Haemorrhage control beyond Advanced Trauma Life Support (ATLS) protocol in life threatening maxillofacial trauma – experience from a level Ⅰ trauma centre

Maxillofacial injuries are usually not life-threatening and do not get priority over other associated injuries. However, some maxillofacial injuries with active oral or nasal bleeding need immediate management due to threatened airway and blood loss. In the case of major active vascular bleeding, measures such as local pressure, anterior nasal packing, posterior nasal packing, and balloon tamponade are ineffective. In these cases, angiography and transcatheter arterial embolisation (TAE) are used to treat life-threatening haemorrhage caused by maxillofacial trauma. We analysed the medical records of 39 patients with severe maxillofacial trauma and life-threatening haemorrhage that was a result of intractable oral or nasal bleeding. These patients were considered for TAE from January 2010 to December 2019. A total of 1668 patients was admitted, out of which 39 (2.3%) had severe maxillofacial injuries with life-threatening oral or nasal bleeding and underwent TAE. Out of a total of 39 patients, 38 were male and one female. Ages ranged from 16 to 65 years. Road traffic injury was the most common cause of injury (79.5%), Lefort I and II were the most common facial fractures, and traumatic brain injury was the most common associated injury. Embolisation and bleeding control were done successfully in all 39 patients with no procedure-related complications. A total of 17 deaths during the study period were due to severe traumatic brain injuries or haemorrhagic shock.     

Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma

Bortezomib, a potent and reversible proteasome inhibitor, affects the myeloma cell and its microenvironment, resulting in down-regulation of growth and survival signaling pathways and durable responses in patients with relapsed and refractory myeloma. Potential associations between baseline parameters and outcomes with bortezomib were explored in 202 patients who received bortezomib 1.3 mg/m2 twice weekly for 2 weeks every 3 weeks for up to 8 cycles in a phase 2 trial. Using European Group for Blood and Marrow Transplantation criteria, the response rate (complete or partial response) to bortezomib alone was 27% and was not associated with sex, race, performance status, isotype, chromosome 13 deletion, number or type of previous therapies, or concentration of hemoglobin or beta2-microglobulin. By multivariate analysis, factors associated with lower response were being age 65 or older versus younger than 65 (19% vs 32%; P < .05) and plasma-cell infiltration in bone marrow greater than 50% versus 50% or less (20% vs 35%; P < .05). Factors that may be indicative of tumor burden (bone marrow plasma-cell infiltration greater than 50%, hypoalbuminemia, thrombocytopenia) were predictive of overall survival. Chromosome 13 deletion and elevated beta2-microglobulin, generally considered poor prognostic factors, were not predictive of poor outcome with bortezomib in this study.     

Infection--an underappreciated cause of bone pain in multiple myeloma

Bone pain, especially back pain, is a common presenting feature of myeloma patients. We report three multiple myeloma patients with exacerbations of back pain and referred shoulder pain resulting from vertebral infections. Two patients were treated with surgery, and one patient had computerized tomography-guided percutaneous needle aspiration for diagnostic purposes. All three patients received a prolonged course of antibiotics. Vertebral infection resolved with this treatment in all three patients without any recurrence. Previous dexamethasone therapy, together with an episode of bacteraemia, appears to be a predisposing factor for vertebral infection. Magnetic resonance imaging enabled the diagnosis in all three patients.     

A perception-based ERP reveals that the magnitude of delay matters for memory-guided reaching

Delayed action research has suggested that perceptual information about a visual stimulus decays over several seconds. With event-related potential (ERP) methodology, one should be able to track the time course of the electrophysiological processes associated with this decay. Recently, Cruikshank et al. (J Vis 12:29, 2012) found that the N170 ERP component reflected ventral stream processes linked to motor planning and perception for action. Specifically, the N170 was larger for actions that relied on perceptual-based information. However, the delay interval was very short (tens of ms). Behavioral and neuroimaging studies suggest that when longer delays are employed, reactivation of ventral areas is necessary in order to access a stored representation of the target’s characteristics. Therefore, the N170 may reflect not only the perception-for-action processes, but also the accuracy of the representation. In order to test this, we traced the time course of the N170 in memory-guided reaching when 1-, 2-, and 3-s delays separated target occlusion and response initiation. During reach initiation, the N170 was more negative and peaked earlier for the 1 s than the 2- and 3-s delays and correlated significantly with performance at the longest delay. These results suggest that the neural mechanisms involved in movement planning change for delays beyond 1 s. The smaller N170 may reflect an impoverished visual perceptual representation in the ventral stream. To our knowledge, these are the first electrophysiological results to suggest that there is decay of visual perceptual information that occurs with increasing time.     

Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN

Mammalian target of rapamycin (mTOR) has been reported to contribute to the development of HIV-associated nephropathy (HIVAN). We hypothesized that HIV may be activating renal tissue mTOR pathway through renin angiotensin system (RAS) via Angiotensin Receptor Type II receptor (AT2R). Renal tissues of Vpr transgenic and Tg26 (HIVAN) mice displayed enhanced phosphorylation of mTOR and p70S6K. Aliskiren, a renin inhibitor attenuated phosphorylation of both mTOR and p70S6K in renal tissues of HIVAN mice. Interestingly, Angiotensin Receptor Type I (AT1R) blockade did not modulate renal tissue phosphorylation of mTOR in HIVAN mice; on the other hand, AT2R blockade attenuated renal tissue phosphorylation of mTOR in HIVAN mice. In vitro studies, both renin and Ang II displayed enhanced mouse tubular cell (MTC) phosphorylation of p70S6K in a dose dependent manner. HIV/MTC also displayed enhanced phosphorylation of both mTOR and p70S6K; interestingly this effect of HIV was further enhanced by losartan (an AT1R blocker). On the other hand, AT2R blockade attenuated HIV-induced tubular cell phosphorylation of mTOR and p70S6K, whereas, AT2R agonist enhanced phosphorylation of mTOR and p70S6K. These findings indicate that HIV stimulates mTOR pathway in HIVAN through the activation of renin angiotensin system via AT2R.     

Polymeric micelle nanocarriers for targeted epidermal delivery of the hedgehog pathway inhibitor vismodegib: formulation development and cutaneous biodistribution in human skin

Background: The aim was to investigate cutaneous delivery and biodistribution of the hedgehog pathway inhibitor, vismodegib (VSD), indicated for basal cell carcinoma (BCC), from polymeric micelle formulations under infinite/finite dose conditions.

Methods: VSD-loaded micelles were characterized for drug content, particle size, and shape; a micelle gel was characterized for its rheological behavior. Cutaneous deposition and biodistribution of VSD were determined using porcine and human skin in vitro with quantification by UHPLC-MS/MS.

Results: The optimal micelle solution (Z_av 20–30 nm) increased the aqueous solubility of VSD by >8000-fold; drug content was stable after 4 weeks at 4°C. Application of micelle solution and micelle gel (0.086% w/v) to human skin for 12 h under infinite dose conditions resulted in statistically equivalent VSD deposition (0.62 ± 0.11 and 0.67 ± 0.14 μg/cm², respectively). Cutaneous biodistribution in human skin under infinite (micelle solution and gel) and finite (micelle gel) dose conditions showed that the VSD concentrations obtained in the basal epidermis, at depths of 120–200 μm, were ?3800- and ?2300-fold greater than the IC₅₀ reported for hedgehog signaling pathway inhibition in vitro.

Conclusion: Cutaneous delivery of VSD from micelle-based formulations might enable targeted, topical treatment of superficial BCC with minimal risk of systemic exposure.     

Stabilized G protein binding site in the structure of constitutively active metarhodopsin-II

G protein-coupled receptors (GPCR) are seven transmembrane helix proteins that couple binding of extracellular ligands to conformational changes and activation of intracellular G proteins, GPCR kinases, and arrestins. Constitutively active mutants are ubiquitously found among GPCRs and increase the inherent basal activity of the receptor, which often correlates with a pathological outcome. Here, we have used the M257Y(6.40) constitutively active mutant of the photoreceptor rhodopsin in combination with the specific binding of a C-terminal fragment from the G protein alpha subunit (GαCT) to trap a light activated state for crystallization. The structure of the M257Y/GαCT complex contains the agonist all-trans-retinal covalently bound to the native binding pocket and resembles the G protein binding metarhodopsin-II conformation obtained by the natural activation mechanism; i.e., illumination of the prebound chromophore 11-cis-retinal. The structure further suggests a molecular basis for the constitutive activity of 6.40 substitutions and the strong effect of the introduced tyrosine based on specific interactions with Y223(5.58) in helix 5, Y306(7.53) of the NPxxY motif and R135(3.50) of the E(D)RY motif, highly conserved residues of the G protein binding site.     

Serial head circumference and neurodevelopmental screening after surgical correction for single- and multiple-suture craniosynostosis

Objective : To evaluate serial head circumference (HC) measurements and neurodevelopmental (ND) screening before and after surgical revision for craniosynostosis. Design : Retrospective assessment. Setting : Tertiary institutional. Patients, Participants : All children treated with single-stage frontal-orbital advancement or total calvarial expansion for single-suture (SS) or multiple-suture (MS) craniosynostosis over a 7-year period. Main Outcome Measures : Changes in ND and HC were measured over postoperative visits after the primary surgery. More importantly, ND and HC changes were measured prerevision and postrevision. Results : Of 183 patients undergoing primary surgery, complete records and adequate follow-up were available for 112 patients. The overall revision rate was 21% (n = 23). Postrevision follow-up was adequate for 18 of the 23 revisions. After primary surgery, but prior to revision, children demonstrated a larger decline in HC (z-score, median = -1) along with higher ND findings (median = 2) from one postoperative visit to the next than those who did not go on revision (HC z-score median = 0, ND median = 0). After revision, patients demonstrated a significant improvement in ND screening findings (median ΔND findings = -2) compared with prerevision ND (p < .001). Head circumference also significantly increased by a z-score of +1 postrevision (p = .001). Conclusions : Patients chosen for revision surgery display not only a larger decline in HC but also more ND findings prior to revision. Furthermore, surgical revision has a significant association with both improved ND screening and HC.