Occurrence of pulmonary oil microembolism (POME) with intramuscular testosterone undecanoate injection: literature review.

Testosterone undecanoate injections (TU), an oil-based depot, is a universal hormonal-based treatment which has been associated with pulmonary oil microembolism (POME). However, the rate of POME during routine intramuscular (IM) TU injection is unknown. Here, we conduct a peer-reviewed literature review investigating POME incidents in the setting of TU injections. A total of 48 articles were selected in the literature review, which included 29 studies that used TU and reported its effects. Relatively few POME cases were reported across multiple published studies, including those that focused particularly on the occurrence rate of POME while administrating IM TU. Of the 29 individual studies, which included 7 978 patients, eight studies reported a total of 88 incidence of POME cases or cough. This included episodes of cough that were not originally declared as POME. One post market review reported 223 cases per 3,107,652 injections. When POME did occur, almost all cases resolved spontaneously within 60 min without intervention. Overall, POME was observed to be rare.

Examining Male Predominance of Severe COVID-19 Outcomes: A Systematic Review.

Although not universal, many epidemiological data sources signal that a higher proportion of males than females with confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections have adverse outcomes, such as intensive care unit (ICU) admission and death. Though likely multifactorial, the various hypotheses that have been proposed as underlying factors behind this trend are related to greater smoking prevalence among males, testosterone (T) deficiency causing an inflammatory storm, androgen-driven pathogenesis of SARS-CoV-2, a protective effect of estrogen in females, and inborn errors of cytokine immunity. This review aims at examining the evidence and at assessing the likelihood that the factors being investigated are contributory to the reported trend of male predominance of severe COVID-19 cases. Sources were obtained using the PubMed database and were selected based on their relevance to one of the primary hypotheses attempting to explain the strong male sex bias of severe SARS-CoV-2 infections. Emphasis was placed on meta-analyses and population-based studies. Sources are current through February 22, 2022. A severe COVID-19 case or outcome is defined in this review as a progression of the SARS-CoV-2 virus that results in either admission to an ICU for management of symptoms and clinical stabilization or which leads to death. Although the trend of male predominance of severe COVID-19 cases is likely multifactorial, the hypothesis of T deficiency causing an inflammatory storm has support from many studies with limited conflicting evidence. An inborn error in cytokine immunity is also well supported, but it needs more studies to add support to the hypothesis. The immunologic protective effect of estrogen is supported by multiple studies, but it also has conflicting evidence. It appears less likely that the trend is caused solely by an increased prevalence of smoking among males or an androgen-driven pathogenesis, based on the extent of conflicting evidence.

Extracellular matrix deformations of the porcine recurrent laryngeal nerve in response to hydrostatic pressure.

