Proteolytic cleavage of elafin by 20S proteasome may contribute to inflammation in acute lung injury

RATIONALE:
We hypothesise that elafin levels in acute lung injury (ALI) decrease over time due, in part, to proteolytic degradation as observed in other lung diseases.
OBJECTIVES:
The aim of this study was to characterise temporal changes in elafin concentration in patients with ALI and to evaluate whether a decrease in elafin levels is due to elevated protease activity.
METHODS:
Bronchoalveolar lavage fluid (BALF) was obtained from patients with ALI within 48 h of onset of ALI (day 0), at day 3 and at day 7. Elafin levels were quantified by ELISA. Elafin susceptibility to proteolytic cleavage by ALI BALF was assessed by Western blot and by high-performance liquid chromatography-mass spectrometry.
MEASUREMENTS AND MAIN RESULTS:
Elafin levels were found to be significantly increased at the onset of ALI compared with healthy volunteers and fell significantly by day 7 compared with day 0. In contrast, levels of secretory leukocyte protease inhibitor did not decrease over time. This decrease in elafin was due to cleavage by the 20S proteasome which was significantly increased in ALI BALF. Incubation of ALI BALF with the proteasome inhibitor epoxomicin confirmed that 20S proteasome protease activity was responsible for proteolytic cleavage of elafin, resulting in diminished anti-elastase activity. In addition, free neutrophil elastase activity significantly increased in ALI BALF from day 0 to day 7.
CONCLUSIONS:
Elafin concentrations fall within the pulmonary compartment over the course of ALI as a result of proteolytic degradation. This loss of elafin may predispose people, in part, to excessive inflammation in ALI.

Understanding the migratory orientation program of birds: extending laboratory studies to study free flying migrants in a natural setting

For many years, orientation in migratory birds has primarily been studied in the laboratory. Although a laboratory-based setting enables greater control over environmental cues, the laboratory-based findings must be confirmed in the wild in free-flying birds to be able to fully understand how birds orient during migration. Despite the difficulties associated with following free-flying birds over long distances, a number of possibilities currently exist for tracking the long distance, sometimes even globe-spanning, journeys undertaken by migrating birds. Birds fitted with radio transmitters can either be located from the ground or from aircraft (conventional tracking), or from space. Alternatively, positional information obtained by onboard equipment (e.g., GPS units) can be transmitted to receivers in space. Use of these tracking methods has provided a wealth of information on migratory behaviors that are otherwise very difficult to study. Here, we focus on the progress in understanding certain components of the migration-orientation system. Comparably exciting results can be expected in the future from tracking free-flying migrants in the wild. Use of orientation cues has been studied in migrating raptors (satellite telemetry) and thrushes (conventional telemetry), highlighting that findings in the natural setting may not always be as expected on the basis of cage-experiments. Furthermore, field tracking methods combined with experimental approaches have finally allowed for an extension of the paradigmatic displacement experiments performed by Perdeck in 1958 on the short-distance, social migrant, the starling, to long-distance migrating storks and long-distance, non-socially migrating passerines. Results from these studies provide fundamental insights into the nature of the migratory orientation system that enables experienced birds to navigate and guide inexperienced, young birds to their species-specific winter grounds.

An Investigation into the Effects of Organisational Change on Occupational Stress in Further Education Lecturers

The aim of this study is to investigate the stress experienced by full-time
maingrade lecturers as a result of changes in college organisation and factors that relate to stress. A questionnaire was constructed to identify possible sources of stress at work and the amount of stress experienced. Two psychometric measures were included—the General Health Questionnaire and the Maslach Burnout Inventory. The former looked at the physiological and psychological effects of stress and the latter, the emotive, cognitive and
behavioural effects, together referred to as 'burnout'. The study sought to investigate stress responses between lecturers employed in colleges that have undergone organisational change compared to those that have not. Two hundred questionnaires and psychometric measures were distributed, by opportunity, to 100 lecturers employed in FE colleges in the north of England and 100 employed in colleges in Northern Ireland. Colleges in the former region had undergone changes in college organisation as a result of incorporation. Colleges in the
latter had not. Incorporation referred to the process whereby colleges became independent of local government control. This led to a series of changes, some of which affected lecturers' terms and conditions. Overall, the indices of reported stress were comparable or markedly greater than earlier research findings, and the trend was for lecturers who had experienced organisational change to report higher measures of stress. GHQ measures showed a significant difference between samples, with the majority of the English sample (69.49%, compared to 40.91%) categorised as 'at risk' of developing symptoms associated with a
transient stress-related disorder, and whilst measures of 'burnout' were more pronounced in the English sample there were no significant differences between samples. In relation to a number of factors, the experience of stress and burnout was more pronounced in the Northern Ireland sample and explanations were offered, such as the influence of cultural variables and the increasing presence of stress-related features in these colleges as they move to incorporation.

