Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II) Protocol

<p>Abstract</p> <p>Background</p> <p>Within the spectrum of spontaneous intracerebral haemorrhage there are some patients with large or space occupying haemorrhage who require surgery for neurological deterioration and others with small haematomas who should be managed conservatively. There is equipoise about the management of patients between these two extremes. In particular there is some evidence that patients with lobar haematomas and no intraventricular haemorrhage might benefit from haematoma evacuation. The STICH II study will establish whether a policy of earlier surgical evacuation of the haematoma in selected patients will improve outcome compared to a policy of initial conservative treatment.</p> <p>Methods/Design</p> <p>an international multicentre randomised parallel group trial. Only patients for whom the treating neurosurgeon is in equipoise about the benefits of early craniotomy compared to initial conservative treatment are eligible. All patients must have a CT scan confirming spontaneous lobar intracerebral haemorrhage (≤1 cm from the cortex surface of the brain and 10-100 ml in volume). Any clotting or coagulation problems must be corrected and randomisation must take place within 48 hours of ictus. With 600 patients, the study will be able to demonstrate a 12% benefit from surgery (2p < 0.05) with 80% power.</p> <p>Stratified randomisation is undertaken using a central 24 hour randomisation service accessed by telephone or web. Patients randomised to early surgery should have the operation within 12 hours. Information about the status (Glasgow Coma Score and focal signs) of all patients through the first five days of their trial progress is also collected in addition to another CT scan at about five days (+/- 2 days). Outcome is measured at six months via a postal questionnaire to the patient. Primary outcome is death or severe disability defined using a prognosis based 8 point Glasgow Outcome Scale. Secondary outcomes include: Mortality, Rankin, Barthel, EuroQol, and Survival.</p> <p>Trial Registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN22153967">ISRCTN22153967</a></p

Intracellular directed evolution of proteins from combinatorial libraries based on conditional phage replication

Directed evolution is a powerful tool to improve the characteristics of biomolecules. Here we present a protocol for the intracellular evolution of proteins with distinct differences and advantages in comparison with established techniques. These include the ability to select for a particular function from a library of protein variants inside cells, minimizing undesired coevolution and propagation of nonfunctional library members, as well as allowing positive and negative selection logics using basally active promoters. A typical evolution experiment comprises the following stages: (i) preparation of a combinatorial M13 phagemid (PM) library expressing variants of the gene of interest (GOI) and preparation of the Escherichia coli host cells; (ii) multiple rounds of an intracellular selection process toward a desired activity; and (iii) the characterization of the evolved target proteins. The system has been developed for the selection of new orthogonal transcription factors (TFs) but is capable of evolving any gene—or gene circuit function—that can be linked to conditional M13 phage replication. Here we demonstrate our approach using as an example the directed evolution of the bacteriophage λ cI TF against two synthetic bidirectional promoters. The evolved TF variants enable simultaneous activation and repression against their engineered promoters and do not cross-react with the wild-type promoter, thus ensuring orthogonality. This protocol requires no special equipment, allowing synthetic biologists and general users to evolve improved biomolecules within ~7 weeks

Blood Magnesium, and the Interaction with Calcium, on the Risk of High-Grade Prostate Cancer

Ionized calcium (Ca) and magnesium (Mg) compete as essential messengers to regulate cell proliferation and inflammation. We hypothesized that inadequate Mg levels, perhaps relative to Ca levels (e.g. a high Ca/Mg ratio) are associated with greater prostate cancer risk.In this biomarker sub-study of the Nashville Men's Health Study (NMHS), we included 494 NMHS participants, consisting of 98 high-grade (Gleason≥7) and 100 low-grade cancer cases, 133 prostate intraepithelial neoplasia (PIN) cases, and 163 controls without cancer or PIN at biopsy. Linear and logistic regression were used to determine associations between blood Ca, Mg, and the Ca/Mg ratio across controls and case groups while adjusting for potential confounding factors.Serum Mg levels were significantly lower, while the Ca/Mg ratio was significantly higher, among high-grade cases vs. controls (p = 0.04, p = 0.01, respectively). Elevated Mg was significantly associated with a lower risk of high-grade prostate cancer (OR = 0.26 (0.09, 0.85)). An elevated Ca/Mg ratio was also associated with an increased risk of high-grade prostate cancer (OR = 2.81 (1.24, 6.36) adjusted for serum Ca and Mg). In contrast, blood Ca levels were not significantly associated with prostate cancer or PIN.Mg, Ca, or Ca/Mg levels were not associated with low-grade cancer, PIN, PSA levels, prostate volume, or BPH treatment.Low blood Mg levels and a high Ca/Mg ratio were significantly associated with high-grade prostate cancer. These findings suggest Mg affects prostate cancer risk perhaps through interacting with Ca

Factors Associated with Work Participation and Work Functioning in Depressed Workers: A Systematic Review

Background Depression is associated with negative work outcomes such as reduced work participation (WP) (e.g., sick leave duration, work status) and work functioning (WF) (e.g., loss of productivity, work limitations). For the development of evidence-based interventions to improve these work outcomes, factors predicting WP and WF have to be identified. Methods This paper presents a systematic literature review of studies identifying factors associated with WP and WF of currently depressed workers. Results A total of 30 studies were found that addressed factors associated with WP (N = 19) or WF (N = 11). For both outcomes, studies reported most often on the relationship with disorder-related factors, whereas personal factors and work-related factors were less frequently addressed. For WP, the following relationships were supported: strong evidence was found for the association between a long duration of the depressive episode and work disability. Moderate evidence was found for the associations between more severe types of depressive disorder, presence of co-morbid mental or physical disorders, older age, a history of previous sick leave, and work disability. For WF, severe depressive symptoms were associated with work limitations, and clinical improvement was related to work productivity (moderate evidence). Due to the cross-sectional nature of about half of the studies, only few true prospective associations could be identified. Conclusion Our study identifies gaps in knowledge regarding factors predictive of WP and WF in depressed workers and can be used for the design of future research and evidence-based interventions. We recommend undertaking more longitudinal studies to identify modifiable factors predictive of WP and WF, especially work-related and personal factors