Does reduced oxygen delivery cause lactic acidosis in falciparum malaria? An observational study.

BACKGROUND: Lactic acidosis with an elevated lactate-pyruvate ratio suggesting anoxia is a common feature of severe falciparum malaria. High lactate levels are associated with parasitized erythrocyte sequestration in the microcirculation. To assess if there is an additional contribution to hyperlactataemia from relatively inadequate total oxygen delivery, oxygen consumption and delivery were investigated in patients with malaria. METHODS: Adult Bangladeshi and Indian patients with uncomplicated (N = 50) or severe (N = 46) falciparum malaria or suspected bacterial sepsis (N = 27) and healthy participants as controls (N = 26) were recruited at Chittagong Medical College Hospital, Chittagong, Bangladesh and Ispat General Hospital, Rourkela, India. Oxygen delivery (DO2I) was estimated from pulse oximetry, echocardiographic estimates of cardiac index and haematocrit. Oxygen consumption (VO2I) was estimated by expired gas collection. RESULTS: VO2I was elevated in uncomplicated median (IQR) 185.1 ml/min/m2 (135-215.9) and severe malaria 192 ml/min/m2 (140.7-227.9) relative to healthy persons 107.9 ml/min/m2 (69.9-138.1) (both p < 0.001). Median DO2I was similar in uncomplicated 515 ml/min/m2 (432-612) and severe 487 ml/min/m2 (382-601) malaria and healthy persons 503 ml/min/m2 (447-517) (p = 0.27 and 0.89, respectively). The VO2/DO2 ratio was, therefore, increased by similar amounts in both uncomplicated 0.35 (0.28-0.44) and severe malaria 0.38 (0.29-0.48) relative to healthy participants 0.23 (0.17-0.28) (both p < 0.001). VO2I, DO2I and VO2/DO2 did not correlate with plasma lactate concentrations in severe malaria. CONCLUSIONS: Reduced total oxygen delivery is not a major contributor to lactic acidosis in severe falciparum malaria.

Identifying Improved and Non-improved Aspects of Health-related Quality of Life After Liver Transplantation Based on the Assessment of the Specific Questionnaire Liver Disease Quality of Life.

INTRODUCTION: The specific questionnaire Liver Disease Quality of Life (LDQOL) is a valid tool for measuring quality of life (QOL) and has been used to show that liver transplantation (LT), which is an effective treatment for end-stage liver disease, may improve QOL. OBJECTIVES: This study aims to identify aspects of QOL that improve after LT and those that do not. PATIENTS AND METHODS: Patients accepted for LT were invited to answer the LDQOL at baseline and after transplantation at 6 and 12 months. LDQOL contains the 36-item Short Form Health Survey (SF-36) and 12 specific dimensions. Responsiveness was assessed using the paired Student t test. RESULTS: The study included a cohort of 156 patients, 73% males, of an average age of 53 (26-67) years, with the following common indications: tumor (35%), hepatitis C (23%), and alcohol-related (21%) liver disease. Mean scores showed a statistically significant (P < .05) improvement after 1 year in 6 of 8 SF-36 dimensions, in the physical component summary score, and in 7 of 12 disease-specific dimensions. The two dimensions that showed no improvement in the SF-36 dimensions were "social functioning" and "vitality," whereas the specific dimensions to not improve were "sleep problems," "social interaction," "activities of daily living," and "concerns about the future." CONCLUSION: Findings suggest that perceived QOL after LT improves but could be further enhanced with the use of specific programs for amending sleep disorders and physical aspects.

Low prevalence of meticillin-resistant Staphylococcus aureus carriage at hospital admission: implications for risk-factor-based vs universal screening.

