Non-invasive ventilation is associated with long-term improvements in lung function and gas exchange in cystic fibrosis adults with hypercapnic respiratory failure.

BACKGROUND: Non-invasive ventilation (NIV) is an established treatment option for cystic fibrosis (CF) patients with type 2 respiratory failure but the benefits of this therapy remain unclear. This study examined the long-term outcomes and response to NIV in a large adult CF cohort. METHODS: All patients attending a UK adult CF Centre receiving NIV as treatment for hypercapnic respiratory failure over a nine-year period were studied prospectively. Detailed clinical data was recorded and longitudinal data measurements were examined for the three years pre and post NIV initiation to assess effect of this intervention. RESULTS: 94 patients, mean age 29.9 (SD 9.7) years, percent predicted FEV1 21.5 (7.3), received NIV. All patients commenced NIV in a hospital setting. 21 remain alive, 24 received double lung transplant, 49 died without lung transplantation. NIV use was associated with a stabilisation and improvement in both FEV1 and FVC from NIV set up to three years post follow-up, in addition to an increase in body mass index and attenuation of PCO2 (all p<0.001). No single parameter was found to predict long-term NIV response but baseline PCO2 (p=0.005), CRP (p=0.004) and age (p=0.009) were identified as independent predictors of mortality. CONCLUSIONS: NIV use in CF adults is associated with improvements in lung function and attenuation of hypercapnia which is maintained for up to three years post NIV initiation. Outcomes for CF patients with severe pulmonary disease commenced on NIV have significantly improved with fifty percent of patients expected to survive for approximately five years.

Alfvénic velocity spikes and rotational flows in the near-Sun solar wind.

The prediction of a supersonic solar wind1 was first confirmed by spacecraft near Earth2,3 and later by spacecraft at heliocentric distances as small as 62 solar radii4. These missions showed that plasma accelerates as it emerges from the corona, aided by unidentified processes that transport energy outwards from the Sun before depositing it in the wind. Alfvénic fluctuations are a promising candidate for such a process because they are seen in the corona and solar wind and contain considerable energy5-7. Magnetic tension forces the corona to co-rotate with the Sun, but any residual rotation far from the Sun reported until now has been much smaller than the amplitude of waves and deflections from interacting wind streams8. Here we report observations of solar-wind plasma at heliocentric distances of about 35 solar radii9-11, well within the distance at which stream interactions become important. We find that Alfvén waves organize into structured velocity spikes with duration of up to minutes, which are associated with propagating S-like bends in the magnetic-field lines. We detect an increasing rotational component to the flow velocity of the solar wind around the Sun, peaking at 35 to 50 kilometres per second-considerably above the amplitude of the waves. These flows exceed classical velocity predictions of a few kilometres per second, challenging models of circulation in the corona and calling into question our understanding of how stars lose angular momentum and spin down as they age12-14.

Clustering of pain and its associations with health in people aged 50†years and older: cross-sectional results from the North Staffordshire Osteoarthritis Project.

OBJECTIVE: Most pain in patients aged ≥50 years affects multiple sites and yet the predominant mode of presentation is single-site syndromes. The aim of this study was to investigate if pain sites form clusters in this population and if any such clusters are associated with health factors other than pain. SETTING: Six general practices in North Staffordshire, UK. DESIGN: Cross-sectional, postal questionnaire, study. PARTICIPANTS: Community-dwelling adults aged ≥50 years registered at the general practices. MAIN OUTCOMES MEASURES: Number of pain sites was measured by asking participants to shade sites of pain lasting ≥1 day in the past 4 weeks on a blank body manikin. Health factors measured included anxiety and depression (Hospital and Anxiety Depression Scale), cognitive complaint (Sickness Impact Profile) and sleep. Pain site clustering was investigated using latent class analysis. Association of clusters with health factors, adjusted for age, sex, body mass index and morbidities, was analysed using multinomial regression models. RESULTS: 13 986 participants (adjusted response 70.6%) completed a questionnaire, of whom 12 408 provided complete pain data. Four clusters of participants were identified: (1) low number of pain sites (36.6%), (2) medium number of sites with no back pain (31.5%), (3) medium number of sites with back pain (17.9%) and (4) high number of sites (14.1%). Compared to Cluster 1, other clusters were associated with poor health. The strongest associations (relative risk ratios, 95% CI) were with Cluster 4: depression (per unit change in score) 1.11 (1.08 to 1.14); cognitive complaint 2.60 (2.09 to 3.24); non-restorative sleep 4.60 (3.50 to 6.05). CONCLUSIONS: These results indicate that in a general population aged ≥50 years, pain forms four clusters shaped by two dimensions-number of pain sites (low, medium, high) and, within the medium cluster, the absence or presence of back pain. The usefulness of primary care treatment approaches based on this simple classification should be investigated.

