The Serpin Superfamily and Their Role in the Regulation and Dysfunction of Serine Protease Activity in COPD and Other Chronic Lung Diseases.

Chronic obstructive pulmonary disease (COPD) is a debilitating heterogeneous disease characterised by unregulated proteolytic destruction of lung tissue mediated via a protease-antiprotease imbalance. In COPD, the relationship between the neutrophil serine protease, neutrophil elastase, and its endogenous inhibitor, alpha-1-antitrypsin (AAT) is the best characterised. AAT belongs to a superfamily of serine protease inhibitors known as serpins. Advances in screening technologies have, however, resulted in many members of the serpin superfamily being identified as having differential expression across a multitude of chronic lung diseases compared to healthy individuals. Serpins exhibit a unique suicide-substrate mechanism of inhibition during which they undergo a dramatic conformational change to a more stable form. A limitation is that this also renders them susceptible to disease-causing mutations. Identification of the extent of their physiological/pathological role in the airways would allow further expansion of knowledge regarding the complexity of protease regulation in the lung and may provide wider opportunity for their use as therapeutics to aid the management of COPD and other chronic airways diseases.

Subcutaneous depth in a traumatized lower extremity.

BACKGROUND: Acute compartment syndrome is a rare but serious consequence of traumatic leg injury. Near-infrared spectroscopy (NIRS) is able to measure oxygenation to a depth of 2 cm to 3 cm below the skin, raising concerns over the ability of NIRS to accurately determine oxygenation of injured leg compartments in the presence of swelling and in the obese. The purpose of this study was to measure the thickness of the subcutaneous tissue overlying the posterior muscle compartment in subjects with tibia fractures to determine if it might compromise rSO2 measurement in the muscle. METHODS: Data were analyzed on 50 patients with severe leg injuries. Distance from the skin to the fascia in the superficial posterior compartment of both legs was measured on each patient using a portable ultrasound device. RESULTS: Subject age ranged from 18 years to 65 years (mean, 39 years), with 43 male and 7 female patients. The mean (SD) subcutaneous adipose tissue thickness (ATT) was 6.98 (3.17) mm for the injured leg and 7.06 (3.37) mm for the uninjured leg, and the mean body mass index for the group was 27.08 kg/m. No significant correlation was found between the ATT of the injured or uninjured legs and body mass index. Mean comparison testing revealed no difference in ATT between the injured and uninjured legs (null hypothesis: equal means, p > 0.05). Of the 50 subjects analyzed, no subject had a subcutaneous depth of more than 2 cm on the injured or uninjured leg. CONCLUSION: These data suggest that, within this traumatically injured population, symptoms associated with leg injury (such as swelling and edema) do not significantly affect the distance from the skin to the fascia. It is also notable that subcutaneous depth beyond the 2-cm mark (validated in previous studies) is a rare occurrence in this population. These results further support the use of continuous NIRS monitoring for diagnosis of acute compartment syndrome. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Assessment of the smoke-free outdoor regulation in the WHO European Region.

OBJECTIVE: The aim of this study is to assess the level of protection of secondhand smoke in outdoor locations among countries belonging to the WHO European Region. METHOD: This cross-sectional study measures the level of protection provided by laws in outdoor locations. A protocol to evaluate the outdoor smoke-free legislation was developed according to the recommendations provided by the WHO Guidelines for implementing smoke-free outdoor places. For each law 6 main sectors and 28 outdoor locations were evaluated. RESULTS: 68 laws from 48 countries were reviewed, totally assessing 1758 locations. Overall 3.1% of the locations specified 100% smoke-free outdoor regulation without exceptions, 2.5% permitted smoking in designated outdoor areas, 37.5% allowed smoking everywhere, and 56.9% did not provide information about how to deal with smoking in outdoor places. In the Education sector 17.8% of the laws specified smoke-free outdoor regulation, mainly in the primary and secondary schools. Three pioneering laws from recreational locations and two from general health facilities specified 100% outdoor smoke-free regulation. CONCLUSION: Outdoor smoke-free policies among countries belonging to the WHO European Region are limited and mainly have been passed in the primary and secondary schools, which protect minors from the hazards of secondhand smoke in educational settings.

Protection from secondhand smoke in countries belonging to the WHO European Region: an assessment of legislation.

