Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFNγ, IL-1α, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1α, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.     

Safety and efficacy of a novel polyethylene glycol hydrogel sealant for watertight dural repair

OBJECT: The authors prospectively evaluated the safety and efficacy of a novel polyethylene glycol (PEG) hydrogel sealant in patients undergoing elective cranial surgery with documented cerebrospinal fluid (CSF) leakage after sutured dural repair. METHODS: The PEG hydrogel sealant was used at 11 different study sites in 111 patients with documented intraoperative CSF leakage after neurosurgical dural repair for a variety of conditions. Intraoperative CSF leakage was either spontaneous or induced by a Valsalva maneuver. Patients were monitored for 3 months postoperatively with physical examinations, clinical laboratory analyses, and diagnostic imaging. The PEG hydrogel sealant was 100% effective in stopping CSF leakage in all patients. There were no sealant-related adverse events and all clinical outcomes were consistent with expectations for seriously ill patients undergoing prolonged neurosurgical procedures. CONCLUSIONS: The PEG hydrogel sealant provides a safe and effective watertight closure when used as an adjunct to sutured dural repair during cranial surgery.     

Age-related decline in nicotinic receptor availability with [(123)I]5-IA-85380 SPECT

Human postmortem studies have reported decreases with age in high affinity nicotine binding in brain. We investigated the effect of age on β₂-containing nicotinic acetylcholine receptor (β₂-nAChR) availability in eight brain regions of living human subjects using the ligand [¹²³I]5-IA-85380 ([¹²³I]5-IA) and single photon emission computed tomography (SPECT). Healthy, nonsmokers (N = 47) ranging in age from 18 to 85 were administered [¹²³I]5-IA using a bolus plus constant infusion paradigm and imaged 6–8 h later under equilibrium conditions. The effect of age on regional β₂-nAChR availability (V_T, regional brain activity/free plasma parent, a measure proportional to the binding potential) was analyzed using linear regression and Pearson's correlation (r). Age and regional β₂-nAChR availability were inversely correlated in seven of the eight brain regions analyzed, with decline ranging from 32% (thalamus) to 18% (occipital cortex) over the adult lifespan, or up to 5% per decade. These results in living human subjects corroborate postmortem reports of decline in high affinity nicotine binding with age and may aid in elucidating the role of β₂-nAChRs in cognitive aging.     

PIK3CA mutations and EGFR overexpression predict for lithium sensitivity in human breast epithelial cells

A high frequency of somatic mutations has been found in breast cancers within the gene encoding the catalytic p110α subunit of PI3K, PIK3CA. Using isogenic human breast epithelial cells, we have previously demonstrated that oncogenic PIK3CA "hotspot" mutations predict for response to the toxic effects of lithium. However, other somatic genetic alterations occur within this pathway in breast cancers, and it is possible that these changes may also predict for lithium sensitivity. We overexpressed the epidermal growth factor receptor (EGFR) into the non-tumorigenic human breast epithelial cell line MCF-10A, and compared these cells to isogenic cell lines previously created via somatic cell gene targeting to model Pten loss, PIK3CA mutations, and the invariant AKT1 mutation, E17K. EGFR overexpressing clones were capable of cellular proliferation in the absence of EGF and were sensitive to lithium similar to the results previously seen with cells harboring PIK3CA mutations. In contrast, AKT1 E17K cells and PTEN -/- cells displayed resistance or partial sensitivity to lithium, respectively. Western blot analysis demonstrated that lithium sensitivity correlated with significant decreases in both PI3K and MAPK signaling that were observed only in EGFR overexpressing and mutant PIK3CA cell lines. These studies demonstrate that EGFR overexpression and PIK3CA mutations are predictors of response to lithium, whereas Pten loss and AKT1 E17K mutations do not predict for lithium sensitivity. Our findings may have important implications for the use of these genetic lesions in breast cancer patients as predictive markers of response to emerging PI3K pathway inhibitors.     

