Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage.

Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinate accumulation within endothelial cells drives glycocalyx degradation through a membrane reorganization-mediated mechanism. We investigated this mechanism in a cultured endothelial cell hypoxia-reoxygenation model, in a rat model of hemorrhage, and in trauma patient plasma samples. We found that succinate metabolism by succinate dehydrogenase mediates glycocalyx damage through lipid oxidation and phospholipase A2-mediated membrane reorganization, promoting the interaction of matrix metalloproteinase 24 (MMP24) and MMP25 with glycocalyx constituents. In a rat hemorrhage model, inhibiting succinate metabolism or membrane reorganization prevented glycocalyx damage and coagulopathy. In patients with trauma, succinate levels were associated with glycocalyx damage and the development of coagulopathy, and the interaction of MMP24 and syndecan-1 was elevated compared to healthy controls.

Dimethyl malonate slows succinate accumulation and preserves cardiac function in a swine model of hemorrhagic shock.

BACKGROUND: Succinate (SI) is a citric acid cycle metabolite that accumulates in tissues during hemorrhagic shock (HS) due to electron transport chain uncoupling. Dimethyl malonate (DMM) is a competitive inhibitor of SI dehydrogenase, which has been shown to reduce SI accumulation and protect against reperfusion injury. Whether DMM can be therapeutic after severe HS is unknown. We hypothesized that DMM would prevent SI buildup during resuscitation (RES) in a swine model of HS, leading to better physiological recovery after RES. METHODS: The carotid arteries of Yorkshire pigs were cannulated with a 5-Fr catheter. After placement of a Swan-Ganz catheter and femoral arterial line, the carotid catheters were opened and the animals were exsanguinated to a mean arterial pressure (MAP) of 45 mm. After 30 minutes in the shock state, the animals were resuscitated to a MAP of 60 mm using lactated ringers. A MAP above 60 mm was maintained throughout RES. One group received 10 mg/kg of DMM (n = 6), while the control received sham injections (n = 6). The primary end-point was SI levels. Secondary end-points included cardiac function and lactate. RESULTS: Succinate levels increased from baseline to the 20-minute RES point in control, while the DMM cohort remained unchanged. The DMM group required less intravenous fluid to maintain a MAP above 60 (450.0 vs. 229.0 mL; p = 0.01). The DMM group had higher pulmonary capillary wedge pressure at the 20-minute and 40-minute RES points. The DMM group had better recovery of cardiac output and index during RES, while the control had no improvement. While lactate levels were similar, DMM may lead to increased ionized calcium levels. DISCUSSION: Dimethyl malonate slows SI accumulation during HS and helps preserve cardiac filling pressures and function during RES. In addition, DMM may protect against depletion of ionized calcium. Dimethyl malonate may have therapeutic potential during HS.

Hematospermia Etiology, Diagnosis, Treatment, and Sexual Ramifications: A Narrative Review.

INTRODUCTION: Hematospermia (HS) is the presence of blood in ejaculatory fluid. It is a rare condition that is historically idiopathic or associated with sexual behavior. Technological advances have identified many of the etiologies behind HS, improving treatment. Though often benign, HS remains a source of considerable sexual anxiety for patients. Few papers have outlined a diagnostic and therapeutic approach to HS, and none have explicitly addressed its sexual consequences. OBJECTIVES: To provide a comprehensive overview of HS, emphasizing its sexual ramifications. METHODS: A PubMed literature search was performed through May 2021 to identify all relevant publications related to etiology, diagnosis, treatment, and sexual effects of HS. Original research and reviews were analyzed, and pertinent studies were included in this review. RESULTS: Iatrogenic interventions (eg, transrectal ultrasound-guided prostate biopsies) are the most common cause of HS. Infection and/or nonspecific inflammation is the most common non-iatrogenic etiology. Malignancies, including prostate, testicular, and other genitourinary cancers, are rarely the cause of HS. Diagnostic approaches to HS can be organized according to patient age (less than or greater than 40 years old), persistence of bleeding, and the presence/absence of concerning symptoms. Though HS often spontaneously resolves, treatment may require various medications (eg, antibiotics, anti-inflammatories) or surgical interventions. HS has several sexual ramifications, including libido-affecting anxiety, social repercussions from sexual partners and non-sexual affiliates, increased risk of erectile dysfunction or transmission of sexual infections, and compromised fertility, especially when cryopreservation is utilized. CONCLUSION: HS may significantly affect sexual health through several mechanisms, though there is a paucity of formal data on this subject. Further research is needed to fully understand the severity and extent of HS's effect on sexual well-being, especially in those with refractory bleeding.

