Medical Encounters and Treatment Outcomes in Ironman-Distance Triathlon.

PURPOSE: This study aimed to examine the injury and illness characteristics, treatments, and outcomes at elite ultraendurance triathlon events. METHODS: We quantified participant demographics, injury types, treatments, and disposition for medical encounters at 27 Ironman-distance triathlon championships from 1989 to 2019. We then calculated the likelihood of concurrent medical complaints in each encounter. RESULTS: We analyzed 10,533 medical encounters among 49,530 race participants for a cumulative incidence of 221.9/1000 participants (95% confidence interval [CI] = 217.7-226.2). Younger (<35 yr; 259.3/1000, 95% CI = 251.6-267.2) and older athletes (70+ yr; 254.0/1000, 95% CI = 217.8-294.4) presented to the medical tent at higher rates than middle-age adults (36-69 yr; 180.1/1000, 95% CI = 175.4-185.0). Female athletes also presented at higher rates when compared with males (243.9/1000, 95% CI = 234.9-253.2 vs 198.0/1000, 95% CI = 193.4-202.6). The most common complaints were dehydration (438.7/1000, 95% CI = 426.2-451.6) and nausea (400.4/1000, 95% CI = 388.4-412.6). Intravenous fluid was the most common treatment (483/1000; 95% CI = 469.8-496.4). Of the athletes who received medical care, 116.7/1000 (95% CI = 110.1-123.4) did not finish the race, and 17.1/1000 (95% CI = 14.7-19.8) required hospital transport. Athletes rarely presented with an isolated medical condition unless their injury was dermatologic or musculoskeletal in nature. CONCLUSIONS: Ultraendurance triathlon events have high rates of medical encounters among female athletes, as well as both younger and older age categories. Gastrointestinal and exertional-related symptoms are among the most common complaints. Intravenous infusions were the most common treatment after basic medical care. Most athletes entering the medical tent finished the race, and a small percentage were dispatched to the hospital. A more thorough understanding of common medical occurrences, including concurrent presentations and treatments, will allow for improved care and optimal race management.

Clinical presentation of exercise-associated hyponatremia in male and female IRONMAN® triathletes over three decades.

PURPOSE: Exercise-associated hyponatremia (EAH) is common in ultra-endurance events and severe cases are more common in females. The purpose of this paper is to compare the clinical presentation of EAH between male and female triathletes in ultra-endurance competitions. METHODS: Medical records with sodium concentrations (n = 3138) from the IRONMAN® World Championships over the timeframe of 1989-2019 were reviewed for both male (n = 2253) and female (n = 885) competitors. Logistic regression was used to explore the relationships between sex, sodium concentration, and various clinical presentations. RESULTS: When comparing male and female triathletes, clinical variables found to have a different relationship with sodium concentration include altered mental status (inversely related in males and not related in females), abdominal pain, muscle cramps, hypotension, and tachycardia (directly related in males and not related in females), and vomiting and hypokalemia (not related in males and inversely related in females). Overall, males lost significantly more weight than females, and notably, approximately half of all athletes were dehydrated and lost weight. CONCLUSIONS: Altered mental status, vomiting, abdominal pain, muscle cramps, hypotension, tachycardia, and hyperkalemia appear to present differently between sexes when comparing hyponatremic to eunatremic athletes. Although overhydration is the most common etiology of hypervolemic hyponatremia, hypovolemic hyponatremia comprises a significant amount of hyponatremic triathletes. Further understanding of how EAH presents helps athletes and medical professionals identify it early and prevent life-threatening complications.

A 10-Year Review of the Management of Ocular Mucous Membrane Pemphigoid: A Private Practice Experience.