HOXA/PBX3 knockdown impairs growth and sensitizes cytogenetically normal acute myeloid leukemia cells to chemotherapy

The cytogenetically normal subtype of acute myeloid leukemia (CN-AML) is associated with Intermediate risk which complicates therapeutic options. Lower overall HOX/TALE expression appears to correlate with more favorable prognosis/better response to treatment in some leukemias and solid cancer. The functional significance of the associated gene expression and response to chemotherapy is not known. Three independent microarray datasets obtained from large patient cohorts along with quantitative PCR validation was used to identify a four gene HOXA/TALE signature capable of prognostic stratification. Biochemical analysis was used to identify interactions between the four encoded proteins and targeted knockdown used to examine the functional importance of sustained expression of the signature in leukemia maintenance and response to chemotherapy. An eleven HOXA/TALE code identified in an Intermediate risk (n=315) compared to a Favourable group of patients (n=105) was reduced to a four gene signature of HOXA6, HOXA9, PBX3 and MEIS1 by iterative analysis of independent platforms. This signature maintained the Favorable/Intermediate risk partition and where applicable, correlated with overall survival in CN-AML. We further show that cell growth and function is dependent on maintained levels of these core genes and that direct targeting of HOXA/PBX3 sensitizes CN-AML cells to standard chemotherapy. Together the data support a key role for HOXA/TALE in CN-AML and demonstrate that targeting of clinically significant HOXA/PBX3 elements may provide therapeutic benefit to these patients.

Incidence and natural history of proliferative sickle cell retinopathy:Observations from a cohort study

Objective: To describe the incidence, prevalence, and natural history of proliferative sickle cell retinopathy (PSR). Design: Prospective longitudinal study over 20 years. Participants: Newborn screening of 100000 consecutive deliveries from 1973 to 1981 identified 315 children with homozygous sickle cell (SS) disease and 201 with SS-hemoglobin C (SC) disease. By the age of 5 years, 307 SS patients and 166 SC patients were alive and living in Jamaica and were recruited for this ophthalmic study. Methods: Description of retinal vascular changes on annual angiography and angioscopy. Main Outcome Measures: Incidence and prevalence of PSR and its behavior on follow-up. Progression of PSR was investigated using the number of eyes affected (none, one, both) and the interval until PSR onset. Results: At last review in January 2000, PSR had developed in 59 patients (14 SS, 45 SC), unilaterally in 36 patients and bilaterally in 23. Incidence increased with age in both genotypes, with crude annual incidence rates of 0.5 cases (95% confidence interval [CI], 0.3-0.8) per 100 SS subjects and 2.5 cases (95% CI, 1.9-3.3) per 100 SC subjects. Prevalence was greater in SC disease, and by the ages of 24 to 26 years, PSR had occurred in 43% subjects with SC disease and in 14% subjects with SS disease. Patients with unilateral PSR had a 16% (11% SS, 17% SC) probability of regressing to no PSR and a 14% (16% SS, 13% SC) probability of progressing to bilateral PSR. Those with bilateral PSR had an 8% (8% SS, 8% SC) probability of regressing to unilateral PSR and a 1% (0 SS, 2% SC) probability of regressing to a PSR-free state. Irretrievable visual loss occurred in only 1 of 82 PSR-affected eyes, and 1 required detachment surgery and recovered normal visual acuity. Conclusions: Longitudinal observations over 20 years in a cohort of patients followed from birth confirms a greater incidence and severity of PSR in SC disease, and shows that spontaneous regression occurred in 32% of PSR-affected eyes. Permanent visual loss was uncommon in subjects observed up to the age of 26 years. © 2005 by the American Academy of Ophthalmology.

Functional outcomes of decompressive hemicraniectomy following malignant middle cerebral artery infarctions: a systematic review

Decompressive hemicraniectomy has been used increasingly in recent years to treat malignant middle cerebral artery territory infarction. This review examines functional outcome data, with the novel analysis of outcomes according to temporal periods post-surgery. Case series data were pooled to determine significant correlates of outcome. Severe disability was frequently the outcome among survivors within one month post-surgery. Time and rehabilitation were later reflected, with fewer deaths and the emergence of mild to moderate disability increasing in prevalence. Mortality and severe disability were consistently more probable with increasing age. Presurgical clinical status in the form of additional cerebral artery involvement and midline shift also correlated with mortality within the 30-day period post-stroke.