Damage to the recurrent laryngeal nerve (RLN) caused by supraphysiological compression or tension imposed by adjacent tissue structures, such as the aorta, may contribute to onset of idiopathic unilateral vocal fold paralysis (iUVP) resulting in difficulty speaking, breathing, and swallowing. We previously demonstrated in adolescent pigs that the right RLN epineurium exhibits uniform composition of adipose tissue, with larger quantities along its length within the neck region in contrast to the left RLN that shows greater collagen composition in the thoracic region and greater quantities of adipose tissue in the neck region. In contrast, the epineurium in piglets was primarily composed of collagen tissue that remained uniform along the length of the left and right RLNs. Tensile testing of the left and right RLN in piglets and pigs showed associated differences in strain by RLN side and segment by age. The goal of this study was to investigate how external hydrostatic compression of the RLN affects the nerve's connective tissue and microstructure. RLN segments were harvested from the distal (cervical/neck) regions and proximal (subclavian for the right RLN, thoracic for the left RLN) regions from eight adolescent pigs and nine piglets. RLN segments were isolated and assessed under fluid compression to test hypotheses regarding epineurium composition and response to applied forces. Second harmonic generation (SHG) imaging of epineurial collagen was conducted at 0, 40, and 80 mmHg of compression. The cartesian strain tensor, principal strain (Eps1), and principal direction of the RLN collagen fibers were determined at each pressure step. Significantly larger values of the 1st principal strain occurred in the proximal segments of the pig left RLN when compared to the same segment in piglets (p = 0.001, pig = 0.0287 [IQR = 0.0161 - 0.0428], piglet = 0.0061 [IQR = 0.0033 - 0.0156]). Additionally, the median transverse strain Eyy) for the second pressure increment was larger in the right proximal segment of pigs compared to piglets (p < 0.001, pig = 0.0122 [IQR = 0.0033 - 0.0171], piglet = 0.0013 [IQR = 0.00001 - 0.0028]). Eyy values were significantly larger in the right proximal RLN versus the left proximal RLNs in pigs but not in piglets (p < 0.001). In contrast to piglets, histological analysis of pig RLN demonstrated increased axial alignment of epineurial and endoneurial collagen in response to compressive pressure. These findings support the hypothesis that the biomechanical response of the RLN to compressive pressure changed from being similar to being different between the right and left RLNs during development in the porcine model. Further investigation of these findings associated with age-related onset of idiopathic UVP may illuminate underlying etiologic mechanisms. STATEMENT OF SIGNIFICANCE: Damage to the recurrent laryngeal nerve (RLN) caused by compression imposed by the aorta may contribute to the onset of left-sided idiopathic unilateral vocal fold paralysis resulting in difficulty speaking, breathing, and swallowing. The goal of this study was to investigate how compression affects the connective tissue and microstructure of the RLN. We quantified the pressure induced deformation of the RLN using multiphoton imaging as a function of both location (proximal versus distal) and age (piglets, adolescent pigs). Our results demonstrate that the biomechanical response of the RLN to compression changes in the right versus left RLN throughout development, providing further evidence that the the left RLN is exposed to increasing dynamic loads with age.

Significant familial clustering of Peyronie's disease in close and distant relatives.

BACKGROUND: Peyronie's disease (PD) has previously been observed to co-aggregate in a small number of first-degree relative pairs (e.g., father-son). However, the familial aggregation of PD in more distant relatives, as well as the aggregation of Dupuytren's disease (DD) in probands and relatives, has not been thoroughly investigated. OBJECTIVE: This study explored the evidence for familial clustering of PD and DD in close and distant relatives. MATERIALS AND METHODS: The Utah Population Database, which includes genealogy information linked to electronic medical records (available since 1995), was used to identify men and their relatives with PD and DD based on ICD9/10 codes. All cases were required to have high-quality genealogy data. We estimated relative risk (RR) of PD and DD in first- through fifth-degree relatives compared to matched population rates of disease. We also investigated the average relatedness of cases compared to the average relatedness of sets of matched controls. Outcome measures include estimation of relative risk and excessive relatedness as measured by a Genealogical Index of Familiality (GIF) analysis. RESULTS: We analyzed 307 individuals with PD, and their first- through fifth-degree relatives. Approximately 0.12% of the population had PD, 95% of these were diagnosed over the age of 30 years (age range: 10-92 years), and 1.3% of PD probands had a comorbid diagnosis of DD. RR estimates for PD were significant for first- and fifth-degree relatives. RR estimates for DD were significant only for probands. The average relatedness of cases was significantly greater than matched controls, even after removing first- and second-degree relatives. We also found that 74.9% of identified PD probands belonged to pedigrees with a statistical excess of PD. CONCLUSION: Despite the low prevalence of PD in our healthcare records, the results provide evidence that support a genetic contribution to at least a subset of PD cases.

Erectile Dysfunction and Peyronie's Disease: Genetic Diseases?

There is considerable interest in understanding the genetics of erectile dysfunction (ED) and Peyronie's disease (PD) in an effort to identify novel therapeutic and preventative targets. Initial support for a genetic component of ED and PD was derived from familial aggregation studies. Candidate gene studies have suggested an association between polymorphisms of eNOS and ED and between TGF-ß1 and PD. More recently, several genome-wide association studies have suggested an association between single-nucleotide polymorphisms of the SIM1 gene and ED. The development of models and functional assays that are able to explore these potential pathways implicated in ED and PD is pivotal for future studies. We highlight the current literature that supports a genetic component for ED and PD. PATIENT SUMMARY: There is great interest in understanding the genetic underpinnings of erectile dysfunction and Peyronie's disease. Candidate gene studies and genome-wide association studies have set a foundation for future work; however, we have yet to determine a true genetic cause. A better understanding of the genetics of these conditions will help advance novel therapeutics and preventative strategies.

