Mechanotransduction pathways in articular chondrocytes and the emerging role of estrogen receptor-α.

In the synovial joint, mechanical force creates an important signal that influences chondrocyte behavior. The conversion of mechanical signals into biochemical cues relies on different elements in mechanotransduction pathways and culminates in changes in chondrocyte phenotype and extracellular matrix composition/structure. Recently, several mechanosensors, the first responders to mechanical force, have been discovered. However, we still have limited knowledge about the downstream molecules that enact alterations in the gene expression profile during mechanotransduction signaling. Recently, estrogen receptor α (ERα) has been shown to modulate the chondrocyte response to mechanical loading through a ligand-independent mechanism, in line with previous research showing that ERα exerts important mechanotransduction effects on other cell types, such as osteoblasts. In consideration of these recent discoveries, the goal of this review is to position ERα into the mechanotransduction pathways known to date. Specifically, we first summarize our most recent understanding of the mechanotransduction pathways in chondrocytes on the basis of three categories of actors, namely mechanosensors, mechanotransducers, and mechanoimpactors. Then, the specific roles played by ERα in mediating the chondrocyte response to mechanical loading are discussed, and the potential interactions of ERα with other molecules in mechanotransduction pathways are explored. Finally, we propose several future research directions that may advance our understanding of the roles played by ERα in mediating biomechanical cues under physiological and pathological conditions.

Acute Traumatic Brain Injury Does Not Exacerbate Amyotrophic Lateral Sclerosis in the SOD1 (G93A) Rat Model

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease in which upper and lower motor neurons degenerate, leading to muscle atrophy, paralysis, and death within 3 to 5 years of onset. While a small percentage of ALS cases are genetically linked, the majority are sporadic with unknown origin. Currently, etiological links are associated with disease onset without mechanistic understanding. Of all the putative risk factors, however, head trauma has emerged as a consistent candidate for initiating the molecular cascades of ALS. Here, we test the hypothesis that traumatic brain injury (TBI) in the SOD1 (G93A) transgenic rat model of ALS leads to early disease onset and shortened lifespan. We demonstrate, however, that a one-time acute focal injury caused by controlled cortical impact does not affect disease onset or survival. Establishing the negligible involvement of a single acute focal brain injury in an ALS rat model increases the current understanding of the disease. Critically, untangling a single focal TBI from multiple mild injuries provides a rationale for scientists and physicians to increase focus on repeat injuries to hopefully pinpoint a contributing cause of ALS.

Postoperative infection risk after splenectomy: A prospective cohort study.

INTRODUCTION: Splenectomy is associated with a life-long risk for overwhelming infections. The risk for early post-operative infectious complications following traumatic and elective splenectomy is, however, understudied. This investigation aimed to determine if splenectomy increases the risk for post-operative infections. METHODS: This was a retrospective review of prospectively collected data on patients admitted to the surgical intensive care unit (SICU) between 1/2011 and 7/2013 investigating the risk for infectious complications in patients undergoing a splenectomy compared with those undergoing any other abdominal surgery. RESULTS: During the 30-month study period, a total of 1884 patients were admitted to the SICU. Of those, 33 (2%) had a splenectomy and 493 (26%) had an abdominal surgery. The two groups were well balanced for age, APACHE IV score >20, and past medical history, including diabetes mellitus, cardiac history, renal failure or immunosuppression. Patients undergoing splenectomy were more likely to have sustained a traumatic injury (30% vs. 7%, p < 0.01). After adjustment, splenectomy was associated with increased risk for infectious complications (49% vs. 29%, Adjusted Odds Ratio (AOR) [95% CI]: 2.7 [1.3, 5.6], p = 0.01), including intra-abdominal abscess (9% vs. 3%, AOR [95% CI]: 4.3 [1.1, 16.2], p = 0.03). On a subgroup analysis, there were no differences between traumatic and elective splenectomy with regards to overall infectious complications (50% vs. 46%, p = 0.84), although, abdominal abscess developed only in those who had an elective splenectomy (0% vs. 12%, p = 0.55). CONCLUSION: Splenectomy increases the risk for post-operative infectious complications. Further studies identifying strategies to decrease the associated morbidity are necessary.

Clostridium difficile increases the risk for venous thromboembolism.

BACKGROUND: Inflammatory bowel disease is associated with a higher risk for venous thromboembolism (VTE). Whether Clostridium difficile infection similarly increases this risk is unknown. METHODS: This was a retrospective analysis of patients admitted to the surgical intensive care unit (ICU) at the Cedars-Sinai Medical Center from February 2011 to July 2013. The 2 groups were compared using standard statistical methodology. RESULTS: During the 30-month study period, a total of 1,728 patients were admitted to the surgical ICU. A total of 64 patients (3.7%) tested positive for C. difficile. The use of chemical prophylaxis for VTE was significantly higher in the C. difficile group (64.1% vs 46.2%, P = .005). Nonetheless, C. difficile patients had a higher risk for development of a VTE (23.4% vs 11.0%, adjusted odds ratio [95% confidence interval]: 1.87 [1.01 to 3.48], P = .048). In a forward logistic regression model, C. difficile was found to be independently associated with the development of VTE (adjusted odds ratio [95% confidence interval]: 1.87 [1.00 to 3.47], P = .049). CONCLUSIONS: C. difficile infection increases the risk for VTE in surgical patients admitted to the ICU.