Biomonitoring aquatic environmental quality in a marine protected area: A biomarker approach

The main aims of the present study, conducted in the framework of the MONIQUA-Egadi Scientific Project, were twofold: first, to make the first step in the development and validation of an ecotoxicological approach for the assessment of marine pollution in coastal environments on the basis of a set of biomarker responses in new sentinel species; and second, to obtain preliminary information on environmental quality in an Italian marine protected area, the Egadi Islands (Sicily). Several cytochrome P450-dependent mixed-function oxidase activities were measured in the following sentinel species: rainbow wrasse Coris julis, gastropod limpet Patella caerulea, and sea urchin Paracentrotus lividus. The results suggest that specimens from the Favignana Harbor may be exposed to P450 inducers, whereas most of the other sites seem to share similar environmental quality. The proposed approach has potential for assessment of environmental quality in marine protected areas.

Using Pedometer Step-Count Goals to Promote Physical Activity in Cardiac Rehabilitation: A Feasibility Study of a Controlled Trial

Background: There is a need to improve the effectiveness of strategies to help cardiac rehabilitation patients achieve recommended levels of physical activity; the use of pedometers requires further research. We aimed to examine the feasibility of a randomised controlled trial, of an intervention using pedometer step-count goals, to promote physical activity for cardiac rehabilitation patients. Methods: We invited patients who completed a supervised cardiac rehabilitation programme to participate in this community-based study. Consenting participants wore a Yamax CW-701 pedometer for one week, blinded to stepcount readings, before being randomly allocated to groups. Intervention groups were told their step-counts; working with a clinical facilitator (nurse or physiotherapist) individually, they set daily step-count goals and reviewed these weekly. Baseline step-counts were hidden from controls, who were not given pedometers but received ongoing weekly facilitator support. After six weeks both groups wore ‘blinded’ pedometers for outcome assessment and participated in semi-structured interviews which explored their experiences of the study. Outcomes included rates of uptake, adherence and completion of measures, including step-counts, quality of life (EQ-5D) and stage of behaviour change. Results: Four programme groups were recruited; two received the intervention. Of 68 invitees, 45 participated (66%) (19 intervention; 26 control). Forty-two (93%) completed the outcomes. Baseline characteristics were comparable between groups. Mean steps/day increased more for intervention participants (2,742; 95%CI 1,169 to 4,315) than controls (-42; 95%CI -1,102 to 1,017) (p=0.004). The intervention and on-going clinical contact were welcomed; participants considered that step-counts, compared to time-related targets, encouraged them to become more active. Conclusion: These findings suggest that an intervention using individually tailored step-count goals may help increase and sustain physical activity following a cardiac rehabilitation programme. A definitive randomised controlled trial using blinded outcome measurements is feasible and of potential value in determining how best to translate physical activity advice into practice.

Oxidized LDL and AGE-LDL in circulating immune complexes strongly predict progression of carotid artery IMT in type 1 diabetes

Over 90% of modified LDL in circulation is associated to specific antibodies circulating as part of immune complexes (IC); however, few studies have examined their relationship with cardiovascular disease.

Nilotinib 300mg BID as frontline treatment of CML:Prospective analysis of the Xpert BCR-ABL Monitor system and significance of 3-month molecular response

Sixty patients with early chronic phase CML (ECPCML) received Nilotinib on a phase II study which included a comparison of the Xpert BCR-ABL Monitor™ PCR system with standardized (IS) BCR-ABL1 real-time quantitative PCR (RQ-PCR). 88% patients achieved MMR with 45% achieving MR4.5. At 3 months BCR-ABL1/ABL1 IS >1% and

Effect of impeller speed on mechanical and dissolution properties of high-shear granules

Impeller speed is one of the most crucial process variables that affect the properties of the granules produced in a high-shear granulator. Several reports can be found in literature that discuss the influence of impeller speed on the granules size. For instance some researchers like Knight report an increase of granule size with impeller speed [1] and [2], while others (Scheaefer et al. and Ramaker et al.) observed a decrease of granules size with increasing impeller speed [3] and [4]. However there is limited work reported in literature on the effect of the impeller speed on the mechanical properties of granules. Mechanical properties are important as they affect the performance of the granules on the other downstream process such as transportation and handling. The work reported here serves to address the missing in knowledge gap regarding the influence of impeller speed on mechanical properties granules. How the granulation system responds to the changes in the impeller speeds depends on binder that is used in the process. For this reason the two extreme cases, of a low viscosity binder system and high viscosity binder system are considered in this research. For low viscosity binder system it was observed that the granule size decreased with increasing impeller speed whilst for the high viscosity binder system the opposite was observed by Knight [1]. The granule strength, the Young's modulus and yield strength of the high viscosity granules increased with increasing impeller speed where as the opposite trends were observed for the low viscosity binder granules.