PURPOSE: Ocular mucous membrane pemphigoid (OcMMP) is a rare and potentially blinding condition for which consensus treatment guidelines do not exist. The purpose of this study was to assess the effectiveness and safety of various immunomodulatory agents in the treatment of OcMMP in a private practice setting. METHODS: We conducted a 10-year retrospective chart review of patients managed with OcMMP (n = 22). The median age at diagnosis was 73 (range: 35-91) years, and 59% (13/22) of patients were female. Visual acuity, Foster stage, and adverse effects (AEs) were documented. Treatment outcomes for each treatment episode were qualified at 3 months as complete response (CR), response (R), or failure (F). After 3 months, CR was then further subqualified as sustained CR, reactivation after initial CR, or AE after initial CR. The Fisher exact test P values were calculated for each outcome in comparison with mycophenolate. RESULTS: Twenty patients were treated with an immunomodulatory agent for a total of 55 treatment episodes. In comparison to dapsone, mycophenolate was more likely to achieve sustained CR (50% vs. 0%, P = 0.022) and R (100% vs. 50%, P = 0.007), and less likely to fail (0% vs. 50%, P = 0.007). Dapsone was also more likely to be discontinued because of AEs than mycophenolate (40% vs. 6%, P = 0.041). CONCLUSIONS: Mycophenolate is a superior first-line agent to dapsone in the treatment of OcMMP. Although not statistically significant, mycophenolate trends toward superiority over methotrexate as well. Mycophenolate is very effective when used in combination with rituximab. Azathioprine remains a reasonable second-line agent.

Pneumomediastinum After COVID-19.

A preadolescent female presented to the emergency department with an acute asthma exacerbation. Chest radiograph and computed tomography scan showed extensive pneumomediastinum with a small pneumopericardium without a distinct source for this air leak. The patient was admitted for noninvasive monitoring, analgesia, and high concentration oxygen. Serial chest radiographs showed marked improvement following high concentration oxygen, and she was discharged on hospital day 3. Spontaneous pneumomediastinum and pneumopericardium are rare complications of asthma that can often be managed conservatively but should be considered on the differential for this patient population, and may be a complication of COVID-19.

Changes in perception of pitch during vocal performance after three- and two-wall orbital decompression surgery.

This case series presents 2 Caucasian females that underwent orbital decompression surgery for symptomatic exophthalmos and postoperatively developed a change in their perception of pitch during vocal performance. One patient went as far as to undergo voice lessons in attempt to regain her pre-operative pitch perception; however, the attempt was unsuccessful. We propose the etiology of this complication is anatomic changes within the ethmoid sinus. Temporary changes in nasalance have previously been reported with functional endoscopic sinus surgery literature, but this specific complication of change in pitch perception has not.

Free-Living Aquatic Turtles as Sentinels of Salmonella spp. for Water Bodies.

Reptile-associated human salmonellosis cases have increased recently in the United States. It is not uncommon to find healthy chelonians shedding Salmonella enterica. The rate and frequency of bacterial shedding are not fully understood, and most studies have focused on captive vs. free-living chelonians and often in relation to an outbreak. Their ecology and significance as sentinels are important to understanding Salmonella transmission. In 2012-2013, Salmonella prevalence was determined for free-living aquatic turtles in man-made ponds in Clarke and Oconee Counties, in northern Georgia (USA) and the correlation between species, basking ecology, demographics (age/sex), season, or landcover with prevalence was assessed. The genetic relatedness between turtle and archived, human isolates, as well as, other archived animal and water isolates reported from this study area was examined. Salmonella was isolated from 45 of 194 turtles (23.2%, range 14-100%) across six species. Prevalence was higher in juveniles (36%) than adults (20%), higher in females (33%) than males (18%), and higher in bottom-dwelling species (31%; common and loggerhead musk turtles, common snapping turtles) than basking species (15%; sliders, painted turtles). Salmonella prevalence decreased as forest cover, canopy cover, and distance from roads increased. Prevalence was also higher in low-density, residential areas that have 20-49% impervious surface. A total of 9 different serovars of two subspecies were isolated including 3 S. enterica subsp. arizonae and 44 S. enterica subsp. enterica (two turtles had two serotypes isolated from each). Among the S. enterica serovars, Montevideo (n = 13) and Rubislaw (n = 11) were predominant. Salmonella serovars Muenchen, Newport, Mississippi, Inverness, Brazil, and Paratyphi B. var L(+) tartrate positive (Java) were also isolated. Importantly, 85% of the turtle isolates matched pulsed-field gel electrophoresis patterns of human isolates, including those reported from Georgia. Collectively, these results suggest that turtles accumulate Salmonella present in water bodies, and they may be effective sentinels of environmental contamination. Ultimately, the Salmonella prevalence rates in wild aquatic turtles, especially those strains shared with humans, highlight a significant public health concern.