Morphometric Differences in the Recurrent Laryngeal Nerve in Patients with Vocal Fold Paralysis.

OBJECTIVES: Injury to the recurrent laryngeal nerve (RLN), if severe enough, can result in vocal fold paralysis. Reinnervation surgery can improve patient outcomes, but previous studies have reported a negative correlation between time since onset of paralysis and surgical outcomes. The ability of the paralyzed nerve to serve as a conduit for donor nerve fibers may be a factor in the success of reinnervation; however, changes in RLN composition after paralysis have not been well studied. Therefore, we investigated the morphometric composition of explanted RLN sections from patients who had experienced vocal fold paralysis for varying length of times. METHODS: Nine nerve sections from unilateral vocal fold paralysis (UVP) patients and seven control nerve sections were analyzed for morphometric parameters including fascicular area, fiber count, fiber density, fiber packing, mean g-ratio, and fiber diameter distribution. Nerves from UVP patients were also compared as a function of time since UVP onset. RESULTS: In comparison to control nerves, paralyzed nerves were found to have significantly lower fiber densities and fiber packing, higher mean g-ratio values, and a shift in diameter distributions toward smaller diameter fibers. With respect to paralysis duration, no significant differences were observed except in fiber diameter distributions, where those with paralysis for >2 years had distributions that were significantly shifted toward smaller diameter fibers. CONCLUSIONS: The morphometric data presented here suggest that correlations between the time since onset of vocal fold paralysis and reinnervation outcomes may be due to fiber size changes in the paralyzed nerve over time.

A review of inflammation and fibrosis: implications for the pathogenesis of Peyronie's disease.

Peyronie's disease (PD) is a superficial fibrosing disorder that causes penile deformity and can interfere with sexual intercourse and reproduction, as well as diminish quality of life. While the exact mechanism of PD is still being investigated, there is likely a genetic component to the predisposition to penile plaque formation. Ultimately, however, perturbations in normal wound healing and aberrant deposition of extracellular matrix components lead to fibrotic tissue deposition. Fibrosis in PD is regulated by a complex pathway of inflammatory and fibrotic mediators. Currently there are no treatments for PD that address an underlying cause or disease progression. In this review, we provide an overview of the known inflammatory and fibrotic mediators of PD and explore the pathophysiology of other human superficial fibrosing disorders to develop further insights into PD.

Biocompatibility and Viscoelastic Properties of Injectable Resilin-Like Polypeptide and Hyaluronan Hybrid Hydrogels in Rabbit Vocal Folds.

Vocal fold scar, characterized by alterations in the lamina propria extracellular matrix, disrupts normal voice quality and function. Due to a lack of satisfactory clinical treatments, there is a need for tissue engineering strategies to restore voice. Candidate biomaterials for vocal fold tissue engineering must match the unique biomechanical and viscoelastic properties of native tissue without provoking inflammation. We sought to introduce elastomeric properties to hyaluronic acid (HA)-based biomaterials by incorporating resilin-like polypeptide (RLP) into hybrid hydrogels. Physically crosslinked RLP/HA and chemically crosslinked RLP-acrylamide/thiolated HA (RLP-AM/HA-SH) hydrogels were fabricated using cytocompatible chemistries. Mechanical properties of hydrogels were assessed in vitro using oscillatory rheology. Hybrid hydrogels were injected into rabbit vocal folds and tissues were assessed using rheology and histology. A small number of animals underwent acute vocal fold injury followed by injection of RLP-AM/HA-SH hydrogel alone or as a carrier for human bone marrow mesenchymal stem cells (BM-MSCs). Rheological testing confirmed that mechanical properties of materials in vitro resembled native vocal fold tissue and that viscoelasticity of vocal fold mucosa was preserved days 5 and 21 after injection. Histological analysis revealed that hybrid hydrogels provoked only mild inflammation in vocal fold lamina propria with demonstrated safety in the airway for up to 3 weeks, confirming acute biocompatibility of crosslinking chemistries. After acute injury, RLP-AM/HA-SH gel with and without BM-MSCs did not result in adverse effects or increased inflammation. Collectively, results indicate that RLP and HA-based hybrid hydrogels are highly promising for engineering the vocal fold lamina propria.

