James H. Quillen VA Medical Center

The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person.

The ability of fungal-derived beta-glucan particles to induce leukocyte activation and the production of inflammatory mediators, such as tumor necrosis factor (TNF)-alpha, is a well characterized phenomenon. Although efforts have been made to understand how these carbohydrate polymers exert their immunomodulatory effects, the receptors involved in generating these responses are unknown. Here we show that Dectin-1 mediates the production of TNF-alpha in response to zymosan and live fungal pathogens, an activity that occurs at the cell surface and requires the cytoplasmic tail and immunoreceptor tyrosine activation motif of Dectin-1 as well as Toll-like receptor (TLR)-2 and Myd88. This is the first demonstration that the inflammatory response to pathogens requires recognition by a specific receptor in addition to the TLRs. Furthermore, these studies implicate Dectin-1 in the production of TNF-alpha in response to fungi, a critical step required for the successful control of these pathogens.

Zymosan is a beta-glucan- and mannan-rich particle that is widely used as a cellular activator for examining the numerous responses effected by phagocytes. The macrophage mannose receptor (MR) and complement receptor 3 (CR3) have historically been considered the major macrophage lectins involved in the nonopsonic recognition of these yeast-derived particles. Using specific carbohydrate inhibitors, we show that a beta-glucan receptor, but not the MR, is a predominant receptor involved in this process. Furthermore, nonopsonic zymosan binding was unaffected by genetic CD11b deficiency or a blocking monoclonal antibody (mAb) against CR3, demonstrating that CR3 was not the beta-glucan receptor mediating this activity. To address the role of the recently described beta-glucan receptor, Dectin-1, we generated a novel anti-Dectin-1 mAb, 2A11. Using this mAb, we show here that Dectin-1 was almost exclusively responsible for the beta-glucan-dependent, nonopsonic recognition of zymosan by primary macro-phages. These findings define Dectin-1 as the leukocyte beta-glucan receptor, first described over 50 years ago, and resolves the long-standing controversy regarding the identity of this important molecule. Furthermore, these results identify Dectin-1 as a new target for examining the immunomodulatory properties of beta-glucans for therapeutic drug design.

The phagocytosis of pathogens is a critical event in host defense, not only for clearance of the invading microorganism, but also for the subsequent immune response. We have examined Dectin-1, a proinflammatory nonopsonic receptor for beta-glucans, and show that it mediates the internalization of beta-glucan-bearing ligands, including yeast particles. Although requiring tyrosine phosphorylation and the cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM)-like motif, uptake mediated by Dectin-1 was different from any previously reported phagocytic receptor and was not dependent on Syk-kinase in macrophages. Furthermore, intracellular trafficking of this receptor was influenced by the nature of the beta-glucan ligand, which has significance for the biologic activity of these immunomodulatory carbohydrates.

To test whether the antiapoptotic protein Bcl-2 prevents apoptosis and injury of cardiomyocytes after ischemia-reperfusion (I/R), we generated a line of transgenic mice that carried a human Bcl-2 transgene under the control of a mouse alpha-myosin heavy chain promoter. High levels of human Bcl-2 transcripts and 26-kDa Bcl-2 protein were expressed in the hearts of transgenic mice. Functional recovery of the transgenic hearts significantly improved when they were perfused as Langendorff preparations. This protection was accompanied by a threefold decrease in lactate dehydrogenase (LDH) released from the transgenic hearts. The transgenic mice were subjected to 50 min of ligation of the left descending anterior coronary artery followed by reperfusion. The infarct sizes, expressed as a percentage of the area at risk, were significantly smaller in the transgenic mice than in the nontransgenic mice (36.6 +/- 5 vs 69.9 +/- 7.3%, respectively). In hearts subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion, Bcl-2 transgenic hearts had significantly fewer terminal deoxynucleodidyl-transferase nick-end labeling-positive or in situ oligo ligation-positive myocytes and a less prominent DNA fragmentation pattern. Our results demonstrate that overexpression of Bcl-2 renders the heart more resistant to apoptosis and I/R injury.