Hematospermia Etiology, Diagnosis, Treatment, and Sexual Ramifications: A Narrative Review.

INTRODUCTION: Hematospermia (HS) is the presence of blood in ejaculatory fluid. It is a rare condition that is historically idiopathic or associated with sexual behavior. Technological advances have identified many of the etiologies behind HS, improving treatment. Though often benign, HS remains a source of considerable sexual anxiety for patients. Few papers have outlined a diagnostic and therapeutic approach to HS, and none have explicitly addressed its sexual consequences. OBJECTIVES: To provide a comprehensive overview of HS, emphasizing its sexual ramifications. METHODS: A PubMed literature search was performed through May 2021 to identify all relevant publications related to etiology, diagnosis, treatment, and sexual effects of HS. Original research and reviews were analyzed, and pertinent studies were included in this review. RESULTS: Iatrogenic interventions (eg, transrectal ultrasound-guided prostate biopsies) are the most common cause of HS. Infection and/or nonspecific inflammation is the most common non-iatrogenic etiology. Malignancies, including prostate, testicular, and other genitourinary cancers, are rarely the cause of HS. Diagnostic approaches to HS can be organized according to patient age (less than or greater than 40 years old), persistence of bleeding, and the presence/absence of concerning symptoms. Though HS often spontaneously resolves, treatment may require various medications (eg, antibiotics, anti-inflammatories) or surgical interventions. HS has several sexual ramifications, including libido-affecting anxiety, social repercussions from sexual partners and non-sexual affiliates, increased risk of erectile dysfunction or transmission of sexual infections, and compromised fertility, especially when cryopreservation is utilized. CONCLUSION: HS may significantly affect sexual health through several mechanisms, though there is a paucity of formal data on this subject. Further research is needed to fully understand the severity and extent of HS's effect on sexual well-being, especially in those with refractory bleeding. Drury RH, King B, Herzog B, et al. Hematospermia Etiology, Diagnosis, Treatment, and Sexual Ramifications: A Narrative Review. Sex Med Rev. 2022;10:669-680.

Pathophysiology and Grayscale Ultrasonography of Penile Corporal Fibrosis.

INTRODUCTION: Penile corporal fibrosis may occur secondary to explantation of an infected penile prosthesis, severe penile trauma, refractory low-flow priapism, Peyronie's disease, or chronic intra-cavernous injection of vasoactive drugs. Other etiologies of corporal fibrosis, presenting primarily with erectile dysfunction, can develop in chronic smokers, hypertensive patients, alcoholics, diabetics, and after radical prostatectomy. Corporal erectile tissue fibrosis is a significant pathophysiologic component of erectile dysfunction; however, current ultrasound-based penile imaging protocols do not directly assess it. OBJECTIVE: To determine if grayscale ultrasonography (US) is a suitable imaging modality to identify and assess penile corporal erectile tissue fibrosis. METHODS: A PubMed literature review was performed for studies that detailed ultrasonographic methods and findings of pathologies causing penile corporal fibrosis. Our main outcome measure was the ultrasonographic findings of pathologies causing penile corporal fibrosis. RESULTS: Grayscale US demonstrates the capability to detect and localize the fibrotic changes of the corpora cavernosa. Ultrasonographic findings capture penile corporal tissue heterogeneity including diffuse, circumscribed, or localized patterns. CONCLUSION: Overall, grayscale US may be a useful and convenient imaging modality to assess penile corporal fibrosis secondary to explantation of an infected penile prosthesis, priapism, penile trauma, chronic intra-cavernous injection of vasoactive drugs, diabetes, Peyronie's disease, and vascular disease. While limited by the skill and knowledge of the US operator, the combined knowledge of pathophysiology and US may help clinicians identify and manage the underlying etiology of penile corporal fibrosis. Kim J, Drury R, Morenas R et al. Pathophysiology and Grayscale Ultrasonography of Penile Corporal Fibrosis. Sex Med Rev 2022;10:99-107.