The foreign body response and morphometric changes associated with mesh-style peripheral nerve cuffs.

Nerve cuffs have been used to anchor and protect penetrating electrodes in peripheral nerves and have been used as non-penetrating electrodes for neural recording and nerve stimulation. The material of choice for such applications is silicone, an inert synthetic biomaterial which elicits a minimal chronic foreign body response (FBR). While histological studies of solid silicone cuffs are available, to the best of our knowledge a comparison to other cuff designs is not well documented. Here, we describe the FBR and morphological changes that accompany nerve cuff implantation in the rat sciatic nerve by comparing a metallic mesh with and without a parylene coating to one made of silicone. Two months after implantation, we observed that such implants, irrespective of the cuff type, were associated with a persistent inflammatory response consisting of activated macrophages attached to the implant surfaces, which extended into the endoneurial space of the encapsulated nerve. We also observed foreign body giant cells in the epineurial space that were more prevalent in the mesh cohorts. The mesh cuff groups showed significant changes in several morphometric parameters that were not seen in the silicon group including reductions in nerve fiber packing density and a greater reduction of large diameter fibers. High magnification microscopy also showed greater evidence of foamy macrophages in the endoneurial space of the mesh implanted cohorts. Although the precise mechanisms are unknown, the results showed that mesh style nerve cuffs show a greater inflammatory response and had greater reductions in morphometric changes in the underlying nerve compared to silicone in the absence of a penetrating injury. STATEMENT OF SIGNIFICANCE: While traditional silicone cuffs have been in use for decades, the inflammatory and morphometric effects of these cuffs on the underlying nerve have not been deeply studied. Further, manipulation of the foreign body response to nerve cuffs by using various materials and/or designs has not been well reported. Therefore, we report the inflammatory response around nerve cuffs of various materials and designs, as well as report morphometric parameters of the underlying nerve. These data provide important information regarding the potential for quantitative morphometric changes associated with the use of nerve cuffs, and, importantly, suggests that these changes are associated with the degree of inflammation associated with the cuff.

MERS versus Standard Surgical Approaches for Porcine Vocal Fold Scarring with Adipose Stem Cell Constructs.

OBJECTIVE: Cells, scaffold, and surgical approaches are important for regeneration of the lamina propria of the scarred vocal fold (VF). Microendoscopy of Reinke's space (MERS) is a surgical approach used to access the lamina propria. The present study evaluated MERS in the treatment of VF scarring as compared with standardized approaches for the treatment of VF scarring with adipose stem cell constructs. STUDY DESIGN: Animal study. SETTING: Academic center. SUBJECTS AND METHODS: VF injury was performed bilaterally to induce scarring in 20 pigs. Eight weeks after injury, pigs were classified into no treatment, minithyrotomy, VF injection, VF incision/dissection, and MERS. All groups (except control) were implanted with adipose stem cell and hyaluronan. Four weeks after treatment, histology for collagen, hyaluronan, and fibronectin; mRNA expression for α-smooth muscle actin, tumor growth factor ß1, collagen 1α1, collagen 3α1, matrix metalloproteinase 2, basic fibroblast growth factor, and hepatocyte growth factor; and tissue rheology were evaluated. RESULTS: Differences were measured among surgical approaches for protein levels of collagen, hyaluronan, and fibronectin (P = .0133, P < .0001, and P = .0025, respectively). Fibroblast growth factor, collagen 1α1, and matrix metalloproteinase 2 transcript levels were different among treatment groups (P = .003, P = .0086, and P = .014, respectively), while no differences were measured for α-smooth muscle actin, tumor growth factor ß1, hepatocyte growth factor, and collagen 3α1. Rheologically, significant differences were not measured between groups. CONCLUSION: MERS is a promising surgical approach for the treatment of VF scarring, optimizing the placement of implanted biomaterials.

A histological analysis of human median and ulnar nerves following implantation of Utah slanted electrode arrays.