Recognition of microbial components by germ-line encoded pattern recognition receptors (PRR) initiates immune responses to infectious agents. We and others have proposed that pairs or sets of PRR mediate host immunity. One such pair comprises the fungal beta-glucan receptor, Dectin-1, which collaborates through an undefined mechanism with Toll-like receptor 2 (TLR2) to induce optimal cytokine responses in macrophages. We show here that Dectin-1 signaling through the spleen tyrosine kinase (Syk) pathway is required for this collaboration, which can also occur with TLR4, 5, 7 and 9. Deficiency of either Syk or the TLR adaptor MyD88 abolished collaborative responses, which include TNF, MIP-1alpha and MIP-2 production, and which are comparable to the previously described synergy between TLR2 and TLR4. Collaboration of the Syk and TLR/MyD88 pathways results in sustained degradation of the inhibitor of kappaB (IkappaB), enhancing NFkappaB nuclear translocation. These findings establish the first example of Syk- and MyD88-coupled PRR collaboration, further supporting the concept that paired receptors collaborate to control infectious agents.

High levels of lactate are positively associated with the prognosis and mortality in patients with heart attack. Endothelial-to-mesenchymal transition (EndoMT) plays an important role in cardiac fibrosis. Here, we report that lactate exerts a previously unknown function that increases cardiac fibrosis and exacerbates cardiac dysfunction by promoting EndoMT following myocardial infarction (MI). Treatment of endothelial cells with lactate disrupts endothelial cell function and induces mesenchymal-like function following hypoxia by activating the TGF-β/Smad2 pathway. Mechanistically, lactate induces an association between CBP/p300 and Snail1, leading to lactylation of Snail1, a TGF-β transcription factor, through lactate transporter monocarboxylate transporter (MCT)-dependent signaling. Inhibiting Snail1 diminishes lactate-induced EndoMT and TGF-β/Smad2 activation after hypoxia/MI. The MCT inhibitor CHC mitigates lactate-induced EndoMT and Snail1 lactylation. Silence of MCT1 compromises lactate-promoted cardiac dysfunction and EndoMT after MI. We conclude that lactate acts as an important molecule that up-regulates cardiac EndoMT after MI via induction of Snail1 lactylation.

Many standardized measures of cognition include items that must be seen or heard. Nevertheless, it is not uncommon to overlook the possible effects of sensory impairment(s) on test scores. In the current study, we investigated whether sensory impairments could affect performance on a widely used screening tool, the Montreal Cognitive Assessment (MoCA). Three hundred and one older adults (mean age = 71 years) completed the MoCA and also hearing and vision tests. Half of the participants had normal hearing and vision, 38% impaired hearing, 5% impaired vision, and 7% had dual-sensory impairment. More participants with normal sensory acuity passed the MoCA compared to those with sensory loss, even after modifying scores to adjust for sensory factors. The results suggest that cognitive abilities may be underestimated if sensory problems are not considered and that people with sensory loss are at greater risk of cognitive decline.

PURPOSE: The purpose of this study was to examine in listeners with normal hearing and listeners with sensorineural hearing loss the within- and between-group differences obtained with 4 commonly available speech-in-noise protocols. METHOD: Recognition performances by 24 listeners with normal hearing and 72 listeners with sensorineural hearing loss were compared for 4 speech-in-noise protocols that varied with respect to the amount of contextual cues conveyed in the target signal. The protocols studied included the Bamford-Kowal-Bench Speech-in-Noise Test (BKB-SIN; Etymōtic Research, 2005; J. Bench, A. Kowal, & J. Bamford, 1979; P. Niquette et al., 2003), the Quick Speech-in-Noise Test (QuickSIN; M. C. Killion, P. A. Niquette, G. I. Gudmundsen, L. J. Revit, & S. Banerjee, 2004), and the Words-in-Noise test (WIN; R. H. Wilson, 2003; R. H. Wilson & C. A. Burks, 2005), each of which used multitalker babble and a modified method of constants, as well as the Hearing in Noise Test (HINT; M. Nilsson, S. Soli, & J. Sullivan, 1994), which used speech-spectrum noise and an adaptive psychophysical procedure. RESULTS: The 50% points for the listeners with normal hearing were in the 1- to 4-dB signal-to-babble ratio (S/B) range and for the listeners with hearing loss in the 5- to 14-dB S/B range. Separation between groups was least with the BKB-SIN and HINT (4-6 dB) and most with the QuickSIN and WIN (8-10 dB). CONCLUSION: The QuickSIN and WIN materials are more sensitive measures of recognition performance in background noise than are the BKB-SIN and HINT materials.