Prehospital hypertension is predictive of traumatic brain injury and is associated with higher mortality.

BACKGROUND: The purpose of the current study was to investigate the effect of early adrenergic hyperactivity as manifested by prehospital (emergency medical service [EMS]) hypertension on outcomes of traumatic brain injury (TBI) patients and to develop a prognostic model of the presence of TBI based on EMS and admission (emergency department [ED]) hypertension. METHODS: This study is a retrospective review of the 2007 to 2008 National Trauma Data Bank including blunt trauma patients 15 years or older with available EMS and ED vital signs. Patients with head Abbreviated Injury Scale (AIS) score of 3 or greater were selected, and mortality was examined within EMS systolic blood pressure (SBP) groups: lower than 100 mm Hg, 110 mm Hg to 150 mm Hg, 160 mm Hg to 180 mm Hg, and 190 mm Hg to 230 mm Hg. A forward logistic regression model including the EMS heart rate, EMS SBP, EMS Glasgow Coma Scale (GCS) score, ED heart rate, and ED SBP was used to identify predictors of a TBI in patients with ED GCS score of less than or equal to 8, 9 to 13, and 14 to 15. RESULTS: For the 5-year study period, 315,242 patients met inclusion criteria. Adjusted odds for mortality increased in a stepwise fashion with increasing EMS SBP compared with patients with normal EMS SBP (adjusted odds ratio [95% confidence interval], 1.33 [1.22-1.44], p < 0.001, for EMS SBP of 160-180 mm Hg and 1.97 [1.76-2.21], p < 0.001, for EMS SBP of 190-230 mm Hg). A 7-point scoring system was developed for each ED GCS score group to predict the presence of a TBI. EMS SBP of greater than 150 mm Hg and ED SBP of greater than 150 mm Hg were both predictive of the presence of a TBI in patients with ED GCS score of 8 or less and in patients with ED GCS score of 9 to 13 or 14 to 15, respectively. CONCLUSION: Prehospital hypertension in TBI is associated with a higher mortality risk. Early hypertension in the prehospital setting and at admission can be used to predict the presence of such injuries. These findings may have important early triage and treatment implications. LEVEL OF EVIDENCE: Prognostic study, level III.

Reactive oxygen species-activated nanoprodrug of Ibuprofen for targeting traumatic brain injury in mice.

Traumatic brain injury (TBI) is an enormous public health problem, with 1.7 million new cases of TBI recorded annually by the Centers for Disease Control. However, TBI has proven to be an extremely challenging condition to treat. Here, we apply a nanoprodrug strategy in a mouse model of TBI. The novel nanoprodrug contains a derivative of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen in an emulsion with the antioxidant α-tocopherol. The ibuprofen derivative, Ibu2TEG, contains a tetra ethylene glycol (TEG) spacer consisting of biodegradable ester bonds. The biodegradable ester bonds ensure that the prodrug molecules break down hydrolytically or enzymatically. The drug is labeled with the fluorescent reporter Cy5.5 using nonbiodegradable bonds to 1-octadecanethiol, allowing us to reliably track its accumulation in the brain after TBI. We delivered a moderate injury using a highly reproducible mouse model of closed-skull controlled cortical impact to the parietal region of the cortex, followed by an injection of the nanoprodrug at a dose of 0.2 mg per mouse. The blood brain barrier is known to exhibit increased permeability at the site of injury. We tested for accumulation of the fluorescent drug particles at the site of injury using confocal and bioluminescence imaging of whole brains and brain slices 36 hours after administration. We demonstrated that the drug does accumulate preferentially in the region of injured tissue, likely due to an enhanced permeability and retention (EPR) phenomenon. The use of a nanoprodrug approach to deliver therapeutics in TBI represents a promising potential therapeutic modality.

Clinical documents: attribute-values entity representation,context, page layout and communication.

This paper presents how acquisition, storage and communication of clinical documents is implemented at the University Hospitals of Geneva. Careful attention has been given to user-interfaces, in order to support complex layouts, spell checking, and templates management with automatic prefilling. A dual architecture has been developed for storage using an entity-attribute-value unified database and a consolidated, patient-centered, layout-respectful file-based storage, providing both representation power and speed of access. This architecture allows a great flexibility for storing a continuum of data types, ranging from simple typed values to complex clinical reports. Finally, communication is entirely based on HTTP-XML internally, and a HL-7 CDA interface V2 is currently studied for external communication. Some of the problems encountered, mostly related to the typology of documents and the ontology of clinical attributes are evoked.