Increased cardiovascular mortality associated with gout: a systematic review and meta-analysis.

BACKGROUND: Hyperuricaemia, the biochemical precursor to gout, has been shown to be an independent risk factor for mortality from cardiovascular disease (CVD), although studies examining the clinical phenomenon of gout and risk of CVD mortality report conflicting results. This study aimed to produce a pooled estimate of risk of mortality from cardiovascular disease in patients with gout. DESIGN: Systematic review and meta-analysis. METHODS: Electronic bibliographic databases were searched from inception to November 2012, with results reviewed by two independent reviewers. Studies were included if they reported data on CVD mortality in adults with gout who were free of CVD at time of entry into the study. Pooled hazard ratios (HRs) for this association were calculated both unadjusted and adjusted for traditional vascular risk factors. RESULTS: Six papers, including 223,448 patients, were eligible for inclusion (all (CVD) mortality n = 4, coronary heart disease (CHD) mortality n = 3, and myocardial infarction mortality n = 3). Gout was associated with an excess risk of CVD mortality (unadjusted HR 1.51 (95% confidence interval, CI, 1.17-1.84)) and CHD mortality (unadjusted HR 1.59, 95% CI 1.25-1.94)). After adjusting for traditional vascular risk factors, the pooled HR for both CVD mortality (HR 1.29, 95% CI 1.14-1.44) and CHD mortality (HR 1.42, 95% CI 1.22-1.63) remained statistically significant, but none of the studies reported a significant association with myocardial infarction. CONCLUSIONS: Gout increases the risk of mortality from CVD and CHD, but not myocardial infarction, independently of vascular risk factors.

Developing Objective Metrics for Unit Staffing (DOMUS) study.

OBJECTIVE: Safe midwifery staffing levels on delivery suites is a priority area for any maternity service. Escalation policies are tools that provide an operational response to emergency pressures. The aim of this study was to assess the feasibility of using a scoring system to contemporaneously assess the required staffing level based on demand and use this to determine delivery suite escalation level and utilise the information generated regarding clinical activity (Demand) and staffing levels (Capacity) to generate unit-specific calculation for the actual number of midwifery staff required. SETTING: A maternity unit of a university-affiliated tertiary referral hospital. DESIGN: Over a 12-month period, specifically designed scoring sheets were completed by delivery suite shift co-ordinators four times a day (04:00, 10:00, 16:00 and 22:00). Based on the dependency score (Demand) and the number of midwifery staff available (Capacity), an escalation level was determined for each shift. The 80th centile of the demand was used to determine optimal capacity. RESULTS: A total of 1160 scoring sheets were completed. Average staff number throughout the year on any shift was 7 (range 3-11). Average dependency score was 7 (range 1-14). The 80th centile for demand was calculated to be 11. CONCLUSIONS: This study stresses the importance and usefulness of a simple tool that can be used to determine the level of escalation on delivery suite based on an objective scoring system and can also be used to determine the appropriate staffing on delivery suite.

