The chaperonin GroEL is a large, double-ring structure that, together with ATP and the cochaperonin GroES, assists protein folding in vivo. GroES forms an asymmetric complex with GroEL in which a single GroES ring binds one end of the GroEL cylinder. Cross-linking studies reveal that polypeptide binding occurs exclusively to the GroEL ring not occupied by GroES (trans). During the folding reaction, however, released GroES can rebind to the GroEL ring containing polypeptide (cis). The polypeptide is held tightly in a proteolytically protected environment in cis complexes, in the presence of ADP. Single turnover experiments with ornithine transcarbamylase reveal that polypeptide is productively released from the cis but not the trans complex. These observations suggest a two-step mechanism for GroEL-mediated folding. First, GroES displaces the polypeptide from its initial binding sites, sequestering it in the GroEL central cavity. Second, ATP hydrolysis induces release of GroES and productive release of polypeptide.

No abstract

No abstract

Objective To measure the sensitivity of modern third generation computed tomography in emergency patients being evaluated for possible subarachnoid haemorrhage, especially when carried out within six hours of headache onset.Design Prospective cohort study.Setting 11 tertiary care emergency departments across Canada, 2000-9.Participants Neurologically intact adults with a new acute headache peaking in intensity within one hour of onset in whom a computed tomography was ordered by the treating physician to rule out subarachnoid haemorrhage.Main outcome measures Subarachnoid haemorrhage was defined by any of subarachnoid blood on computed tomography, xanthochromia in cerebrospinal fluid, or any red blood cells in final tube of cerebrospinal fluid collected with positive results on cerebral angiography. ResultsOf the 3132 patients enrolled (mean age 45.1, 2571 (82.1%) with worst headache ever), 240 had subarachnoid haemorrhage (7.7%). The sensitivity of computed tomography overall for subarachnoid haemorrhage was 92.9% (95% confidence interval 89.0% to 95.5%), the specificity was 100% (99.9% to 100%), the negative predictive value was 99.4% (99.1% to 99.6%), and the positive predictive value was 100% (98.3% to 100%). For the 953 patients scanned within six hours of headache onset, all 121 patients with subarachnoid haemorrhage were identified by computed tomography, yielding a sensitivity of 100% (97.0% to 100.0%), specificity of 100% (99.5% to 100%), negative predictive value of 100% (99.5% to 100%), and positive predictive value of 100% (96.9% to 100%). ConclusionModern third generation computed tomography is extremely sensitive in identifying subarachnoid haemorrhage when it is carried out within six hours of headache onset and interpreted by a qualified radiologist.

nvestigation of the neurologically intact (ie, no neurologic deficits) patient with headache is a potentially difficult clinical decision for physicians. Headache accounts for approximately 2% of all emergency department visits, and subarachnoid hemorrhage is one of the most serious diagnoses, accounting for only 1% to 3% of these headaches. [1][2][3][4] Although the decision to evaluate patients with new neurologic deficits is relatively straightforward, it is much more difficult to determine which alert, neurologically intact patients who present with headache alone require investigations-yet such patients account for half of all subarachnoid hemorrhages at initial presentation. 5 This diagnostic dilemma is illustrated by the report that 5.4% of confirmed subarachnoid hemorrhages were misdiagnosed during the patients' initial emergency department assessment. 6 Patients suspected of having subarachnoid hemorrhage are typically evaluated with an unenhanced computed tomography (CT) scan followed by a lumbar puncture if results of the CT scan are negative. Computed tomography is highly sensitive when performed soon after headache onset. 7 Lumbar puncture can be a painful procedure and can result in a headache that may be worse than the original headache. 8 A clinical decision rule is derived from original research and is defined as a decision-making tool that incorporates 3 or more variables from the history, examination, or simple tests. [9][10][11][12] These rules help clinicians with diagnostic or thera-IMPORTANCE Three clinical decision rules were previously derived to identify patients with headache requiring investigations to rule out subarachnoid hemorrhage.OBJECTIVE To assess the accuracy, reliability, acceptability, and potential refinement (ie, to improve sensitivity or specificity) of these rules in a new cohort of patients with headache. DESIGN, SETTING, AND PATIENTS Multicenter cohort study conducted at 10 university-affiliated Canadian tertiary care emergency departments from April 2006 to July 2010. Enrolled patients were 2131 adults with a headache peaking within 1 hour and no neurologic deficits. Physicians completed data forms after assessing eligible patients prior to investigations. MAIN OUTCOMES AND MEASURES Subarachnoid hemorrhage, defined as (1) subarachnoid blood on computed tomography scan; (2) xanthochromia in cerebrospinal fluid; or (3) red blood cells in the final tube of cerebrospinal fluid, with positive angiography findings.RESULTS Of the 2131 enrolled patients, 132 (6.2%) had subarachnoid hemorrhage. The decision rule including any of age 40 years or older, neck pain or stiffness, witnessed loss of consciousness, or onset during exertion had 98.5% (95% CI, 94.6%-99.6%) sensitivity and 27.5% (95% CI, 25.6%-29.5%) specificity for subarachnoid hemorrhage. Adding "thunderclap headache" (ie, instantly peaking pain) and "limited neck flexion on examination" resulted in the Ottawa SAH Rule, with 100% (95% CI, 97.2%-100.0%) sensitivity and 15.3% (95% CI, 13.8%-16.9%) specificity.CONCLUSIONS ...

