Highlighting adalimumab as a treatment option for systemic treatment of toxic epidermal necrolysis: A case series from a tertiary specialised burns centre.

Toxic epidermal necrolysis and Stevens-Johnson Syndrome describe a spectrum of severe cutaneous skin reactions constituting a medical emergency, and no formal treatment guidelines exist to direct systemic immunosuppressive therapy although referral to a burns unit and wound management remains a mainstay of treatment. We performed a retrospective chart review on all patients at a single centre with TEN between 2017 to 2021 to compare clinical characteristics and outcomes of those treated with the tumour necrosis factor-alpha (TNF-α) inhibitor adalimumab against non-TNF-α immunosuppressants such as glucocorticoids, intravenous immunoglobulin and cyclosporine. All patients treated with adalimumab had successful resolution of their TEN, resulting in a mean duration of hospital admission of 22.5 days compared to 33 days for patients treated with non-TNF-α inhibitors. We highlight adalimumab as a promising systemic immunomodulator in the treatment of TEN with efficacy comparable to other immunosuppressive agents and associated with a shorter duration of hospital admission.

The effects of substance P and acetylcholine on human tenocyte proliferation converge mechanistically via TGF-ß1.

Previous in vitro studies on human tendon cells (tenocytes) have demonstrated that the exogenous administration of substance P (SP) and acetylcholine (ACh) independently result in tenocyte proliferation, which is a prominent feature of tendinosis. Interestingly, the possible link between SP and ACh has not yet been explored in human tenocytes. Recent studies in other cell types demonstrate that both SP and ACh independently upregulate TGF-ß1 expression via their respective receptors, the neurokinin 1 receptor (NK-1R) and muscarinic ACh receptors (mAChRs). Furthermore, TGF-ß1 has been shown to downregulate NK-1R expression in human keratocytes. The aim of this study was to examine if TGF-ß1 is the intermediary player involved in mediating the proliferative pathway shared by SP and ACh in human tenocytes. The results showed that exogenous administration of SP and ACh both caused significant upregulation of TGF-ß1 at the mRNA and protein levels. Exposing cells to TGF-ß1 resulted in increased cell viability of tenocytes, which was blocked in the presence of the TGFßRI/II kinase inhibitor. In addition, the proliferative effects of SP and ACh on tenocytes were reduced by the TGFßRI/II kinase inhibitor; this supports the hypothesis that the proliferative effects of these signal substances are mediated via the TGF-ß axis. Furthermore, exogenous TGF-ß1 downregulated NK-1R and mAChRs expression at both the mRNA and protein levels, and these effects were negated by simultaneous exposure to the TGFßRI/II kinase inhibitor, suggesting a negative feedback loop. In conclusion, the results indicate that TGF-ß1 is the intermediary player through which the proliferative actions of both SP and ACh converge mechanistically.

Abordaje transmaxilar segmentado para resección de tumores del clivus: Reporte de un caso / Segmented trans-maxillary approach for clivus tumor resection: Case report

La compleja anatomía de las estructuras vitales de la base del cráneo dificulta mucho la resección quirúrgica de los tumores que afectan esta zona. El problema fundamental de los tumores que afectan a la base del cráneo es elegir el abordaje ideal. El desarrollo inicial de la cirugía de la base del cráneo fue producto de la colaboración entre la otorrinolaringología y la neurocirugía; la participación del cirujano maxilofacial ha sido un fenómeno relativamente reciente. En este caso se presenta un abordaje transmaxilar para acceso al clivus y eliminar el tumor.

The complex anatomy exhibited by the vital structures of the skull base hinders surgical resection of tumors present in that area. The main problem when facing tumors lodged in the skull base resides in choosing the most suitable approach. The initial development of skull base surgery was a product of the collaboration between otorhinolaryngology and neurosurgery techniques. The participation of maxillofacial surgeons in these events has been a relatively recent endeavor. In the present instance a case of trans-maxillary approach to access clivus and remove a tumor was presented.

Substance P enhances collagen remodeling and MMP-3 expression by human tenocytes.

The loss of collagen organization is considered a hallmark histopathologic feature of tendinosis. At the cellular level, tenocytes have been shown to produce signal substances that were once thought to be restricted to neurons. One of the main neuropeptides implicated in tendinosis, substance P (SP), is known to influence collagen organization, particularly after injury. The aim of this study was to examine the influence of SP on collagen remodeling by primary human tendon cells cultured in vitro in three-dimensional collagen lattices. We found that SP stimulation led to an increased rate of collagen remodeling mediated via the neurokinin-1 receptor (NK-1 R), the preferred cell receptor for SP. Gene expression analysis showed that SP stimulation resulted in significant increases in MMP3, COL3A1 and ACTA2 mRNA levels in the collagen lattices. Furthermore, cyclic tensile loading of tendon cell cultures along with the administration of exogenous SP had an additive effect on MMP3 expression. Immunoblotting confirmed that SP increased MMP3 protein levels via the NK-1 R. This study indicates that SP, mediated via NK-1 R, increases collagen remodeling and leads to increased MMP3 mRNA and protein expression that is further enhanced by cyclic mechanical loading.