The fraction of exhaled nitric oxide improves prediction of clinical allergic reaction to peanut challenge in children.

BACKGROUND: Retrospective studies of childhood peanut allergy demonstrate serum-specific IgE (IgE) levels against the peanut allergen Ara h2 may help predict a clinical reaction at food challenge. Fraction of exhaled nitric oxide (FeNO) is a non-invasive tool correlating to allergic airways inflammation and has been independently associated with increased food-specific IgE. OBJECTIVE: To assess the validity of serum-specific Ara h2 IgE measured prospectively to diagnose peanut allergy and explore the utility of FeNO as a non-invasive screening tool for childhood food challenge. METHODS: We recruited 53 participants from a cohort of consecutive children scheduled for an open-labelled peanut food challenge (OFC) by their paediatric allergist. Participants underwent skin prick test (SPT) measurement for sensitization to whole peanut extract, and serum was collected for Ara h2-specific IgE. FeNO was also measured in all cooperative children before the challenge. OFC and assessment of reaction were undertaken by clinicians blinded to test results. RESULTS: Ara h2-specific IgE and FeNO each showed improved diagnostic accuracy when compared to SPT. Receiver operator characteristic curve analysis gave an area under the curve (AUC) for Ara h2 sIgE of 0.84 (95% CI, 0.72-0.96). The AUC for FeNO, 0.83 (95% CI, 0.71-0.95), was equivalent to that of Ara h2. Combined AUC for SPT, sIgE to Ara h2 and FeNO was 0.96 (95% CI 0.90-1.00). There was no correlation between FeNO and serum nitrite levels (rs = -0.13, P = 0.6, n = 18). CONCLUSION AND CLINICAL RELEVANCE: Prospectively measured Ara h2-specific IgE improves diagnostic accuracy and reduces unsuccessful challenge to peanut. FeNO levels may provide improved diagnostic accuracy in a paediatric population undergoing OFC. The proposed FeNO-based diagnostic algorithm requires further validation studies.

Statin use and clinical osteoarthritis in the general population: a longitudinal study.

BACKGROUND: One hypothesis has posited whether abnormal lipid metabolism might be a causal factor in the pathogenesis of osteoarthritis (OA). Routine statin use in clinical practice provides the basis for a natural experiment in testing this hypothesis. OBJECTIVE: To test the hypothesis that statins reduce the long-term occurrence of clinically defined OA. DESIGN: Cohort design with a 10-year follow-up. PARTICIPANTS: 16,609 adults cardiovascular disease cohorts aged 40 years and over from the UK General Practice Research Database with data available to 31 December 2006. INTERVENTION: Statins were summarised as annual mean daily dose and dose change over two-year time periods. MAIN MEASURES: Incident episode of clinically defined osteoarthritis was assessed within 2 years, and at 4-year and 10-year follow-up time periods, using Cox and discrete time survival analysis. Covariates included age, gender, deprivation, body mass index, cholesterol level, pain-modifying drug co-therapies, and duration and severity of cardiovascular disease. KEY RESULTS: Higher therapeutic dose of statin, with a treatment duration of at least 2 years was associated with a significant reduction in clinical OA compared to non-statin users in the follow-up time period. The estimated adjusted rate ratios were as follows: lowest statin dose quartile 1: 2.5 (95 % CI 2.3, 2.9); quartile 2: 1.3 (1.1, 1.5); quartile 3: 0.8 (0.7, 0.95); and highest statin dose quartile 4: 0.4 (0.3, 0.5). The largest statin dose increments were associated with significant reductions estimated at 18 % in OA outcome within 2 years and 40 % after 4 years, compared to non-statin users. CONCLUSIONS: This longitudinal study from a national clinical practice setting provides evidence that higher statin dose and larger statin dose increments were associated with a reduction in clinically defined OA outcome.

The risk of a subsequent cancer diagnosis after herpes zoster infection: primary care database study.