OBJECTIVES: Comprehensive smokefree laws, as recommended by the WHO Framework Convention of Tobacco Control (WHO FCTC), are the most effective tool to protect the population from secondhand smoke (SHS) and to ensure healthy environments. Studies evaluating how laws govern SHS protection are scarce. This study assessed the level of protection from SHS of laws from countries belonging to the WHO European Region. METHODS: A new methodology system was developed to evaluate the smokefree legislation according to the principles provided by the WHO guidelines for the correct implementation of Article 8 of the FCTC. For each law, six main sectors and 28 facilities were evaluated. RESULTS: Overall 68 laws from 48 countries from the WHO European Region were reviewed. 'Education' and 'Public transport' were the most protected sectors from SHS. Many WHO European laws do not provide protection from SHS across all public sectors. For example, 48.5% of general health facilities and 71.2% of restaurants are unprotected from SHS. The level of protection provided in the 28 facilities studied was low; many WHO European laws still allow smoking under certain conditions, permitting smoking in designated and/or ventilated areas. CONCLUSIONS: Nine years after the adoption of the WHO FCTC there are still legal formulas in which smoking is allowed in several facilities, through the inclusion of separated areas, ventilated areas and other conditions. Tobacco control efforts still face the challenge of eradicating the legal clauses that prevent 100% smokefree environments.

Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury.

OBJECTIVE: Ubiquitin C-terminal hydrolase (UCH-L1), also called neuronal-specific protein gene product (PGP 9.3), is highly abundant in neurons. To assess the reliability of UCH-L1 as a potential biomarker for traumatic brain injury (TBI) this study compared cerebrospinal fluid (CSF) levels of UCH-L1 from adult patients with severe TBI to uninjured controls; and examined the relationship between levels with severity of injury, complications and functional outcome. DESIGN: This study was designed as prospective case control study. PATIENTS: This study enrolled 66 patients, 41 with severe TBI, defined by a Glasgow coma scale (GCS) score of < or =8, who underwent intraventricular intracranial pressure monitoring and 25 controls without TBI requiring CSF drainage for other medical reasons. SETTING: : Two hospital system level I trauma centers. MEASUREMENTS AND MAIN RESULTS: Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, 120, 144, and 168 hrs following TBI and analyzed for UCH-L1. Injury severity was assessed by the GCS score, Marshall Classification on computed tomography and a complicated postinjury course. Mortality was assessed at 6 wks and long-term outcome was assessed using the Glasgow outcome score 6 months after injury. TBI patients had significantly elevated CSF levels of UCH-L1 at each time point after injury compared to uninjured controls. Overall mean levels of UCH-L1 in TBI patients was 44.2 ng/mL (+/-7.9) compared with 2.7 ng/mL (+/-0.7) in controls (p <.001). There were significantly higher levels of UCH-L1 in patients with a lower GCS score at 24 hrs, in those with postinjury complications, in those with 6-wk mortality, and in those with a poor 6-month dichotomized Glasgow outcome score. CONCLUSIONS: These data suggest that this novel biomarker has the potential to determine injury severity in TBI patients. Further studies are needed to validate these findings in a larger sample.

Gynaecological ultrasound in community sexual and reproductive health clinics.

BACKGROUND AND METHODOLOGY: Many women seen in community sexual and reproductive health (SRH) clinics have gynaecological problems and a pelvic ultrasound scan forms part of their investigation. We present a retrospective analysis of 24 months' provision of a gynaecological ultrasound service in the Department of Sexual and Reproductive Health, Southwark Primary Care Trust, London, UK. RESULTS: A total of 327 women attended for ultrasound examination; 258 required a pelvic scan and 69 had an Implanon-related problem. Of the women analysed, 152 were managed entirely in the community; eight women required referral to gynaecological outpatients and five women needed an abdominal pelvic X-ray. CONCLUSIONS: We believe we have demonstrated that gynaecological ultrasound can be performed in the community. This seems to be acceptable to patients and also reduces the requirement for hospital appointments.

Traumatic brain injury biomarkers: from pipeline to diagnostic assay development.

In recent years, the term proteomics is often mentioned together with biomarker discovery, as proteomic studies have the capability of identifying unique and unobvious protein biomarkers from tissues or biofluids derived from animal models or human clinical samples inflicted with various diseases. Proteomics has yielded hundreds of potential biomarker candidates. However, biomarker discovery is only the beginning of a long road for generating a validated, clinically relevant, and FDA-approved biomarker assay. Many technical, financial, legal, and regulatory hurdles have to be overcome before the components can be commercially produced (1, 2). This chapter outlines in a condensed version the steps to successfully develop clinically acceptable biomarkers, given the marker of choice withstands the rigor of developmental challenges along the road.

Translation of neurological biomarkers to clinically relevant platforms.

