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. 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.

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.

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.