Although pressure ulcer (PrU) development is now generally considered an indicator for quality of care, questions and concerns about situations in which they are unavoidable remain. Considering the importance of this issue and the lack of available research data, in 2010 the National Pressure Ulcer Advisory Panel (NPUAP) hosted a multidisciplinary conference to establish consensus on whether there are individuals in whom pressure ulcer development may be unavoidable and whether a difference exists between end-of-life skin changes and pressure ulcers. Thirty-four stakeholder organizations from various disciplines were identified and invited to send a voting representative. Of those, 24 accepted the invitation. Before the conference, existing literature was identified and shared via a webinar. A NPUAP task force developed standardized consensus questions for items with none or limited evidence and an interactive protocol was used to develop consensus among conference delegates and attendees. Consensus was established to be 80% agreement among conference delegates. Unanimous consensus was achieved for the following statements: most PrUs are avoidable; not all PrUs are avoidable; there are situations that render PrU development unavoidable, including hemodynamic instability that is worsened with physical movement and inability to maintain nutrition and hydration status and the presence of an advanced directive prohibiting artificial nutrition/hydration; pressure redistribution surfaces cannot replace turning and repositioning; and if enough pressure was removed from the external body the skin cannot always survive. Consensus was not obtained on the practicality or standard of turning patients every 2 hours nor on concerns surrounding the use of medical devices vis-à-vis their potential to cause skin damage. Research is needed to examine these issues, refine preventive practices in challenging situations, and identify the limits of prevention.

In spite of recent advances with experiments on animal models, strongyloidiasis, an infection caused by the nematode parasite Strongyloides stercoralis, has still been an elusive disease. Though endemic in some developing countries, strongyloidiasis still poses a threat to the developed world. Due to the peculiar but characteristic features of autoinfection, hyperinfection syndrome involving only pulmonary and gastrointestinal systems, and disseminated infection with involvement of other organs, strongyloidiasis needs special attention by the physician, especially one serving patients in areas endemic for strongyloidiasis. Strongyloidiasis can occur without any symptoms, or as a potentially fatal hyperinfection or disseminated infection. Th2 cell-mediated immunity, humoral immunity and mucosal immunity have been shown to have protective effects against this parasitic infection especially in animal models. Any factors that suppress these mechanisms (such as intercurrent immune suppression or glucocorticoid therapy) could potentially trigger hyperinfection or disseminated infection which could be fatal. Even with the recent advances in laboratory tests, strongyloidiasis is still difficult to diagnose. But once diagnosed, the disease can be treated effectively with antihelminthic drugs like Ivermectin. This review article summarizes a case of strongyloidiasis and various aspects of strongyloidiasis, with emphasis on epidemiology, life cycle of Strongyloides stercoralis, clinical manifestations of the disease, corticosteroids and strongyloidiasis, diagnostic aspects of the disease, various host defense pathways against strongyloidiasis, and available treatment options.

We identified the C-type-lectin-like receptor, Dectin-1, as the major receptor for fungal beta-glucans on murine macrophages and have demonstrated that it plays a significant role in the cellular response to these carbohydrates. Using two novel, isoform-specific mAb, we show here that human Dectin-1, the beta-glucan receptor (betaGR), is widely expressed and present on all monocyte populations as well as macrophages, DC, neutrophils and eosinophils. This receptor is also expressed on B cells and a subpopulation of T cells, demonstrating that human Dectin-1 is not myeloid restricted. Both major functional betaGR isoforms - betaGR-A and betaGR-B - were expressed by these cell populations in peripheral blood; however, only betaGR-B was significantly expressed on mature monocyte-derived macrophages and immature DC, suggesting cell-specific control of isoform expression. Inflammatory cells, recruited in vivo using a new skin-window technique, demonstrated that Dectin-1 expression was not significantly modulated on macrophages during inflammation, but is decreased on recruited granulocytes. Despite previous reports detailing the involvement of other beta-glucan receptors on mature human macrophages, we have demonstrated that Dectin-1 acted as the major beta-glucan receptor on these cells and contributed to the inflammatory response to these carbohydrates.

Moisture-associated skin damage (MASD) is caused by prolonged exposure to various sources of moisture, including urine or stool, perspiration, wound exudate, mucus, saliva, and their contents. MASD is characterized by inflammation of the skin, occurring with or without erosion or secondary cutaneous infection. Multiple conditions may result in MASD; 4 of the most common forms are incontinence-associated dermatitis, intertriginous dermatitis, periwound moisture-associated dermatitis, and peristomal moisture-associated dermatitis. Although evidence is lacking, clinical experience suggests that MASD requires more than moisture alone. Instead, skin damage is attributable to multiple factors, including chemical irritants within the moisture source, its pH, mechanical factors such as friction, and associated microorganisms. To prevent MASD, clinicians need to be vigilant both in maintaining optimal skin conditions and in diagnosing and treating minor cases of MASD prior to progression and skin breakdown.