BACKGROUND: Herpes zoster and cancer are associated with immunosuppression. Zoster occurs more often in patients with an established cancer diagnosis. Current evidence suggests some risk of cancer after zoster but is inconclusive. We aimed to assess the risk of cancer following zoster and the impact of prior zoster on cancer survival. METHODS: A primary care database retrospective cohort study was undertaken. Subjects with zoster were matched to patients without zoster. Risk of cancer following zoster was assessed by generating hazard ratios using Cox regression. Time to cancer was generated from the index date of zoster diagnosis. RESULTS: In total, 2054 cancers were identified in 74,029 patients (13,428 zoster, 60,601 matches). The hazard ratio for cancer diagnosis after zoster was 2.42 (95% confidence interval 2.21, 2.66) and the median time to cancer diagnosis was 815 days. Hazard ratios varied between cancers, and were highest in younger patients. There were more cancers in patients with zoster than those without for all age groups and both genders. Prior immunosuppression was not associated with change in risk, and diagnosis of zoster before cancer did not affect survival. CONCLUSION: This study establishes an association between zoster and future diagnosis of cancer having implications for cancer case finding after zoster diagnosis.

The effectiveness of national guidance in changing analgesic prescribing in primary care from 2002 to 2009: an observational database study.

BACKGROUND: Numerous national guidelines have been issued to assist general practitioners' safe analgesic prescribing. Their effectiveness is unclear. The objective of this study was to examine trends in general practitioners' prescribing behaviour in relation to national guidelines. METHODS: This was a retrospective observational database study of registered adult patients prescribed an analgesic (2002-2009) from the Consultations in Primary Care Archive--12 North Staffordshire general practices. Prescribing guidance from the UK Medicines Regulatory Health Authority (MHRA) regarding non-steroidal anti-inflammatory drugs (NSAIDs) and co-proxamol, and the National Institute for Health and Clinical Excellence (NICE) osteoarthritis (OA) management guidelines were considered. Analgesic prescribing rates were examined, arranged according to a classification of six equipotent medication groups: (1) basic analgesics; (2)-(5) increasingly potent opioids and (6) NSAIDs. In each quarter from 2002 to 2009, the number of patients per 10,000 registered population receiving a prescription for the first time from each group was determined. Quarters associated with significant changes in the underlying prescribing trend were determined using joinpoint regression. RESULTS: A significant decrease in incident co-proxamol and Cox-2 prescribing occurred around the time of the first MHRA advice to stop using them and were rarely prescribed thereafter. The new prescribing of weak analgesics (e.g., co-codamol 8/500) increased at this same time. Initiating topical NSAIDs significantly increased around the time of the NICE OA guidelines. CONCLUSIONS: Significant prescribing changes occurred when national advice and guidelines were issued. The effectiveness of this advice may vary depending upon the content and method of dissemination. Further evaluation of the optimal methods for delivering prescribing guidance is required.

Predictors of liver donation without kidney recovery in a cohort of expanded criteria donors: identifying opportunities to improve expanded criteria donor kidney utilization.

To maximize deceased donation, it is necessary to facilitate organ recovery from expanded criteria donors (ECDs). Utilization of donors meeting the kidney definition for ECDs increases access to kidney transplantation and reduces waiting times; however, ECDs often do not proceed to kidney recovery. Based on a prospective study of three Organ Procurement Organizations in the United States, we describe the characteristics of donors meeting the Organ Procurement and Transplant Network (OPTN) ECD kidney definition (donor age 60+ or donor age 50-60 years with two of the following: final serum creatinine > 1.5 mg/dL, history of hypertension, or death from cerebral vascular accident) who donated a liver without kidney recovery. ECDs with organs recovered between February 2003 and September 2005 by New England Organ Bank, Gift of Life Michigan, and LifeChoice Donor Services were studied (n = 324). All donors were declared dead by neurological criteria. Data on a wide range of donor characteristics were collected, including donor demographics, medical history, cause of death, donor status during hospitalization, serological status, and donor kidney quality. Logistic regression models were used to identify donor characteristics predictive of liver-alone donation. Seventy-four of the 324 donors fulfilling the ECD definition for kidneys donated a liver alone (23%). History of diabetes, final serum creatinine > 1.5 mg/dL, age 70+, and presence of proteinuria were associated with liver-alone donation in univariate models. On multivariate analysis, only final serum creatinine > 1.5 mg/dL and age 70+ were independently predictive of liver donation alone. Older age and elevated serum creatinine may be perceived as stronger contraindications to kidney donation than the remaining elements of the ECD definition. It is likely that at least a proportion of these liver-alone donors represent missed opportunities for kidney transplantation.