Human tenocytes are stimulated to proliferate by acetylcholine through an EGFR signalling pathway.

Studies of human patellar and Achilles tendons have shown that primary tendon fibroblasts (tenocytes) not only have the capacity to produce acetylcholine (ACh) but also express muscarinic ACh receptors (mAChRs) through which ACh can exert its effects. In patients with tendinopathy (chronic tendon pain) with tendinosis, the tendon tissue is characterised by hypercellularity and angiogenesis, both of which might be influenced by ACh. In this study, we have tested the hypothesis that ACh increases the proliferation rate of tenocytes through mAChR stimulation and have examined whether this mechanism operates via the extracellular activation of the epidermal growth factor receptor (EGFR), as shown in other fibroblastic cells. By use of primary human tendon cell cultures, we identified cells expressing vimentin, tenomodulin and scleraxis and found that these cells also contained enzymes related to ACh synthesis and release (choline acetyltransferase and vesicular acetylcholine transporter). The cells furthermore expressed mAChRs of several subtypes. Exogenously administered ACh stimulated proliferation and increased the viability of tenocytes in vitro. When the cells were exposed to atropine (an mAChR antagonist) or the EGFR inhibitor AG1478, the proliferative effect of ACh decreased. Western blot revealed increased phosphorylation, after ACh stimulation, for both EGFR and the extracellular-signal-regulated kinases 1 and 2. Given that tenocytes have been shown to produce ACh and express mAChRs, this study provides evidence of a possible autocrine loop that might contribute to the hypercellularity seen in tendinosis tendon tissue.

Substance P is a mechanoresponsive, autocrine regulator of human tenocyte proliferation.

It has been hypothesised that substance P (SP) may be produced by primary fibroblastic tendon cells (tenocytes), and that this production, together with the widespread distribution of the neurokinin-1 receptor (NK-1 R) in tendon tissue, could play an important role in the development of tendinopathy, a condition of chronic tendon pain and thickening. The aim of this study was to examine the possibility of endogenous SP production and the expression of NK-1 R by human tenocytes. Because tendinopathy is related to overload, and because the predominant tissue pathology (tendinosis) underlying early tendinopathy is characterized by tenocyte hypercellularity, the production of SP in response to loading/strain and the effects of exogenously administered SP on tenocyte proliferation were also studied. A cell culture model of primary human tendon cells was used. The vast majority of tendon cells were immunopositive for the tenocyte/fibroblast markers tenomodulin and vimentin, and immunocytochemical counterstaining revealed that positive immunoreactions for SP and NK-1 R were seen in a majority of these cells. Gene expression analyses showed that mechanical loading (strain) of tendon cell cultures using the FlexCell© technique significantly increased the mRNA levels of SP, whereas the expression of NK-1 R mRNA decreased in loaded as compared to unloaded tendon cells. Reduced NK-1 R protein was also observed, using Western blot, after exogenously administered SP at a concentration of 10⁻7 M. SP exposure furthermore resulted in increased cell metabolism, increased cell viability, and increased cell proliferation, all of which were found to be specifically mediated via the NK-1 R; this in turn involving a common mitogenic cell signalling pathway, namely phosphorylation of ERK1/2. This study indicates that SP, produced by tenocytes in response to mechanical loading, may regulate proliferation through an autocrine loop involving the NK-1 R.

Second harmonic generation analysis of early Achilles tendinosis in response to in vivo mechanical loading.

BACKGROUND: Tenocytes have been implicated in the development of tendinosis, a chronic condition commonly seen in musculoskeletal overuse syndromes. However, the relation between abnormal tenocyte morphology and early changes in the fibrillar collagen matrix has not been closely examined in vivo. Second harmonic generation (SHG) microscopy is a recently developed technique which allows examination of fibrillar collagen structures with a high degree of specificity and resolution. The goal of this study was to examine the potential utility of SHG and multiphoton excitation fluorescence (MPEF) microscopy in understanding the relation between tenocytes and their surrounding collagenous matrix in early tendon overuse lesions. METHODS: Histological preparations of tendon were prepared from adult male Sprague-Dawley rats subjected to an Achilles tendon loading protocol for 12 weeks (Rat-A-PED), or from sedentary age-matched cage controls. Second harmonic generation and multiphoton excitation fluorescence were performed simultaneously on these tissue sections in at least three different areas. RESULTS: SHG microscopy revealed an association between abnormal tenocyte morphology and morphological changes in the fibrillar collagen matrix of mechanically loaded Achilles tendons. Collagen density and organization was significantly reduced in focal micro-regions of mechanically loaded tendons. These pathological changes occurred specifically in association with altered tenocyte morphology. Normal tendons displayed a regular distribution of fibre bundles, and the average size of these bundles as determined by Gaussian analysis was 0.47 µm ± 0.02. In comparison, fibre bundle measures from tendon regions in the vicinity of abnormal tenocytes could not be quantified due to a reduction in their regularity of distribution and orientation. CONCLUSIONS: SHG microscopy allowed high resolution detection of focal tendon abnormalities affecting the fibrillar collagen matrix. With ongoing repetitive loading, these tenocyte-associated focal collagen defects could predispose to the progression of overuse pathology.