BACKGROUND: There is debate over the optimal policy for detecting meticillin-resistant Staphylococcus aureus (MRSA) colonization at hospital admission. The emergence of community-associated (CA)-MRSA may compromise targeted screening strategies based on risk factors for healthcare-associated (HA)-MRSA. AIM: To determine the prevalence of MRSA colonization at admission, and the genotype and molecular epidemiology of the strains involved. METHODS: A 12-month observational study was performed at a 1200-bed London tertiary referral hospital from 1 April 2008 to 1 March 2009. All available MRSA isolates were genotyped by spa and staphylococcal cassette chromosome mec (SCCmec) typing. FINDINGS: The overall MRSA colonization rate was 2.0% of 28,892 admissions (range 6.6% in critical care to 0.8% in obstetrics/gynaecology/neonatology). The overall frequency of previously unknown carriage of MRSA on admission was 1.4%. Most colonizing strains were epidemic HA-MRSA-15 and -16. However, heterogeneous CA strains accounted for 18% of recovered isolates, including 37.5% of MRSA from accident and emergency and 23.1% of MRSA from surgery. The CA-MRSA strain types had significantly different epidemiological associations from the HA-MRSA strains, so risk factors used for the identification of HA-MRSA may not detect CA-MRSA reliably. CONCLUSION: The low rate of HA-MRSA in the UK increases the relative proportion due to CA-MRSA, for which conventional risk-factor-based screening strategies may be less effective. Cost-benefit analyses of universal MRSA admission screening will need to take account of this new epidemiology.

Clinical application of real-time PCR to screening critically ill and emergency-care surgical patients for methicillin-resistant Staphylococcus aureus: a quantitative analytical study.

The clinical utility of real-time PCR screening assays for methicillin (methicillin)-resistant Staphylococcus aureus (MRSA) colonization is constrained by the predictive values of their results: as MRSA prevalence falls, the assay's positive predictive value (PPV) drops, and a rising proportion of positive PCR assays will not be confirmed by culture. We provide a quantitative analysis of universal PCR screening of critical care and emergency surgical patients using the BD GeneOhm MRSA PCR system, involving 3,294 assays over six months. A total of 248 PCR assays (7.7%) were positive; however, 88 failed to be confirmed by culture, giving a PPV of 65%. Multivariate analysis was performed to compare PCR-positive culture-positive (P+C+) and PCR-positive culture-negative (P+C-) assays. P+C- results were positively associated with a history of methicillin-sensitive Staphylococcus aureus infection or colonization (odds ratio [OR], 3.15; 95% confidence interval [CI], 1.32 to 7.54) and high PCR thresholds of signal intensity, indicative of a low concentration of target DNA (OR, 1.19 per cycle; 95% CI, 1.11 to 1.26). P+C- results were negatively associated with a history of MRSA infection or colonization (OR, 0.19; 95% CI, 0.09 to 0.42) and male sex (OR, 0.40; 95% CI, 0.20 to 0.81). P+C+ patients were significantly more likely to have subsequent positive MRSA culture assays and microbiological evidence of clinical MRSA infection. The risk of subsequent MRSA infection in P+C- patients was not significantly different from that in case-matched PCR-negative controls. We conclude that, given the low PPV and poor correlation between a PCR-positive assay and the clinical outcome, it would be prudent to await culture confirmation before altering infection control measures on the basis of a positive PCR result.

Characterization of naturally occurring HPV16 integration sites isolated from cervical keratinocytes under noncompetitive conditions.

As the high-risk human papillomavirus (HPV) integrants seen in anogenital carcinomas represent the end-point of a clonal selection process, we used the W12 model to study the naturally occurring integration events that exist in HPV16-infected cervical keratinocytes before integrant selection. We performed limiting dilution cloning to identify integrants present in cells that also maintain episomes. Such integrants arise in a natural context and exist in a noncompetitive environment, as they are transcriptionally repressed by episome-derived E2. We found that integration can occur at any time during episome maintenance, providing biological support for epidemiologic observations that persistent HPV infection is a major risk factor in cervical carcinogenesis. Of 24 different integration sites isolated from a single nonclonal population of W12, 12 (50%) occurred within chromosome bands containing a common fragile site (CFS), similar to observations for selected integrants in vivo. This suggests that such regions represent relatively accessible sites for insertion of foreign DNA, rather than conferring a selective advantage when disrupted. Interestingly, however, integrants and CFSs did not accurately colocalize. We further observed that local DNA rearrangements occur frequently and rapidly after the integration event. The majority of integrants were in chromosome bands containing a cancer-associated coding gene or microRNA, indicating that integration occurs commonly in these regions, regardless of selective pressure. The cancer-associated genes were generally a considerable distance from the integration site, and there was no evidence for altered expression of nine strong candidate genes. These latter observations do not support an important role for HPV16 integration in causing insertional mutagenesis.