Variation in hydrogen cyanide production between different strains of Pseudomonas aeruginosa.

There is increasing interest in using the cyanogenic properties of Pseudomonas aeruginosa to develop a nonmicrobiological method for its detection. Prior to this, the variation in cyanide production between different P. aeruginosa strains needs to be investigated. Hydrogen cyanide (HCN) released into the gas phase by 96 genotyped P. aeruginosa samples was measured using selected ion flow tube-mass spectrometry after 24, 48, 72 and 96 h of incubation. The HCN produced by a range of non-P. aeruginosa cultures and incubated blank plates was also measured. All P. aeruginosa strains produced more HCN than the control samples, which generated extremely low levels. Analysis across all time-points demonstrated that nonmucoid samples produced more HCN than the mucoid samples (p=0.003), but this relationship varied according to strain. There were clear differences in the headspace HCN concentration for different strains. Multivariate analysis of headspace HCN for the commonest strains (Liverpool, Midlands_1 and Stoke-on-Trent, UK) revealed a significant effect of strain (p<0.001) and a borderline interaction of strain and phenotype (p=0.051). This evidence confirms that all P. aeruginosa strains produce HCN but to varying degrees and generates interest in the possible future clinical applications of the cyanogenic properties of P. aeruginosa.

A systematic review of radiographic definitions of foot osteoarthritis in population-based studies.

OBJECTIVE: To identify the methods used in population-based epidemiological studies to diagnose radiographic foot osteoarthritis (OA) and to estimate the population prevalence of radiographic foot OA. METHOD: Electronic databases searched included Medline, Embase, CINAHL and Ageline (inception to May 2009). The search strategy combined search terms for radiography, OA, foot, and specific foot joints. Predetermined selection criteria were applied. Data extracted from each paper included: sample population, radiographic views taken, foot joints examined, scoring system used, definition of OA applied, reliability of radiographic scoring and prevalence of radiographic OA in the foot. RESULTS: Titles and abstracts of 1035 papers were reviewed and full-texts of 21 papers were obtained. Fifteen papers met inclusion criteria and a further 12 papers were included after screening references. Radiographic views were frequently not specified (NS) but a combination of antero-posterior (AP) and lateral (Lat) views was most commonly reported. The first metatarsophalangeal (MTP) joint was the most commonly examined joint (n=20, 74%). Nineteen studies (70%) used the Kellgren and Lawrence (K&L) grading system, 95% of which defined OA as K&L grade> or =2. Estimates of the prevalence of radiographic first MTP joint OA (defined as K&L> or =2) in middle-aged to older adults ranged from 6.3 to 39%. Significant statistical heterogeneity prevented pooling of prevalence estimates. CONCLUSION: There are comparatively few studies examining radiographic foot OA. Existing studies mainly focus on the first MTP joint and use the K&L grading system. Future studies are needed to quantify the prevalence of radiographic OA at the different joint complexes within the foot.

Influence of acetabular and femoral version on fractures of the femoral neck.