Dectin-1 is the major macrophage receptor for beta-glucans and generates a proinflammatory response through the recognition of these carbohydrates on fungal pathogens. We have examined the effects of cytokines and other agents on the expression and functions of dectin-1 in both resident and elicited murine peritoneal macrophages (Mphi). Dectin-1 expression was found to be highly up-regulated by GM-CSF and by the cytokines that induce alternative macrophage activation, IL-4 and IL-13. In contrast, IL-10, LPS, and dexamethasone, but not IFN-gamma, down-regulated the expression of this receptor. Modulation of dectin-1 receptor levels correlated with the ability of these macrophages to bind zymosan and significantly affected the contribution of this receptor to the resultant proinflammatory response, as measured by the production of TNF-alpha, although some Mphi-specific differences were observed. These results correlate with the known effects of these cytokines and other agents on the ability of the immune system to recognize and respond to fungal pathogens.

BACKGROUND: Nasal carriage of Staphylococcus aureus is common among health care workers, but outbreaks caused by such carriers are relatively uncommon. We previously reported outbreaks of S. aureus skin infections that affected newborn infants and were attributed to an S. aureus nasal carrier who had had an associated upper respiratory tract infection (UR) during the outbreak period. OBJECTIVE: To investigate the contribution of a nasal methicillin-resistant S. aureus (MRSA) carrier (physician 4) who contracted a URI to an outbreak of MRSA infections that involved 8 of 43 patients in a surgical intensive care unit during a 3-week period. DESIGN: An epidemiologic study of an outbreak of MRSA infections and a quantitative investigation of airborne dispersal of S. aureus associated with an experimentally induced rhinoviral infection. SETTING: A university hospital. PARTICIPANTS: 43 patients in a surgical intensive care unit and 1 physician. MEASUREMENTS: Molecular typing was done, and risk factors for MRSA colonization were analyzed. Agar settle plates and volumeric air cultures were used to evaluate the airborne dispersal of S. aureus by physician 4 before and after a rhinoviral infection and with or without a surgical mask. RESULTS: A search for nasal carriers of MRSA identified a single physician (physician 4); molecular typing showed that the MRSA strain from physician 4 and those from the patients were identical. Multivariate logistic regression analysis identified exposure to physician 4 and duration of ventilation as independent risk factors for colonization with MRSA (P < or = 0.008). Air cultures showed that physician 4 dispersed little S. aureus in the absence of a URI. After experimental induction of a rhinovirus URI, physician 4's airborne dispersal of S. aureus without a surgical mask increased 40- fold; dispersal was significantly reduced when physician 4 wore a mask (P < or = 0.015). CONCLUSIONS: Physician 4 became a "cloud adult," analogous to the "cloud babies" described by Eichenwald and coworkers who shed S. aureus into the air in association with viral URIs. Airborne dispersal of S. aureus in association with a URI may be an important mechanism of transmission of S. aureus.

BACKGROUND: Laparoscopic myomectomy is a new procedure that is growing in popularity. The natural history of pregnancy following laparoscopic myomectomy is unknown. CASE: A 24-year-old white woman, gravida 0, with infertility and endometriosis, conceived after a laparoscopic procedure that included myomectomy. At 34 weeks' gestation, the patient experienced uterine dehiscence at the site of myomectomy. An emergency cesarean delivery was performed and the uterus was oversewn. Both mother and infant had satisfactory hospital courses. CONCLUSION: Meticulous closure of the myometrial bed following myomectomy is difficult via the laparoscope, and this could interfere with the integrity of the scar. If further studies confirm this experience, then laparoscopic myomectomy may need to be limited to patients who do not desire further childbearing.

A simple word-recognition task in multitalker babble for clinic use was developed in the course of four experiments involving listeners with normal hearing and listeners with hearing loss. In Experiments 1 and 2, psychometric functions for the individual NU No. 6 words from Lists 2, 3, and 4 were obtained with each word in a unique segment of multitalker babble. The test paradigm that emerged involved ten words at each of seven signal-to-babble ratios (S/B) from 0 to 24 dB. Experiment 3 examined the effect that babble presentation level (70, 80, and 90 dB SPL) had on recognition performance in babble, whereas Experiment 4 studied the effect that monaural and binaural listening had on recognition performance. For listeners with normal hearing, the 90th percentile was 6 dB S/B. In comparison to the listeners with normal hearing, the 50% correct points on the functions for listeners with hearing loss were at 5 to 15 dB higher signal-to-babble ratios.