Interleukin-22 mitigates acute respiratory distress syndrome (ARDS).

BACKGROUND: The goal of this study was to determine if IL-22:Fc would Acute Respiratory Distress Syndrome (ARDS). SUMMARY BACKGROUND DATA: No therapies exist for ARDS and treatment is purely supportive. Interleukin-22 (IL-22) plays an integral component in recovery of the lung from infection. IL-22:Fc is a recombinant protein with a human FC immunoglobulin that increases the half-life of IL-22. STUDY DESIGN: ARDS was induced in C57BL/6 mice with intra-tracheal lipopolysaccharide (LPS) at a dose of 33.3 or 100 ug. In the low-dose LPS group (LDG), IL-22:FC was administered via tail vein injection at 30 minutes (n = 9) and compared to sham (n = 9). In the high-dose LPS group (HDG), IL-22:FC was administered (n = 11) then compared to sham (n = 8). Euthanasia occurred after bronchioalveolar lavage (BAL) on post-injury day 4. RESULTS: In the LDG, IL-22:FC resulted in decreased protein leak (0.15 vs. 0.25 ug/uL, p = 0.02). BAL protein in animals receiving IL-22:Fc in the HDG was not different. For the HDG, animals receiving IL-22:Fc had lower BAL cell counts (539,636 vs 3,147,556 cells/uL, p = 0.02). For the HDG, IL-6 (110.6 vs. 527.1 pg/mL, p = 0.04), TNF-α (5.87 vs. 25.41 pg/mL, p = 0.04), and G-CSF (95.14 vs. 659.6, p = 0.01) levels were lower in the BAL fluid of IL-22:Fc treated animals compared to sham. CONCLUSIONS: IL-22:Fc decreases lung inflammation and lung capillary leak in ARDS. IL-22:Fc may be a novel therapy for ARDS.

Hemorrhagic Shock and Resuscitation Causes Glycocalyx Shedding and Endothelial Oxidative Stress Preferentially in the Lung and Intestinal Vasculature.

INTRODUCTION: Hemorrhagic shock has recently been shown to cause shedding of a carbohydrate surface layer of endothelial cells known as the glycocalyx. This shedding of the glycocalyx is thought to be a mediator of the coagulopathy seen in trauma patients. Clinical studies have demonstrated increases in shed glycocalyx in the blood after trauma, and animal studies have measured glycocalyx disruption in blood vessels in the lung, skeletal muscle, and mesentery. However, no study has measured glycocalyx disruption across a wide range of vascular beds to quantify the primary locations of this shedding. METHODS: In the present study, we used a rat model of hemorrhagic shock and resuscitation to more comprehensively assess glycocalyx disruption across a range of organs. Glycocalyx disruption was assessed by fluorescent-labeled wheat germ agglutinin or syndecan-1 antibody staining in flash frozen tissue. RESULTS: We found that our model did elicit glycocalyx shedding, as assessed by an increase in plasma syndecan-1 levels. In tissue sections, we found that the greatest glycocalyx disruption occurred in vessels in the lung and intestine. Shedding to a lesser extent was observed in vessels of the brain, heart, and skeletal muscle. Liver vessel glycocalyx was unaffected, and kidney vessels, including the glomerular capillaries, displayed an increase in glycocalyx. We also measured reactive oxygen species (ROS) in the endothelial cells from these organs, and found that the greatest increase in ROS occurred in the two beds with the greatest glycocalyx shedding, the lungs, and intestine. We also detected fibrin deposition in lung vessels following hemorrhage-resuscitation. CONCLUSIONS: We conclude that the endothelium in the lungs and intestine are particularly susceptible to the oxidative stress of hemorrhage-resuscitation, as well as the resulting glycocalyx disruption. Thus, these two vessel beds may be important drivers of coagulopathy in trauma patients.

