to failure of markers in 13 patients (2.4%) and to biopsy failure in 97 (18%; P <0.001 vs Fibrotest and Actitest), and was nonattributable in 44 patients (8.2%). The most frequent failures attributable to markers were false negatives (1.3%) attributable to inflammation. The most frequent failures attributable to biopsy were false negatives of activity grading (10.1%) and of fibrosis staging (4.5%), both associated with smaller biopsy size and steatosis. False positives of fibrosis staging (3.5%) were associated with fragmented biopsies. CONCLUSION: In this series, the size of liver biopsy is adequate in only a minor proportion (approximately 14%) of patients with chronic hepatitis C. When biopsy and marker results are discordant, a reason can be identified in more than two-thirds of cases and, in those cases, biopsy failure is >7 times more common than diagnostic failure of markers.