For decades, epineurial electrodes have been used in clinical therapies involving the stimulation of peripheral nerves. However, next generation peripheral nerve interfaces for applications such as neuroprosthetics would benefit from an increased ability to selectively stimulate and record from nerve tissue. This increased selectivity may require the use of more invasive devices, such as the Utah Slanted Electrode Array (USEA). Previous research with USEAs has described the histological response to the implantation of these devices in cats and rats; however, no such data has been presented in humans. Therefore, we describe here the degree of penetration and foreign body reaction to USEAs after a four-week implantation period in human median and ulnar nerves. We found that current array designs penetrate a relatively small percentage of the available endoneurial tissue in these large nerves. When electrode tips were located within the endoneurial tissue, labels for axons and myelin were found in close proximity to electrodes. Consistent with other reports, we found activated macrophages attached to explanted devices, as well as within the tissue surrounding the implantation site. Despite this inflammatory response, devices were able to successfully record single- or multi-unit action potentials and elicit sensory percepts. However, modifying device design to allow for greater nerve penetration, as well as mitigating the inflammatory response to such devices, would likely increase device performance and should be investigated in future research.

Development of a bilayer ring system for achieving high strain in commercial rheometers.

Mechanical stimulation of cell cultures has been shown be an effective means of enhancing ECM production. ECM produced from vocal fold fibroblast cultures has the potential for therapeutic use for vocal fold repair. However, current bioreactor designs generally fail to produce physiological relevant frequency and strain values. Here we present an approach for using commercial oscillatory rheometers and an elastic ring bilayer system to produce physiologically relevant strain values at frequencies in the range of 20-100 Hz. We demonstrate the ability to target specific strain and frequency values by manipulating system parameters, and also show that it is possible to maintain high oscillatory strains for extended periods of time. Such a system could be used to mechanically stimulate cell cultures contained within gel carrier systems and has the potential to be extended to other applications requiring high strains at low frequencies.

Tensile properties of the rectal and sigmoid colon: a comparative analysis of human and porcine tissue.

For many patients, rectal catheters are an effective means to manage bowel incontinence. Unfortunately, the incidence of catheter leakage in these patients remains troublingly high. Matching the mechanical properties of the catheter and the surrounding tissue may improve the catheter seal and reduce leakage. However, little data is available on the mechanical properties of colorectal tissue. Therefore, our group examined the mechanical properties of colorectal tissue obtained from both a common animal model and humans. Uniaxial tension tests were performed to determine the effects of location, orientation, and species (porcine and human) on bowel tissue tensile mechanical properties. Bowel tissue ultimate strength, elongation at failure, and elastic modulus were derived from these tests and statistically analyzed. Ultimate tensile strength (0.58 MPa, 0.87 MPa), elongation at failure (113.19%, 62.81%), and elastic modulus (1.83 MPa, 5.18 MPa) for porcine and human samples respectively exhibited significant differences based on species. Generally, human tissues were stronger and less compliant than their porcine counterparts. Furthermore, harvest site location and testing orientation significantly affected several mechanical properties in porcine derived tissues, but very few in human tissues. The data suggests that porcine colorectal tissue does not accurately model human colorectal tissue mechanical properties. Ultimately, the tensile properties reported herein may be used to help guide the design of next generation rectal catheters with tissue mimetic properties, as well as aid in the development of physical and computer based bowel models.

BBB leakage, astrogliosis, and tissue loss correlate with silicon microelectrode array recording performance.

The clinical usefulness of brain machine interfaces that employ penetrating silicon microelectrode arrays is limited by inconsistent performance at chronic time points. While it is widely believed that elements of the foreign body response (FBR) contribute to inconsistent single unit recording performance, the relationships between the FBR and recording performance have not been well established. To address this shortfall, we implanted 4X4 Utah Electrode Arrays into the cortex of 28 young adult rats, acquired electrophysiological recordings weekly for up to 12 weeks, used quantitative immunohistochemical methods to examine the intensity and spatial distribution of neural and FBR biomarkers, and examined whether relationships existed between biomarker distribution and recording performance. We observed that the FBR was characterized by persistent inflammation and consisted of typical biomarkers, including presumptive activated macrophages and activated microglia, astrogliosis, and plasma proteins indicative of blood-brain-barrier disruption, as well as general decreases in neuronal process distribution. However, unlike what has been described for recording electrodes that create only a single penetrating injury, substantial brain tissue loss generally in the shape of a pyramidal lesion cavity was observed at the implantation site. Such lesions were also observed in stab wounded animals indicating that the damage was caused by vascular disruption at the time of implantation. Using statistical approaches, we found that blood-brain barrier leakiness and astrogliosis were both associated with reduced recording performance, and that tissue loss was negatively correlated with recording performance. Taken together, our data suggest that a reduction of vascular damage at the time of implantation either by design changes or use of hemostatic coatings coupled to a reduction of chronic inflammatory sequela will likely improve the recording performance of high density intracortical silicon microelectrode arrays over long indwelling periods and lead to enhanced clinical use of this promising technology.