Renal transplants: what ultrasound can and cannot do

Renal transplantation has emerged as the most cost-effective and patient-supportive way to treat chronic renal failure, with excellent graft survival rates thanks to improved surgical techniques and rejection management. Its success has placed a heavy burden on imaging, especially ultrasound, which is used in the selection of live donors and in monitoring each stage of the postoperative care of the recipient.Ultrasound is particularly useful for detecting vascular complications such as early occlusions and arterial stenosis. It can detect and monitor perinephric complications and transplant hydronephrosis, all clinically significant complications that affect management. Ultrasound can detect many of the late acquired diseases, especially intercurrent tumors that require surgery. It is the best method to guide interventions such as aspiration of collections and insertion of nephrostomy drains.It can also detect postbiopsy arteriovenous shunts and the end-stage kidney of chronic rejection. These, however, are of no great clinical significance, and the findings rarely affect clinical decisions. Ultrasound fails to discriminate between the important causes of early graft dysfunction, especially acute tubular necrosis, rejection, and drug toxicity: these important distinctions still rely on biopsy. There is hope that some of the newer ultrasound methods, especially the functional data from microbubble contrast agent dynamics, might supply useful information for their detection and differentiation.     

Clinical and economic burden of antimicrobial resistance

Knowledge of the clinical and economic impact of antimicrobial resistance is useful to influence programs and behavior in healthcare facilities, to guide policy makers and funding agencies, to define the prognosis of individual patients and to stimulate interest in developing new antimicrobial agents and therapies. There are a variety of important issues that must be considered when designing or interpreting studies into the clinical and economic outcomes associated with antimicrobial resistance. One of the most misunderstood issues is how to measure cost appropriately. Although imperfect, existing data show that there is an association between antimicrobial resistance in Staphylococcus aureus, enterococci and Gram-negative bacilli and increases in mortality, morbidity, length of hospitalization and cost of healthcare. Patients with infections due to antimicrobial-resistant organisms have higher costs (US $6,000-30,000) than do patients with infections due to antimicrobial-susceptible organisms; the difference in cost is even greater when patients infected with antimicrobial-resistant organisms are compared with patients without infection. Given limited budgets, knowledge of the clinical and economic impact of antibiotic-resistant bacterial infections, coupled with the benefits of specific interventions targeted to reduce these infections, will allow for optimal control and improved patient safety. In this review, the authors discuss a variety of important issues that must be considered when designing or interpreting studies of the clinical and economic outcomes associated with antimicrobial resistance. Representative literature is reviewed regarding the associations between antimicrobial resistance in specific pathogens and adverse outcomes, including increased mortality, length of hospital stay and cost.     

Inadequate assessment of the airway and ventilation in acute poisoning. a need for improved education?

Aims and objectives: To analyse the initial management of acute poisoning patients, and whether respiratory morbidity was related to inadequate assessment of airway and ventilation. Methods: A retrospective analysis of the assessment and resuscitation of a group of acute poisoning patients, as documented in the clinical records. Subjects and setting: Forty one patients admitted to either Intensive Care or Coronary Care Units in a UK teaching hospital with a diagnosis of acute poisoning, between 12 January 1997 and 21 January 1998. Standards: Advanced Life Support Guidelines were used to compare initial assessment. Criteria for intubation and ventilation described by Gentleman was used as the standard for intubation. Results: Thirty seven patients had documented Glasgow Coma Scales at the time of admission, 27 were managed appropriately; one exhibited signs of aspiration. Ten patients were judged to be managed inappropriately; six exhibited clinical signs of aspiration. Four patients had unidentified Glasgow Coma Scales. Conclusions: Increased emphasis on ‘Airway and Breathing’ remains necessary in medical education. Regional recommendations for the management of acute poisoning require ‘intubation guidelines’. Appropriate ward settings for monitoring such patients may pre-empt the onset of major respiratory problems.     

Randomised clinical trial of chest drainage systems.

BACKGROUND: Problems in the management of thoracic trauma have stimulated the search for an alternative to underwater seals for drainage of the pleural cavity. A chest drainage bag incorporating a one way flutter valve has been compared with underwater seal drains in a randomised clinical trial. METHODS: During June-December 1989 119 patients undergoing elective thoracotomy were randomised to receive postoperative chest drainage by drainage bags (56 patients, 87 drains) or by underwater seal drains (63 patients, 98 drains). Daily drainage volumes, the requirement for pleural suction, mobility, and complications were recorded prospectively. RESULTS: There was no significant difference between the two groups in the mean volume drained, the requirements for pleural suction, or the occurrence of complications. Patients with drainage bags were fully mobile 23 hours (95% confidence interval 0-47 hours) earlier than the others. CONCLUSIONS: When used after elective thoracotomy drainage bags are safe and effective and permit earlier mobility than underwater seal drains.