An increase in DNA double-strand breaks, induced by Ku70 depletion, is associated with human papillomavirus 16 episome loss and de novo viral integration events.

Integration of human papillomavirus type 16 (HPV16) is a common event in cervical carcinogenesis, although mechanisms of integration are poorly understood. We have tested the hypothesis that an increased number of DNA double-strand breaks (DSBs) affect HPV16 episome maintenance and integration in cervical keratinocytes. Increased DSBs were generated over prolonged periods of up to 50 population doublings in the unique polyclonal cervical keratinocyte cell line W12, which stably maintains HPV16 episomes. This was achieved using repeated treatments with short interfering RNA to obtain sustained depletion of Ku70, a key mediator of DNA non-homologous end joining. An increase in DSBs was seen shortly after commencement of Ku70 depletion. Continuous depletion was reproducibly associated with loss of HPV16 episomes and also with a new viral integration event, which was rapidly selected in outgrowing W12 cells. Despite the prolonged presence of DSBs, high-level chromosomal instability (detected by marked changes in genomic copy number) was not observed until cells containing the new integrant were almost fully selected, with no evidence of such chromosomal instability prior to integration. Our data show that increased DNA DSBs are associated with HPV16 episomal loss and integration in cervical keratinocytes. We found no evidence to support the notion that major chromosomal instability precedes HPV16 integration, although such instability is an important consequence of the integration event.

Interferon-beta treatment of cervical keratinocytes naturally infected with human papillomavirus 16 episomes promotes rapid reduction in episome numbers and emergence of latent integrants.

Following integration of human papillomavirus (HPV) into the host genome, overexpression of the viral oncogenes E6 and E7 requires loss of the transcriptional repressor functions of E2. A key step in HPV-related carcinogenesis is therefore clearance of residual viral episomes, which encode E2. As spontaneous loss of HPV-16 episomes in vitro is associated with increased expression of antiviral genes inducible by type I interferon (IFN), we used the W12 model to examine the effects of exogenous IFN-beta on cervical keratinocytes containing HPV-16 episomes as a result of 'natural' infection in vivo. In contrast to studies of cells transfected with HPV-31 or bovine papillomavirus, IFN-beta caused rapid reduction in numbers of HPV-16 episomes. This was associated with the emergence of cells bearing previously latent integrants, in which there was increased expression of E6 and E7. Our data indicate that integrated HPV-16 can exist in a minority of cells in a mixed population without exerting a selective advantage until episome numbers are reduced. The kinetics of cell death and changes in viral transcription and translation that we observed support a model where integrants are initially present in cells also containing episomes, with generalized episome clearance by IFN-beta resulting in integrant de-repression. We conclude that IFN-beta can hasten the transition from episomal to integrated HPV-16 in naturally infected cervical keratinocytes. Greater emphasis should be placed on episome loss in models of HPV-related carcinogenesis. We provide the strongest evidence to date that treating HPV-16 lesions by inducing an IFN response may cause clinical progression.

Selection of cervical keratinocytes containing integrated HPV16 associates with episome loss and an endogenous antiviral response.