Dectin-1 is a fungal pattern recognition receptor that binds to beta-glucans and triggers cytokine production by facilitating interaction with TLR2 or by directly activating spleen tyrosine kinase (Syk). To assess the possible role of Dectin-1 in the innate response to mycobacteria, we used an in vitro system in which IL-12p40 production is measured in splenic dendritic cells (SpDC) following exposure to live Mycobacterium tuberculosis bacilli. Treatment of SpDC with laminarin or glucan phosphate, two molecules known to block Dectin-1-dependent activity, led to a reduction in M. tuberculosis-induced IL-12p40 as well as IL-12p70 production. Moreover, SpDC from Dectin-1-/- chimeric mice displayed reduced IL-12p40 production in response to mycobacteria when compared with Dectin-sufficient DC. Laminarin treatment also inhibited mycobacterial-induced IL-12p40 production in DC from TLR2-/- mice, arguing that Dectin-1 functions independently of TLR2 signaling in this system. Importantly, a Dectin-1 fusion protein was found to directly bind to live mycobacteria in a laminarin-inhibitable manner indicating the presence of ligands for the receptor in the bacterium and laminarin pretreatment resulted in reduced association of mycobacteria to SpDC. In additional experiments, mycobacterial stimulation was shown to be associated with increased phosphorylation of Syk and this response was inhibited by laminarin. Furthermore, pharmacologic inhibition of Syk reduced the M. tuberculosis-induced IL-12p40 response. Together, these findings support a role for Dectin-1 in promoting M. tuberculosis-induced IL-12p40 production by DC in which the receptor augments bacterial-host cell interaction and enhances the subsequent cytokine response through an unknown mechanism involving Syk signaling.

In the vast majority of cases, appropriate identification and mitigation of risk factors can prevent or minimize pressure ulcer (PU) formation. However, some PUs are unavoidable. Based on the importance of this topic and the lack of literature focused on PU unavoidability, the National Pressure Ulcer Advisory Panel hosted a multidisciplinary conference in 2014 to explore the issue of PU unavoidability within an organ system framework, which considered the complexities of nonmodifiable intrinsic and extrinsic risk factors. Prior to the conference, an extensive literature review was conducted to analyze and summarize the state of the science in the area of unavoidable PU development and items were developed. An interactive process was used to gain consensus based on these items among stakeholders of various organizations and audience members. Consensus was reached when 80% agreement was obtained. The group reached consensus that unavoidable PUs do occur. Consensus was also obtained in areas related to cardiopulmonary status, hemodynamic stability, impact of head-of-bed elevation, septic shock, body edema, burns, immobility, medical devices, spinal cord injury, terminal illness, and nutrition.

We recently demonstrated that the beta-glucan receptor Dectin-1 (betaGR) was the major nonopsonic beta-glucan receptor on macrophages (Mphi) for the yeast-derived particle zymosan. However, on resident peritoneal Mphi, we identified an additional mannan-inhibitable receptor for zymosan that was distinct from the Mphi mannose receptor (MR). In this study, we have studied the mannose-binding potential of murine Mphi and identified the dendritic cell-specific ICAM-3-grabbing nonintegrin homolog, SIGN-related 1 (SIGNR1), as a major MR on murine resident peritoneal Mphi. Both SIGNR1 and betaGR cooperated in the nonopsonic recognition of zymosan by these Mphi. When SIGNR1 was introduced into NIH3T3 fibroblasts or RAW 264.7 Mphi, it conferred marked zymosan-binding potential on these cells. However, in the nonprofessional phagocytes (NIH3T3), SIGNR1 was found to be poorly phagocytic, suggesting that other receptors such as betaGR may play a more dominant role in particle internalization on professional phagocytes. Binding of zymosan to RAW 264.7 Mphi expressing SIGNR1 resulted in TNF-alpha production. Treatment of RAW 264.7 Mphi expressing SIGNR1, which express low levels of betaGR, with beta-glucans had little effect on binding or TNF-alpha production, indicating that there was no absolute requirement for betaGR in this process. These studies have identified SIGNR1 as a major MR for fungal and other pathogens present on specific subsets of Mphi.