BACKGROUND: Fractures through the proximal femur are broadly grouped into intertrochanteric fractures and intracapsular fractures. It is not clear why a patient may sustain an intertrochanteric fracture as compared with an intracapsular fracture. There is an established relationship between relative hip retroversion and the development of osteoarthritis. We postulate retroversion also may be a risk factor for having intracapsular fractures develop. QUESTIONS/PURPOSES: We looked specifically at the geometry of the hip to analyze the possibility of a relationship between acetabular version, femoral version, and Mckibbin's instability index and fracture type. PATIENTS AND METHODS: We recruited 40 patients with fractures of the femoral neck for the study. There were 15 men and 25 women with a mean age of 80 years (range, 57-92 years). There were 14 intertrochanteric fractures and 26 intracapsular fractures. After treating their fracture, the contralateral hip was scanned in a CT scanner and assessed by two independent observers to establish the acetabular and femoral version. RESULTS: We found no correlation between proximal femoral fracture type and the contralateral femoral version, femoral neck length, acetabular version, or Mckibbin's instability index or between fracture type and age or gender. CONCLUSIONS: There appears to be no correlation between proximal femoral fracture type and acetabular or femoral version. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Mediation by illness perceptions of the effect of personality and health threat communication on coping with the diagnosis of diabetes.

OBJECTIVES: (1) To examine the relationship of personality traits and diabetes health threat communication (DHTC) to the coping strategies of newly diagnosed diabetes patients; (2) to determine to what extent these postulated effects are mediated by illness representations (IRs). DESIGN: A longitudinal prospective study based on the common sense model. METHODS: Patients were assessed shortly after diagnosis and 2 years after the diagnosis of diabetes. Personality traits (Mini-markers) were assessed at baseline. The DHTC Questionnaire was completed at baseline and 2 years. The Revised Illness Perception Questionnaire and the coping orientation to problems experienced were completed at 2 years. Mediation by IRs of the potential influence of personality and DHTC on coping behaviour was assessed by the method of Baron and Kenny. RESULTS: Multiple regression analyses showed that educational level, agreeableness, openness/intellect, conscientiousness, and perceptions of a more reassuring health message since diagnosis were related to more adaptive coping (e.g., active coping, planning). The association of openness and perceived reassuring health message with active coping showed complete mediation by illness coherence and personal control. Openness led to seeking emotional support mediated by perceived personal control. Coherence associated with (partial mediation) the relation of openness to planning. Similarly, personal control and coherence mediated the relation of openness to positive reinterpretation and growth (PRG). Agreeableness had a direct relationship with active coping and PRG but led to planning and seeking instrumental support mediated by perceived treatment effectiveness. Perceptions of a threatening health message were associated with seeking instrumental and emotional support and this was mediated by symptom perception but threat had a direct relationship with planning. CONCLUSIONS: Both personality traits and health threat communication predict the way individuals cope with diabetes. The relationships of these factors are largely mediated through measurable IRs. The results suggest targets for intervention to achieve greater problem-focused coping.

A new tilt on pelvic radiographs: a pilot study.

AIM: The aim of this study was to evaluate pelvic tilt on commonly performed measurements on radiography in primary protrusio acetabuli and developmental dysplasia of the hip. MATERIALS AND METHODS: A dry assembled pelvis and spine skeleton was positioned in an isocentric skull unit and films exposed with increasing degrees of angulation of pelvic tilt. The films were then read by two independent readers for seven different measurements used to evaluate the hips and acetabular: acetabular line to ilioischial line, teardrop appearance, intercristal/intertuberous ratio, co-ordinates of femoral head, centre edge angle, acetabular depth/width ratio and acetabular angle. RESULTS: There was so much variation in the protrusio results that no formal recommendation of any standard radiographic test can be given. Only the inter tuberous distance is not effected by pelvic tilt. The acetabular angles for developmental dysplasia of the hip showed the most potential with pelvic tilt below 15 degrees. CONCLUSION: As pelvic tilt increases, measurements used in protusio become unreliable, and computed tomography/magnetic resonance imaging are probably going to be more accurate as one can directly visualise pelvic intrusion. We recommend a lateral view to assess the degree of pelvic tilt in patients with protrusion to ensure these measurements are valid.