The Contribution of Eimeria Coinfection and Intestinal Inflammation to Cecal Colonization and Systemic Spread of Salmonella Typhimurium Deficient in Tetrathionate Reductase or Type III Secretion Systems Salmonella Pathogenicity Island 1 or 2.

Intestinal inflammation may provide a growth advantage for Salmonella and enhance its systemic spread in chickens. Salmonella triggers intestinal inflammation in the host by using type III secretion systems (T3SS) and produces the inflammatory end product tetrathionate. In mice, tetrathionate respiration confers a growth advantage for Salmonella Typhimurium over the competitive microbiome in the inflamed intestine. Coccidia also promote intestinal inflammation and enhance Salmonella intestinal growth and systemic spread in chickens. The objective of this study was to evaluate the contribution of inflammation, induced by Eimeria spp. or Salmonella Typhimurium, to Salmonella colonization and dissemination in chickens. In addition, the fitness costs associated with defects in tetrathionate reductase and T3SS associated with Salmonella Pathogenicity Island 1 or 2 (SPI-1 or SPI-2) were evaluated in in vivo competition experiments with wild-type Salmonella strain, with or without Eimeria coinfection. One-day-old specific-pathogen-free chickens were orally inoculated with a sham inoculum or with 4 × 102Eimeria oocysts cocktail of Eimeria tenella, Eimeria acervulina, Eimeria maxima, and Eimeria mitis. At 6 days of age, birds were orally administered a 1:1 ratio of Salmonella Typhimurium wild-type and mutant deficient in tetrathionate reductase, SPI-1, or SPI-2 (108 colony forming units/bird). Ceca, livers, and drumsticks were collected at 3, 7, 14, and 42 days after Salmonella infection, for bacteriology. Intestinal inflammation was scored by histology. Significantly higher intestinal inflammation was observed in challenge groups compared with the control. However, there were no significant differences in intestinal inflammation scores between groups coinfected with both Eimeria spp. and Salmonella Typhimurium and birds infected with Salmonella alone, and Eimeria coinfection did not increase Salmonella prevalence or abundance. Contrary to mouse studies, tetrathionate reductase did not enhance Salmonella Typhimurium cecal colonization or systemic spread in chickens. SPI-1 and SPI-2 played a significant role in Salmonella dissemination and cecal colonization in chickens, respectively.

Contribución de la coinfección por Eimeria y de la inflamación intestinal a la colonización cecal y a la propagación sistémica de Salmonella Typhimurium deficiente en tetrationato reductasa o de sistemas de secreción de tipo III de islas de patogenicidad 1 o 2 de Salmonella. La inflamación intestinal puede proporcionar una ventaja para el crecimiento de Salmonella y aumentar su propagación sistémica en pollos. Salmonella desencadena la inflamación intestinal en el huésped mediante el uso de sistemas de secreción tipo III (T3SS) y produce el producto final inflamatorio, tetrationato. En ratones, la respiración con tetrationato confiere una ventaja de crecimiento para Salmonella Typhimurium sobre el microbioma competitivo en el intestino inflamado. Coccidia también promueve la inflamación intestinal y mejora el crecimiento intestinal de Salmonella y la propagación sistémica en pollos. El objetivo de este estudio fue evaluar la contribución de la inflamación, inducida por Eimeria spp. o Salmonella Typhimurium, en la colonización y diseminación de Salmonella en pollos. Además, se evaluaron los costos de aptitud asociados con defectos en la tetrationato reductasa y T3SS asociados con las islas de patogenicidad 1 o 2 de Salmonella (SPI-1 o SPI-2) mediante experimentos de competencia in vivo con cepas de Salmonella de tipo silvestre, con o sin coinfección con Eimeria. Pollos libres de patógenos específicos de un día de edad se inocularon por vía oral con un inóculo falso o con 4 × 102 de un coctel de ooquistes de Eimeria que incluyó Eimeria tenella, Eimeria acervulina, Eimeria maxima y Eimeria mitis. A los seis días de edad, se les administró a las aves administró por vía oral una proporción 1: 1 de Salmonella Typhimurium de tipo silvestre o tipo mutante que es deficiente de tetrationato reductasa, SPI-1 o SPI-2 (108 unidades formadoras de colonias/ave). Se recolectaron ciegos, hígados y pernas a los tres, siete, catorce y 42 días después de la infección por Salmonella, para bacteriología. La inflamación intestinal se calificó por histología. Se observó inflamación intestinal significativamente mayor en los grupos de desafío en comparación con el control. Sin embargo, no hubo diferencias significativas en las puntuaciones de inflamación intestinal entre los grupos coinfectados con Eimeria spp. y Salmonella Typhimurium y las aves infectadas con Salmonella por si sola y la coinfección con Eimeria no aumentó la prevalencia o abundancia de Salmonella. A diferencia de los estudios en ratones, la tetrationato reductasa no mejoró la colonización cecal de Salmonella Typhimurium o la diseminación sistémica en pollos. Las islas de patogenicidad SPI-1 y SPI-2 jugaron un papel importante en la diseminación de Salmonella y en la colonización cecal en pollos, respectivamente.

Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling.

Microglia rapidly respond to changes in neural activity and inflammation to regulate synaptic connectivity. The extracellular signals, particularly neuron-derived molecules, that drive these microglial functions at synapses remain a key open question. Here we show that whisker lesioning, known to dampen cortical activity, induces microglia-mediated synapse elimination. This synapse elimination is dependent on signaling by CX3CR1, the receptor for microglial fractalkine (also known as CXCL1), but not complement receptor 3. Furthermore, mice deficient in CX3CL1 have profound defects in synapse elimination. Single-cell RNA sequencing revealed that Cx3cl1 is derived from cortical neurons, and ADAM10, a metalloprotease that cleaves CX3CL1 into a secreted form, is upregulated specifically in layer IV neurons and in microglia following whisker lesioning. Finally, inhibition of ADAM10 phenocopies Cx3cr1-/- and Cx3cl1-/- synapse elimination defects. Together, these results identify neuron-to-microglia signaling necessary for cortical synaptic remodeling and reveal that context-dependent immune mechanisms are utilized to remodel synapses in the mammalian brain.

TIMP-1 Promotes Oligodendrocyte Differentiation Through Receptor-Mediated Signaling.

The extracellular protein tissue inhibitor of metalloproteinase (TIMP)-1 is both a matrix metalloproteinase (MMP) inhibitor and a trophic factor. Mice lacking TIMP-1 exhibit delayed central nervous system myelination during postnatal development and impaired remyelination following immune-mediated injury in adulthood. We have previously determined that the trophic action of TIMP-1 on oligodendrocyte progenitor cells (OPCs) to mature into oligodendrocytes is independent of its MMP inhibitory function. However, the mechanism by which TIMP-1 promotes OPC differentiation is not known. To address this gap in our understanding, herein, we report that TIMP-1 signals via a CD63/ß1-integrin receptor complex to activate Akt (protein kinase B) to promote ß-catenin signaling in OPCs. The regulation of ß-catenin by TIMP-1 to promote OPC differentiation was counteracted, but not abrogated, by canonical signaling evoked by Wnt7a. These data provide a previously uncharacterized trophic action of TIMP-1 to regulate oligodendrocyte maturation via a CD63/ß1-integrin/Akt pathway mechanism. These findings contribute to our emerging understanding on the role of TIMP-1 as a growth factor expressed to promote CNS myelination during development and induced in the adult to promote myelin repair.

A microglia-cytokine axis to modulate synaptic connectivity and function.

Microglia have recently been recognized as key regulators of synapse development, function, and plasticity. Critical to progressing the field is the identification of molecular underpinnings necessary for microglia to carry out these important functions within neural circuits. Here, we focus a review specifically on roles for microglial cytokine signaling within developing and mature neural circuits. We review exciting new studies demonstrating essential roles for microglial cytokine signaling in axon outgrowth, synaptogenesis and synapse maturation during development, as well as synaptic transmission and plasticity in adulthood. Together, these studies identify microglia and cytokines as critical modulators of neural circuits within the healthy brain, with implications for a broad range of neurological disorders with disruptions in synaptic structure and function.

iPS-derived neural progenitor cells from PPMS patients reveal defect in myelin injury response.

