Bazedoxifene protects cerebral autoregulation after traumatic brain injury and attenuates impairments in blood–brain barrier damage: involvement of anti-inflammatory pathways by blocking MAPK signaling

Abstract

Objective

Traumatic brain injury (TBI) is a significant cause of death and long-term deficits in motor and cognitive functions for which there are currently no effective chemotherapeutic drugs. Bazedoxifene (BZA) is a third-generation selective estrogen receptor modulator (SERM) and has been investigated as a treatment for postmenopausal osteoporosis. It is generally safe and well tolerated, with favorable endometrial and breast safety profiles. Recent findings have shown that SERMs may have therapeutic benefits; however, the role of BZA in the treatment of TBI and its molecular and cellular mechanisms remain poorly understood. The aim of the present study was to examine the neuroprotective effects of BZA on early TBI in rats and to explore the underlying mechanisms of these effects.

Materials and methods

TBI was induced using a modified weight-drop method. Neurological deficits were evaluated according to the neurological severity score (NSS). Morris water maze and open-field behavioral tests were used to test cognitive functions. Brain edema was measured by brain water content, and impairments in the blood–brain barrier (BBB) were evaluated by expression analysis of tight junction-associated proteins, such as occludin and zonula occludens-1 (ZO-1). Neuronal injury was assessed by hematoxylin and eosin (H&E) staining. LC–MS/MS analysis was performed to determine the ability of BZA to cross the BBB.

Results

Our results indicated that BZA attenuated the impaired cognitive functions and the increased BBB permeability of rats subjected to TBI through activation of inflammatory cascades. In vivo experiments further revealed that BZA provided this neuroprotection by suppressing TBI-induced activation of the MAPK/NF-κB signaling pathway. Thus, mechanically, the anti-inflammatory effects of BZA in TBI may be partially mediated by blocking the MAPK signaling pathway.

Conclusions

These findings suggest that BZA might attenuate neurological deficits and BBB damage to protect against TBI by blocking the MAPK/NF-κB signaling pathway.

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The Effect of Stimulus Polarity on the Relation Between Pitch Ranking and ECAP Spread of Excitation in Cochlear Implant Users

Abstract

Although modern cochlear implants (CIs) use cathodic-leading symmetrical biphasic pulses to stimulate the auditory nerve, a growing body of evidence suggests that anodic-leading pulses may be more effective. The positive polarity has been shown to produce larger electrically evoked compound action potential (ECAP) amplitudes, steeper slope of the amplitude growth function, and broader spread of excitation (SOE) patterns. Polarity has also been shown to influence pitch perception. It remains unclear how polarity affects the relation between physiological SOE and psychophysical pitch perception. Using a within-subject design, we examined the correlation between performance on a pitch-ranking task and spatial separation between SOE patterns for anodic and cathodic-leading symmetric biphasic pulses for 14 CI ears. Overall, there was no effect of polarity on either ECAP SOE patterns, pitch ranking performance, or the relation between the two. This result is likely due the use of symmetric biphasic pulses, which may have reduced the size of the effect previously observed for pseudomonophasic pulses. Further research is needed to determine if a pseudomonophasic stimulus might further improve the relation between physiology and pitch perception.

http://bit.ly/2TpFoBN

Dried blood spot testing for estimation of renal function and analysis of metformin and sitagliptin concentrations in diabetic patients: a cross-sectional study

Abstract

Purpose

Dried blot spot (DBS) analysis of drugs or clinical parameters offers many advantages. We investigated the feasibility of using DBS for analysis of anti-diabetic drugs concomitantly with the estimated creatinine clearance (Cl_crea).

Methods

The cross-sectional study involved physicians in an enabling analysis with 70 diabetic patients and community pharmacists in a field investigation with 84 participants. All 154 DBS samples were analyzed for creatinine, metformin, and sitagliptin.