Industrial packaging developments for the global meat market.

Packaging companies must carefully monitor retail and consumer trends to best utilize, direct, or prioritize their research dollars in developing packaging and packaging systems to meet these demands. This paper reviews packaging developments that are resulting from numerous trends taking place in the meat industry and in the retail sector. Current case ready packaging solutions that meet the needs of retailers to reduce labor in the back of the retail stores, and the consumer needs for a fresh product with excellent quality and palatability are also discussed. It will also review the current packaging options that are being developed to help consumers battle their "time crunch" with ready meal solutions. Finally, the necessity to increase food safety or eliminate pathogens while producing a high quality product continues to drive packaging development. Current systems and packaging available for post packaging pasteurization will be discussed.

Human cytomegalovirus causes endothelial injury through the ataxia telangiectasia mutant and p53 DNA damage signaling pathways.

Atherosclerosis is the leading cause of death in the United States, and human cytomegalovirus (HCMV), a member of the herpes virus family, may play a role in the development of the disease. We previously showed that HCMV regulated endothelial apoptosis. In this study, we investigated the induction of apoptosis and signal transduction pathways regulating this process in HCMV-infected endothelial cells. As observed previously, HCMV induced a typical cytopathic effect in human aortic endothelial cells (HAECs), ie, the formation of single nucleated or multinucleated giant cells. Although infected HAECs were resistant to apoptosis at earlier stages of infection, they became apoptotic with prolonged infection as demonstrated by positive staining using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). This apoptotic process was mediated by the caspase-dependent mitochondrial apoptotic pathway as indicated by increased expression and cleavage of caspases 3 and 9 as well as increased expressions of pro-apoptotic molecules Bax and Bak. Blocking caspases 3 or 9 significantly inhibited the HCMV-induced apoptosis. Further exploration of the upstream pathway demonstrated upregulation of the tumor suppressor p53 gene and activation of the ataxia telangiectasia mutant (ATM) pathway in the infected cells. Blocking p53 inhibited HCMV-stimulated Bax and Bak expression as well as caspase-3 activation and blocking the ATM pathway inhibited HCMV-stimulated p53 activation. Although early infection may render cells antiapoptotic, prolonged infection, however, induced endothelial apoptosis through ATM and p53-dependent activation of the mitochondrial death pathway. This proapoptotic effect may be relevant to endothelial dysfunction and HCMV-associated vascular diseases.

Cytomegalovirus inhibits p53 nuclear localization signal function.

Endothelial cells (EC) infected with the VHL strain of cytomegalovirus (CMV) are resistant to p53-mediated apoptosis, which may be relevant to EC dysfunction and atherogenesis. This resistance to apoptosis may be mediated by cytoplasmic sequestration of p53, which functions only in the nucleus. We explored the hypothesis that CMV sequesters p53 in the cytoplasm by blocking p53 nuclear localization signal (NLS) function. We transfected VHL CMV infected EC with recombinant p53 NLSI conjugated with chicken muscle pyruvate kinase (PK) plasmid. NLSI is responsible for 90% of p53 nuclear localization, and PK is not normally translocated to the nucleus after cytoplasmic production. Thus it cannot be localized in the nucleus without the assistance of the artificial NLSI. A double-labeling immunofluorescence staining method was used to identify the localization of p53 NLSI-conjugated PK in CMV-infected EC. We found that CMV infection sequesters PK and p53 in the cytoplasm by blocking NLSI function. This inactivation of NLSI function is dependent upon infection stage; it occurs only in the early and late phases and not the immediate early phase of infection. These findings may be relevant to endothelial dysfunction and initiation of atherogenesis. Our study also suggests a novel mechanism of the p53 inactivation by virus, which may be important for atherogenesis and tumorgenesis.