Primary progressive multiple sclerosis (PPMS) is a chronic demyelinating disease of the central nervous system (CNS) currently lacking any effective treatment. Promoting endogenous brain repair offers a potential strategy to halt and possibly restore neurologic function in PPMS. To understand how the microenvironment within white matter lesions plays a role in repair we have focused on neural progenitor cells (NPCs) since these are found in lesions in PPMS and have been found to influence oligodendrocyte progenitor cell maturation (OPCs). To better understand the cellular nature of NPCs in PPMS we developed iPS cells from blood samples of PPMS patients and age matched non-disease spouse or blood relative controls. Using these iPS cell lines we determined that the NPCs from PPMS cases provided no neuroprotection against active CNS demyelination compared to NPCs from control iPS lines which were capable of completely preventing injury. Conditioned media (CM) from PPMS NPCs provides no protection to OPCs and prevents maturation of OPCs into oligodendrocytes in vitro. We also found that CM from PPMS iPS NPCs elicited patient-specific differences in the response to compounds that should foster oligodendrocyte (OL) maturation. Together, these data establish a new model for understanding the nature of myelination defects in PPMS which may lead to novel targeted approaches for preventing demyelination in these patients.

TIMP-1 couples RhoK activation to IL-1ß-induced astrocyte responses.

Interleukin-1ß (IL-1ß) is a pleotropic cytokine known to influence the central nervous system (CNS) responses to injury or infection. IL-1ß also directly induces astrocytic expression of tissue inhibitor of metalloproteinases (TIMP)-1, a potent trophic factor and regulator of matrix metalloproteinase activity. In this study, we examined the functional relationship between IL-1ß and TIMP-1 and determined that the behavior of astrocytes in response to IL-1ß is determined by TIMP-1 expression. Using primary astrocytes from C57Bl/6 mice, we found astrocytes from wildtype (Wt) mice exhibited a robust wound healing response to a scratch wound that was arrested in response to IL-1ß. In contrast, TIMP-1 knockout (TIMP-1KO) astrocytes, exhibited minimal response to the scratch wound but an accelerated response following IL-1ß-treatment. We also determined that the scratch wound effect in Wt cultures was attenuated by inhibition of Rho kinase but amplified in the TIMP-1KO cultures. We propose that the specific induction of TIMP-1 from astrocytes in response to IL-1ß reflects a previously unrecognized physiological relationship where the directionality of astrocytic behavior is determined by the actions of TIMP­1. These findings may provide additional insight into glial responses in the context of neuropathology where expression of TIMP-1 may vary and astrocytic responses may be impacted by the inflammatory milieu of the CNS.

Extracellular matrix composition determines astrocyte responses to mechanical and inflammatory stimuli.

Astrocytes perform critical homeostatic physiological functions in the central nervous system (CNS) and are robustly responsive to injury, inflammation, or infection. We hypothesized that the components of the extracellular matrix (ECM), which are known to vary during development and in response to disease, determine astrocytic responses to injury and inflammation. We examined the response of primary astrocyte cultures grown on different ECM proteins to a mechanical wound (i.e., scratch). ECM substrates selected were laminin (Ln), vitronectin (Vn), fibronectin (Fn) or Tenascin C (TnC). We found that regrowth of the scratch wound was ECM dependent: recovery was arrested on fibronectin (Fn), almost complete on either Vn, Ln, or TnC. To determine whether ECM responses were also influenced by inflammation, we treated ECM plated cultures with interleukin-1ß (IL-1ß). We found that IL-1ß arrested astrocyte growth on Ln, accelerated astrocyte growth on Fn and had no significant effect on astrocyte growth on TnC or Vn. We also determined that blocking ß1integrins, the major class of receptors for all ECM proteins tested, prevented the robust response of astrocytes exposed to TnC, Ln and Vn, and also inhibited the robust effect of IL-1ß to stimulate astrocyte growth on Fn. In addition, we evaluated downstream targets of integrin signaling, specifically the mammalian target of rapamycin (mTOR), and determined that activation of this pathway contributed to the response of astrocytes grown on TnC, but not on Ln, Vn or Fn. These findings provide new insights into the role of ECM as a source of heterogeneity of glial responses that may have important implications for neuropathological sequelae.

An in vitro model for the study of cellular pathophysiology in globoid cell leukodystrophy.