Integration of high-risk human papillomavirus (HRHPV) into the host genome is a key event in cervical neoplastic progression. Integration is associated with deregulated expression of the viral oncogenes E6 and E7 and acquisition of a selective growth advantage for cells containing integrants. Overexpression of the viral transcriptional regulator E2 from heterologous promoters has an inhibitory effect on transcription from integrated HRHPV. Therefore, we hypothesized that loss of E2-expressing episomes from cells in which integration had previously occurred would be required for such cells to gain a growth advantage. Using the unique W12 model of cervical squamous carcinogenesis, we show that cells containing integrated HPV16 reproducibly emerged during long-term culture when there had been a rapid fall in episome numbers. During the period of emergence, it is possible to isolate single-cell clones containing an intracellular mixture of the integrant being selected and episomes at reduced load. The lower level of E2 expression seen in such cells is associated with partial inhibition of transcription from the HPV16 integrant. Full deregulation is not observed until complete loss of E2-expressing episomes occurs. Microarray analysis showed that episome loss was closely associated with endogenous activation of antiviral response genes that are also inducible by the type I IFN pathway. Taken together, our results indicate that episome loss, associated with induction of antiviral response genes, is a key event in the spontaneous selection of cervical keratinocytes containing integrated HPV16. We conclude that cervical carcinogenesis requires not only HRHPV integration, but also loss of inhibitory episomes.

Effect of mode of administration on I-PSS scores in a large BPH patient population.

OBJECTIVES: The International Prostate Symptoms Score (I-PSS) was designed to be self-administered to patients with benign prostatic hyperplasia. This study tested for a possible mode of administration effect on the I-PSS and assessed the reliability of the I-PSS over time when modes of administration varied. METHODS: Benign prostatic hyperplasia patients over 50 years of age were recruited at 52 Spanish centres. The I-PSS was administered on two occasions 1 month apart. Patients were sequentially classified into groups A-D according to the mode of administration (S = self-administered, I = interview administered) at the two visits (A = S-S, B = S-I, C = I-S, and D = I-I). The intraclass correlation coefficient was used to assess test-retest reliability, and multiple regression analysis was used to test the effects of the mode of administration and the visit number on I-PSS scores. RESULTS: 926 patients (mean age 66 years) were evaluated. The mean I-PSSs symptoms score at visit 1 in groups A-D were, respectively, 13.19, 13.57, 12.06, and 12.29. Multiple regression analysis between-group scores were 0.93 points higher when the I-PSS was self-administered and 1.98 points lower at the second visit. The intraclass correlation coefficients were: group A = 0.77, group B = 0.70, group C = 0.67, and group D = 0.76. CONCLUSIONS: Interview administration of the I-PSS results in slightly lower scores. The reliability is higher when the same mode of administration is used at two recurrent visits.

The importance of health-related quality-of-life data in determining the value of drug therapy.

BACKGROUND: The rapid evolution of outcomes research during the last decade has led to increasing emphasis on measures of health-related quality of life (HRQOL). However, the relatively recent advent of these measures makes it difficult to decide how much weight to attribute to them in decisions about the value of drug therapy. OBJECTIVE: The aim of this article is to discuss the factors that affect the relative importance of HRQOL data in determining the value of drug therapy. CONCLUSIONS: The relative importance of HRQOL data depends on the type of condition and the type of treatment. In chronic conditions, HRQOL may be considered a primary measure of efficacy. In acute conditions, HRQOL is not likely to be a primary efficacy measure, although excluding HRQOL measures may lead to an underestimation of treatment effects. Measures of HRQOL are also likely to be important in the assessment of palliative treatments and, to some extent, preventive treatments (primarily in the measurement of adverse effects). HRQOL measures will be less important in the assessment of curative treatments because these types of treatment are most relevant in acute conditions.

Using the EuroQol-5D to measure changes in quality of life 12 months after discharge from an intensive care unit.