Reviewing the evidence for shockwave- and cell-based regenerative therapies in the treatment of erectile dysfunction.

Erectile dysfunction (ED) is both a common and complex disease process. Existing ED treatments do not always achieve adequate results. There is clinical interest in employing regenerative therapies, including low-intensity extracorporeal shockwave therapy (Li-ESWT), platelet rich plasma (PRP), and stem cell therapy (SCT), in the treatment of ED as adjunct or alternative treatments. Here, we present evidence for emerging shockwave- and cell-based regenerative therapies for the treatment of ED following a thorough review of the existing PubMed literature pertaining to Li-ESWT, PRP, and SCT in relation to the treatment of ED. Li-ESWT causes microtrauma in tissue that hypothetically upregulates angiogenesis and recruits stem cells. Several large-scale systematic reviews and meta-analyses have reported that Li-ESWT improved ED in humans. Additionally, evidence has commenced to show that Li-ESWT may be effective against two recognized and complex etiologies of ED: diabetic and neurogenic. PRP delivers an autologous sample rich in growth factors to damaged tissue. Animal model studies have demonstrated improved erectile function recovery as well as preservation of cavernous nerve axons. Studies with PRP in humans are limited. SCT utilizes the regenerative potential of stem cells for healing of damaged tissue. In the treatment of ED, SCT has been used in the setting of diabetic and post-prostatectomy ED. Results of human studies are varied, although SCT treatments did result in increased erectile rigidity with some patients recovering the ability to achieve penetration. While these regenerative therapies show potential to augment the current treatment regimen for ED, there is a paucity of evidence to support the safety and efficacy of these treatments. Further research is necessary to define the role of these alternative therapies in the treatment of ED.

Hypoxia/reoxygenation decreases endothelial glycocalyx via reactive oxygen species and calcium signaling in a cellular model for shock.

BACKGROUND: Ischemia/reperfusion injury (IRI) has been shown to cause endothelial glycocalyx (EG) damage.Whether the hypoxic/ischemic insult or the oxidative and inflammatory stress of reperfusion plays a greater part in glycocalyx damage is not known. Furthermore, the mechanisms by which IRI causes EG damage have not been fully elucidated. The aims of this study were to determine if hypoxia alone or hypoxia/reoxygenation (H/R) caused greater damage to the glycocalyx, and if this damage was mediated by reactive oxygen species (ROS) and Ca signaling. METHODS: Human umbilical vein endothelial cells were cultured to confluence and exposed to either normoxia (30 minutes), hypoxia (2% O2 for 30 minutes), or H/R (30 minutes hypoxia followed by 30 minutes normoxia). Some cells were pretreated with ROS scavengers TEMPOL, MitoTEMPOL, Febuxostat, or Apocynin, or with the Ca chelator BAPTA or Ca channel blockers 2-aminoethoxydiphenyl borate, A967079, Pyr3, or ML204. Intracellular ROS was quantified for all groups. Endothelial glycocalyx was measured using fluorescently tagged wheat germ agglutinin and imaged with fluorescence microscopy. RESULTS: Glycocalyx thickness was decreased in both hypoxia and H/R groups, with the decrease being greater in the H/R group. TEMPOL, MitoTEMPOL, BAPTA, and 2-aminoethoxydiphenyl borate prevented loss of glycocalyx in H/R. The ROS levels were likewise elevated compared with normoxia in both groups, but were increased in the H/R group compared with hypoxia alone. BAPTA did not prevent ROS production in either group. CONCLUSION: In our cellular model for shock, we demonstrate that although hypoxia alone is sufficient to produce glycocalyx loss, H/R causes a greater decrease in glycocalyx thickness. Under both conditions damage is dependent on ROS and Ca signaling. Notably, we found that ROS are generated upstream of Ca, but that ROS-mediated damage to the glycocalyx is dependent on Ca.