The precise function of multi-nucleated microglia, called globoid cells, that are uniquely abundant in the central nervous system of globoid cell leukodystrophy (GLD) is unclear. This gap in knowledge has been hindered by the lack of an appropriate in vitro model for study. Herein, we describe a primary murine glial culture system in which treatment with psychosine results in multinucleation of microglia resembling the characteristic globoid cells found in GLD. Using this novel system, we defined the conditions and modes of analysis for study of globoid cells. The potential use of this model system was validated in our previous study, which identified a potential role for matrix metalloproteinase (MMP)-3 in GLD. This novel in vitro system may be a useful model in which to study the formation and function, but also the potential therapeutic manipulation, of these unique cells.

Aberrant production of tenascin-C in globoid cell leukodystrophy alters psychosine-induced microglial functions.

Globoid cell leukodystrophy (GLD), or Krabbe disease, is a rare and often fatal demyelinating disease caused by mutations in the galactocerebrosidase (galc) gene that result in accumulation of galactosylsphingosine (psychosine). We recently reported that the extracellular matrix (ECM) protease, matrix metalloproteinase-3, is elevated in GLD and that it regulates psychosine-induced microglial activation. Here, we examined central nervous system ECM component expression in human GLD patients and in the twitcher mouse model of GLD using immunohistochemistry. The influence of ECM proteins on primary murine microglial responses to psychosine was evaluated using ECM proteins as substrates and analyzed by quantitative real-time polymerase chain reaction, immunocytochemistry, and ELISA. Functional analysis of microglial cytotoxicity was performed on oligodendrocytes in coculture, and cell death was measured by lactose dehydrogenase assay. Tenascin-C (TnC) was expressed at higher levels in human GLD and in twitcher mice versus controls. Microglial responses to psychosine were enhanced by TnC, as determined by an increase in globoid-like cell formation, matrix metalloproteinase-3 mRNA expression, and higher toxicity toward oligodendrocytes in culture. These findings were consistent with a shift toward the M1 microglial phenotype in TnC-grown microglia. Thus, elevated TnC expression in GLD modified microglial responses to psychosine. These data offer a novel perspective and enhance understanding of the microglial contribution to GLD pathogenesis.

Astrocyte regulation of CNS inflammation and remyelination.

Astrocytes regulate fundamentally important functions to maintain central nervous system (CNS) homeostasis. Altered astrocytic function is now recognized as a primary contributing factor to an increasing number of neurological diseases. In this review, we provide an overview of our rapidly developing understanding of the basal and inflammatory functions of astrocytes as mediators of CNS responsiveness to inflammation and injury. Specifically, we elaborate on ways that astrocytes actively participate in the pathogenesis of demyelinating diseases of the CNS through their immunomodulatory roles as CNS antigen presenting cells, modulators of blood brain barrier function and as a source of chemokines and cytokines. We also outline how changes in the extracellular matrix can modulate astrocytes phenotypically, resulting in dysregulation of astrocytic responses during inflammatory injury. We also relate recent studies describing newly identified roles for astrocytes in leukodystrophies. Finally, we describe recent advances in how adapting this increasing breadth of knowledge on astrocytes has fostered new ways of thinking about human diseases, which offer potential to modulate astrocytic heterogeneity and plasticity towards therapeutic gain. In summary, recent studies have provided improved insight in a wide variety of neuroinflammatory and demyelinating diseases, and future research on astrocyte pathophysiology is expected to provide new perspectives on these diseases, for which new treatment modalities are increasingly necessary.

The relationship of audiometric thresholds elicited with pulsed, warbled, and pulsed-warbled tones in adults with normal hearing.

OBJECTIVE: American Speech-Language-Hearing Association (ASHA) guidelines allow pulsed and warbled tones in measuring audiometric thresholds and include test frequencies of 3000 and 6000 Hz. However, no research has examined the relationship between thresholds obtained with these stimuli at these frequencies. This study investigated the relationship between thresholds obtained with pulsed, warbled, and pulsed-warbled tones. DESIGN: Thresholds from 25 listeners were obtained using pulsed, warbled, and pulsed-warbled tones at test frequencies recommended by ASHA. RESULTS: Thresholds elicited with pulsed, warbled, and pulsed-warbled tones did not significantly differ. CONCLUSIONS: Findings support using pulsed, warbled, and pulsed-warbled tones for threshold measurements at the frequencies recommended by ASHA.