OBJECTIVE: To compare changes in the health-related quality of life (HRQOL) of critical care patients by diagnostic category. DESIGN: Prospective, cohort study. HRQOL assessed 3 months before admission and 1 year after discharge from the intensive care unit (ICU). Patients were classified as: trauma injury (TI), scheduled surgery (SS), unscheduled surgery (US), and other medical conditions (MC). SETTING: Department of Intensive Medicine, University Hospital of Bellvitge, Barcelona, Spain. PATIENTS: Three hundred and thirty-four patients admitted to ICU from October 1994 to June 1995 (62 TI patients, 181 SS patients, 19 US patients, and 72 MC patients). INTERVENTIONS: Surgical and medical procedures. MEASUREMENTS AND RESULTS: Changes in HRQOL varied considerably between diagnostic categories, with TI patients having significantly worse HRQOL one year after discharge from the ICU compared to 3 months prior to admission [change in median EQ Visual Analogue Scale (EQ-VAS) score from 100 to 65, P<0.001], and SS patients reporting improved HRQOL (change in median EQ-VAS scores from 60 to 75, P<0.001). Slight deterioration was observed in the other two diagnostic categories. Twelve months after discharge, the EQ dimension in which the largest proportion of patients in all groups reported problems was usual activities (47% of SS and US patients; 69% of TI patients). Using proxy scores at baseline or follow-up had little effect on results. CONCLUSIONS: The degree and direction of change in ICU patients' HRQOL 1 year after discharge depends considerably on diagnostic category. Proxy responses can be reliably used with the EQ-5D when measuring change in HRQOL.

Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma.

The effect of prolonged inhaled corticosteroid treatment on bronchial immunopathology was assessed in 25 nonsmoking mildly asthmatic subjects previously receiving intermittent inhaled beta 2-agonist alone. Inhaled beclomethasone dipropionate (BDP), 500 micrograms twice per day or placebo was administered for 4 mo in a double-blind parallel group study. Histamine bronchial provocation, fiberoptic bronchoscopic biopsy, and bronchoalveolar lavage (BAL) were performed before and after treatment. There was no difference in bronchial responsiveness or lung function between groups. In patients treated with BDP compared with placebo, there was a significant reduction in toluidine blue-staining mast cells (p = 0.028) and total (p = 0.005) and activated eosinophils (p = 0.05) in biopsies but no difference in eosinophils or eosinophil cationic protein in BAL. Granulocyte-macrophage colony-stimulating factor expression was significantly reduced in the bronchial epithelium, and the thickness of Type III collagen deposition in the bronchial lamina reticularis reduced from 29.7 +/- 4.4 to 19.8 +/- 3.4 microns (mean +/- 95% confidence interval) (p = 0.04). No change in helper or activated helper T cells occurred. Prolonged BDP treatment reduces inflammatory infiltration, proinflammatory cytokine expression, and subepithelial collagen deposition, a recognized abnormality in asthma.

Role of computed tomography in evaluating asbestos related lung disease.

To find how computed tomography (CT) may be effectively used in individuals with suspected asbestos related lung disease 30 men with a history of exposure to asbestos were studied. All subjects underwent high kilovoltage posteroanterior and left lateral chest radiographs and chest CT. Eighteen were randomly selected asbestos workers referred for routine surveillance. The remaining 12 were patients who had been referred for investigation of respiratory symptoms or abnormal routine chest radiograph, or both, and found to have chest radiographic changes compatible with asbestos related lung disease. In the group referred for routine surveillance both pleural shadowing and pulmonary shadowing were shown on CT but not chest radiographs in only one case. Five were thought to have pleural shadowing on chest radiographs but this was confirmed on CT in only one case. All 12 patients referred for investigation showed pleural shadowing on chest radiographs; this was confirmed in all cases on CT which also showed unsuspected pulmonary shadowing in five cases. These findings suggest that it is not appropriate to use chest CT routinely in all asbestos workers referred for routine surveillance. When CT is used selectively in those with pleural shadowing on plain chest radiography, however, it is helpful in refuting or confirming the presence of pleural disease and may show unsuspected pulmonary shadowing.