Differences Exist in the Left and Right Sciatic Nerves of Naïve Rats and Cats.

The sciatic nerve of rats and cats is commonly used in experimental models of peripheral nerve injury and repair, as well as experiments involving peripheral nerve electrode implantation. In such experiments, morphometric parameters from the implanted nerve are commonly evaluated and compared to control values obtained from the contralateral nerves. However, this may not be an appropriate approach as differences may naturally exist in the structure of the two nerves owing to developmental or behavioral asymmetry. Additionally, in the cat, baseline values for standard morphometric parameters are not well established. In this study, we characterized fascicle area, fiber count, fiber density, fiber packing, mean g-ratio, and fiber diameter distributions in the rat and cat, as well as investigated the potential for naturally occurring sided differences in these parameters in both species. We also investigated whether animal age or location along the nerve influenced these parameters. We found that sided or left/right leg differences exist in some parameters in both the rat and the cat, calling into question the validity of using the contralateral nerve as a control. We also found that animal age and location along the nerve can make significant differences in the parameters tested, establishing the importance of using control nerves from age- and behaviorally matched animals whose morphometric parameters are collected and compared from the same location.

Acute monitoring of genitourinary function using intrafascicular electrodes: selective pudendal nerve activity corresponding to bladder filling, bladder fullness, and genital stimulation.

OBJECTIVE: To investigate the use of a microelectrode array with a high spatial density of penetrating intrafascicular electrodes for selective recording of pudendal nerve activity evoked by a variety of genitourinary stimuli. MATERIALS AND METHODS: Felines were anesthetized with alpha-chloralose and high-density Utah slanted electrode arrays (48 microelectrodes; 200-µm spacing) were implanted into the pudendal nerve for acute experimentation. Neural activity was recorded during bladder filling, spontaneous reflexive distention-evoked bladder contractions, and tactile somatosensory stimulation. RESULTS: The intrafascicularly implanted pudendal nerve electrodes were able to selectively record neural activity that corresponded to various genitourinary stimuli. Across all seven experimental animals, a total of 10 microelectrodes recorded neural units that were selectively driven by bladder filling or distention-evoked bladder contractions. Twenty-two electrodes were selectively driven by tactile stimulation. CONCLUSION: Microelectrode arrays implanted intrafascicularly into the pudendal nerve can be used to selectively record the neural responses that reflect bladder status and urogenital tactile stimulation. This work sets the stage for developing future implantable closed-loop neuroprosthetic devices for restoration of bladder function.

A comparison of the tissue response to chronically implanted Parylene-C-coated and uncoated planar silicon microelectrode arrays in rat cortex.

In this study we employed a quantitative immunohistochemical approach to compare the brain tissue response to planar silicon microelectrode arrays that were conformally coated with Parylene-C to uncoated controls at 2, 4, and 12 weeks following implantation into the cortex of adult male Sprague-Dawley rats. We did not find any difference in the relative intensity or the spatial distribution of neuronal or glial markers over the indwelling period, even though Parylene-C-coated substrates supported significantly less cell attachment, indicating that the foreign body response to planar silicon microelectrode arrays has little to do with the composition or decomposition of the silicon electrode. Moreover, our results suggest that changes in microelectrode surface chemistry do not have a strong influence on the cytoarchitectural changes that accompany the brain foreign body response to planar silicon microelectrode arrays. Our quantitative comparison over the indwelling period does not support progressive increases in astrocyte encapsulation and/or progressive neuronal loss in the recording zone as dominant failure mechanisms of the type of chronic recording device. Finally, we found evidence of two potentially new failure mechanisms that were associated with CD68 immunoreactivity including demyelination of adjacent neurons and BBB breakdown surrounding implanted electrodes at long indwelling times.