BackgroundAdverse drug events, the unintended and harmful effects of medications, are important outcome measures in health services research. Yet no universally accepted set of International Classification of Diseases (ICD) revision 10 codes or coding algorithms exists to ensure their consistent identification in administrative data. Our objective was to synthesize a comprehensive set of ICD-10 codes used to identify adverse drug events.MethodsWe developed a systematic search strategy and applied it to five electronic reference databases. We searched relevant medical journals, conference proceedings, electronic grey literature and bibliographies of relevant studies, and contacted content experts for unpublished studies. One author reviewed the titles and abstracts for inclusion and exclusion criteria. Two authors reviewed eligible full-text articles and abstracted data in duplicate. Data were synthesized in a qualitative manner.ResultsOf 4241 titles identified, 41 were included. We found a total of 827 ICD-10 codes that have been used in the medical literature to identify adverse drug events. The median number of codes used to search for adverse drug events was 190 (IQR 156–289) with a large degree of variability between studies in the numbers and types of codes used. Authors commonly used external injury (Y40.0–59.9) and disease manifestation codes. Only two papers reported on the sensitivity of their code set.ConclusionsSubstantial variability exists in the methods used to identify adverse drug events in administrative data. Our work may serve as a point of reference for future research and consensus building in this area.

Phenotype and commitment of thymus‐colonizing precursors are unknown. Here we report the identification of T lineage‐committed precursors (designated prothymocytes) in murine fetal blood at day 15.5 of development. Fetal blood pro‐thymocytes are Thy‐1+c‐kit(low)CD3‐ in contrast to fetal blood‐derived pluripotent hematopoietic progenitors which are Thy‐1‐c‐kit+. Upon transfer into the thymus, fetal blood pro‐thymocytes generate a single wave of CD4+CD8+ thymocytes and subsequently mature TCR alpha beta+ peripheral T cells. However, fetal blood pro‐thymocytes lack multipotent progenitor potential since they fail to reconstitute B lymphocytes and myeloid and erythroid lineages. In contrast, T and B lymphocytes as well as myeloid and erythroid lineages are reconstituted from fetal blood‐derived pluripotent progenitors. Pro‐thymocytes are equally present in peripheral blood of athymic fetal mice, suggesting that this novel precursor population is T lineage‐committed prior to thymus colonization and represents the earliest T lineage precursor identified.

Objectives: Adverse drug events (ADEs) are unintended and harmful consequences of medication use. They are associated with high health resource use and cost. Yet, high levels of inaccuracy exist in their identification in clinical practice, with over one-third remaining unidentified in the emergency department (ED). The study objective was to derive clinical decision rules (CDRs) that are sensitive for the detection of ADEs, allowing their systematic identification early in a patient's hospital course.Methods: This was a prospective observational cohort study carried out in two Canadian tertiary care hospitals. Participants were adults presenting to the ED having ingested at least one prescription or overthe-counter medication within 2 weeks. Nurses and physicians evaluated patients for standardized clinical findings. A second evaluator performed interobserver assessments of predictor variables in a subset of patients. Pharmacists, who were blinded to the predictor variables, evaluated all patients for ADEs. An independent committee reviewed and adjudicated cases where the ADE assessment was uncertain or the pharmacist's diagnosis differed from the physician's working diagnosis. The primary outcome was an ADE that required a change in medical therapy, diagnostic testing, consultation, or hospital admission. CDRs were derived using kappa coefficients, chi-square statistics, and recursive partitioning.Results: Among 1,591 patients, 131 (8.2%, 95% confidence interval [CI] = 7.0% to 9.7%) were diagnosed with the primary outcome. The following variables were associated with ADEs and were used to derive two CDRs: 1) presence of comorbid conditions, 2) antibiotic use within 7 days, 3) medication changes within 28 days, 4) age ‡80 years, 5) arrival by ambulance, 6) triage acuity, 7) recent hospital admission, 8) renal failure, and 9) use of three or more prescription medications. The more sensitive rule had a sensitivity of 96.7% (95% CI = 91.8% to 98.6%) and required 40.8% (95% CI = 37.7% to 42.9%) of patients to have medication review. The more specific rule had a sensitivity 90.8% (95% CI = 81.4% to 95.7%) and required 28.3% of patients to proceed to medication review. Conclusions:The authors derived CDRs that identified patients with ADEs with high sensitivity. These rules may improve the identification of ADEs early in a patient's hospital course while limiting the number of patients requiring a detailed medication review.