Like proteomics more generally, neuroproteomics has recently been linked to the discovery of biochemical markers of central nervous system (CNS) injury and disease. Although neuroproteomics has enjoyed considerable success in discovery of candidate biomarkers, there are a number of challenges facing investigators interested in developing clinically useful platforms to assess biomarkers for damage to the CNS. These challenges include intrinsic physiological complications such as the blood-brain barrier. Effective translation of biomarkers to clinical practice also requires development of entirely novel pathways and product development strategies. Drawing from lessons learned from applications of biomarkers to traumatic brain injury, this study outlines major elements of such a pathway. As with other indications, biomarkers can have three major areas of application: (1) drug development; (2) diagnosis and prognosis; (3) patient management. Translation of CNS biomarkers to practical clinical platforms raises a number of integrated elements. Biomarker discovery and initial selection needs to be integrated at the earliest stages with components that will allow systematic prioritization and triage of biomarker candidates. A number of important criteria need to be considered in selecting clinical biomarker candidates. Development of proof of concept assays and their optimization and validation represent an often overlooked feature of biomarker translational research. Initial assay optimization should confirm that assays can detect biomarkers in relevant clinical samples. Since access to human clinical samples is critical to identification of biomarkers relevant to injury and disease as well as for assay development, design of human clinical validation studies is an important component of translational biomarker research platforms. Although these clinical studies share much in common with clinical trials for assessment of drug therapeutic efficacy, there are a number of considerations unique to these efforts. Finally, platform selection and potential assay commercialization need to be considered. Decisions regarding whether or not to seek FDA approval also significantly influence translational research structures.

Neuroproteomics and systems biology-based discovery of protein biomarkers for traumatic brain injury and clinical validation.

The rapidly growing field of neuroproteomics has expanded to track global proteomic changes underlying various neurological conditions such as traumatic brain injury (TBI), stroke, and Alzheimer's disease. TBI remains a major health problem with approximately 2 million incidents occurring annually in the United States, yet no affective treatment is available despite several clinical trials. The absence of brain injury diagnostic biomarkers was identified as a significant road-block to therapeutic development for brain injury. Recently, the field of neuroproteomics has undertaken major advances in the area of neurotrauma research, where several candidate markers have been identified and are being evaluated for their efficacy as biological biomarkers in the field of TBI. One scope of this review is to evaluate the current status of TBI biomarker discovery using neuroproteomics techniques, and at what stage we are at in their clinical validation. In addition, we will discuss the need for strengthening the role of systems biology and its application to the field of neuroproteomics due to its integral role in establishing a comprehensive understanding of specific brain disorder and brain function in general. Finally, to achieve true clinical input of these neuroproteomic findings, these putative biomarkers should be validated using preclinical and clinical samples and linked to clinical diagnostic assays including ELISA or other high-throughput assays.

Use of biomarkers for diagnosis and management of traumatic brain injury patients.

BACKGROUND: Advances in the understanding of human biochemistry and physiology have provided insight into new pathways by which we can understand traumatic brain injury (TBI). Increased sophistication of laboratory techniques and developments in the field of proteomics has led to the discovery and rapid detection of new biomarkers not previously available. OBJECTIVE: To review recent advances in biomarker research for traumatic brain injury, describe the features of the ideal biomarker and to explore the potential role of these biomarkers in improving clinical management of brain injured patients. METHODS: Through a literature review of recent research on TBI biomarkers and through experience with TBI research, important elements of biomarker development are described together with potential applications to patient care. CONCLUSIONS: TBI biomarkers could have a significant impact on patient care by assisting in the diagnosis, risk stratification and management of TBI. Biomarkers could provide major opportunities for the conduct of clinical research, including confirmation of injury mechanism(s) and drug target identification. Continuing studies by the authors' group are now being conducted to elucidate more fully the relationships between new biomarkers and severity of injury and clinical outcomes in all severities of TBI patients.

Neuroprotection targets after traumatic brain injury.

PURPOSE OF REVIEW: The scarcity of pharmacological neuroprotective treatments for traumatic brain injury is a concern being targeted on various fronts. This review examines the latest treatments under investigation. RECENT FINDINGS: In the last 12-18 months, no drug has completed phase III clinical trials as a clearly proven method to treat traumatic brain injury. While the drugs work in rodents, when they make it to clinical trial they have failed primarily due to negative side-effects. Those still in trial show promise, and even those rejected have undergone modifications and now show potential, e.g. second-generation N-methyl-D-aspartic acid and alpha-amino-3-hydroxy-methyl-4-isoxazolyl-propionic acid receptor antagonists, calpain inhibitors, and cyclosporine A analogues. Also, several drugs not previously given much attention, such as the antibiotic minocycline, estrogen and progesterone, and a drug already approved for other diseases, erythropoietin, are being examined. Finally, a treatment generating some controversy, but showing potential, is the application of hypothermia to the patients. SUMMARY: Clearly, finding treatments for traumatic brain injury is not going to be easy and is evidently going to require numerous trials. The good news is that we are closer to finding one or more methods for treating traumatic brain injury patients.