Heart Rate Variability in Dental Science.

Dentistry has made progress as a profession by integration with both medicine and other human sciences, especially when it uses empirical metrics to study process and outcome variables. Notably, progress in our understanding of genomic, biomic, and other molecular biological phenomena has been valuable. As has been identified by Drury (1, 2), it is proposed in this commentary that the inclusion of heart rate variability (HRV) as a biomarker of health may further this integrative progress. HRV is derived by various linear and non-linear statistical analyses of the R-R, beat-to-beat ECG interval in microseconds. Over twenty three thousand reports are identified in a recent PubMed search of the term heart rate variability, most of which demonstrate HRV's sensitivity to a wide diversity of physical and psychosocial pathologies. The small literature of dental use of HRV in both assessment and treatment will be selectively reviewed and relevant exemplars for other important health applications of HRV will be discussed. This will lead to a proposed agenda for researching HRV's value to professional dentistry as a human health and wellness profession.

School-Aged Children With Higher Reflective Functioning Exhibit Lower Cardiovascular Reactivity.

Despite extensive theorizing regarding the regulatory role of reflective functioning (RF), few studies have explored the links between RF and physiological indices of emotion regulation, and none have examined these associations in children. Further, while scholars contend that RF promotes resilience via enhanced ability to process emotional experiences, including those occurring in attachment relationships, this argument has seldom been tested empirically in children. In the current study, we explore the association between RF and physiological measures of emotion reactivity and regulation, as well as the interaction of RF and attachment insecurity. We test these associations by examining children's (N = 76; 8-12 years old) cardiovascular responses [respiratory sinus arrhythmia (RSA)] to a standardized paradigm designed to evoke reactions regarding the experience and expression of attachment-related needs. Children also completed a semi-structured attachment interview, which was later coded for children's attachment insecurity (operationalized as attachment dismissal and preoccupation) and RF. Our findings were largely consistent with theory and our hypotheses, suggesting that higher RF is associated with lesser cardiovascular reactivity (higher levels of RSA) during the stressor task and better recovery following the task. These links were especially strong for children with greater attachment preoccupation but did not vary as a function of children's levels of attachment dismissal. These findings contribute to developmental theory in suggesting that RF is closely linked to physiological emotion regulation in children.

Wearable biosensor systems and resilience: a perfect storm in health care?

We begin by placing our discussion in the context of the chronic crisis in medical care, noting key features, including economic, safety and conceptual challenges. Then we review the most promising elements of a broadened conceptual approach to health and wellbeing, which include an expanded role for psychological, social, cultural, spiritual and environmental variables. The contributions of positive and evolutionary psychology, complex adaptive systems theory, genomics and neuroscience are described and the rapidly developing synthetic field of resilience as a catalytic unifying development is traced in some detail, including analysis of the rapidly growing empirical literature on resilience and its constituents, particularly heart rate variability. Finally, a review of the use of miniaturized ambulatory data collection, analysis and self-management and health management systems points out an exemplar, the Extensive Care System (ECS), which takes advantage of the continuing advances in biosensor technology, computing power, networking dynamics and social media to facilitate not only personalized health and wellbeing, but higher quality evidence-based preventive, treatment and epidemiological outcomes. This development will challenge the acute care episode model typified by the ER or ICU stay and replace it with an ECS capable of facilitating not only healthy autonomic functioning, but both ipsative/individual and normative/population health.