Results

The diabetic patients revealed of a wide range of age (32–88 years), BMI values (19.8–54.7 kg/m²), and extent of polypharmacotherapy (1–21 drugs). A correlation factor to convert capillary blood creatinine from DBS into plasma concentrations was determined. Patients' Cl_crea ranged from 21.6–155.9 mL/min. The results indicated statistically significant correlations (p < 0.05) between the use of two or three particular drug classes (diuretics, NSAIDs, renin-angiotensin system blockers) and a decreased renal function. DBS concentrations of metformin ranged between 0.23–4.99 μg/mL. The estimated elimination half-life (t ½) of metformin was 11.9 h in patients with a Cl_Crea higher than 60 mL/min and 18.5 h for diabetics with lower Cl_Crea. Sitagliptin capillary blood concentrations ranged between 11.12–995.6 ng/mL. Calculated t ½ of sitagliptin were 8.4 h and 13.0 h in patients with a Cl_Crea above and below 60 mL/min, respectively.

Conclusions

DBS allow for the analysis of concentrations of predominantly renally eliminated drugs and community pharmacists can provide a valuable contribution to DBS sampling.

http://bit.ly/2G538ID

Unique considerations in pediatric skull base surgery

Publication date: Available online 30 January 2019Source: Operative Techniques in Otolaryngology-Head and Neck SurgeryAuthor(s): Irit Duek, Dan M. FlissPediatric skull base and craniofacial surgery presents a unique challenge since the potential benefits of therapy must be balanced against the cumulative impact of multimodality treatment on craniofacial growth, donor-site morbidity, and the potential for serious psychosocial issues. Skull base reconstruction using locoregional flaps or free flaps may be safely performed in pediatrics. Although the general principles of skull base reconstruction are applicable to nearly all patients, the unique demands of skull base surgery in pediatrics merit special attention. Multidisciplinary care in experienced centers is of utmost importance. (Source:...

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The Effect of Stimulus Polarity on the Relation Between Pitch Ranking and ECAP Spread of Excitation in Cochlear Implant Users

Abstract

Although modern cochlear implants (CIs) use cathodic-leading symmetrical biphasic pulses to stimulate the auditory nerve, a growing body of evidence suggests that anodic-leading pulses may be more effective. The positive polarity has been shown to produce larger electrically evoked compound action potential (ECAP) amplitudes, steeper slope of the amplitude growth function, and broader spread of excitation (SOE) patterns. Polarity has also been shown to influence pitch perception. It remains unclear how polarity affects the relation between physiological SOE and psychophysical pitch perception. Using a within-subject design, we examined the correlation between performance on a pitch-ranking task and spatial separation between SOE patterns for anodic and cathodic-leading symmetric biphasic pulses for 14 CI ears. Overall, there was no effect of polarity on either ECAP SOE patterns, pitch ranking performance, or the relation between the two. This result is likely due the use of symmetric biphasic pulses, which may have reduced the size of the effect previously observed for pseudomonophasic pulses. Further research is needed to determine if a pseudomonophasic stimulus might further improve the relation between physiology and pitch perception.

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The Effect of Stimulus Polarity on the Relation Between Pitch Ranking and ECAP Spread of Excitation in Cochlear Implant Users

Abstract

Although modern cochlear implants (CIs) use cathodic-leading symmetrical biphasic pulses to stimulate the auditory nerve, a growing body of evidence suggests that anodic-leading pulses may be more effective. The positive polarity has been shown to produce larger electrically evoked compound action potential (ECAP) amplitudes, steeper slope of the amplitude growth function, and broader spread of excitation (SOE) patterns. Polarity has also been shown to influence pitch perception. It remains unclear how polarity affects the relation between physiological SOE and psychophysical pitch perception. Using a within-subject design, we examined the correlation between performance on a pitch-ranking task and spatial separation between SOE patterns for anodic and cathodic-leading symmetric biphasic pulses for 14 CI ears. Overall, there was no effect of polarity on either ECAP SOE patterns, pitch ranking performance, or the relation between the two. This result is likely due the use of symmetric biphasic pulses, which may have reduced the size of the effect previously observed for pseudomonophasic pulses. Further research is needed to determine if a pseudomonophasic stimulus might further improve the relation between physiology and pitch perception.

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Survival and Long-Term Biochemical Cure in Medullary Thyroid Carcinoma in Denmark 1997–2014: A Nationwide Study

Thyroid, Ahead of Print.


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