The use of fondaparinux and rituximab for recurrent thrombotic events in antiphospholipid syndrome.

Limited evidence exists to guide the management of recurrent thrombosis occurring despite therapeutic anticoagulation in patients with thrombotic antiphospholipid syndrome (APS). In this case series, fondaparinux, with or without an antiplatelet agent, provided an effective and safe option in three patients with thrombotic APS, all two triple and one single positive for antiphospholipid antibodies, who had recurrent venous and/or arterial thromboembolism. Rituximab was also used in all patients. Recurrent events occurred despite therapeutic anticoagulation, including at high-intensity, with warfarin and subsequent low-molecular-weight heparin. There were no major bleeding events. Adjunctive therapies used for thrombosis included catheter-directed thrombolysis and rituximab.

Risk of thrombosis with thrombocytopenia syndrome after COVID-19 vaccination prior to the recognition of vaccine-induced thrombocytopenia and thrombosis: A self-controlled case series study in England.

Background: Several studies have found increased risks of thrombosis with thrombocytopenia syndrome (TTS) following the ChAdOx1 vaccination. However, case ascertainment is often incomplete in large electronic health record (EHR)-based studies. Objectives: To assess for an association between clinically validated TTS and COVID-19 vaccination. Methods: We used the self-controlled case series method to assess the risks of clinically validated acute TTS after a first COVID-19 vaccine dose (BNT162b2 or ChAdOx1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Case ascertainment was performed uninformed of vaccination status via a retrospective clinical review of hospital EHR systems, including active ascertainment of thrombocytopenia. Results: One hundred seventy individuals were admitted to the hospital for a TTS event at the study sites between January 1 and March 31, 2021. A significant increased risk (relative incidence [RI], 5.67; 95% confidence interval [CI], 1.02-31.38) of TTS 4 to 27 days after ChAdOx1 was observed in the youngest age group (18- to 39-year-olds). No other period had a significant increase, although for ChAdOx1 for all ages combined the RI was >1 in the 4- to 27- and 28- to 41-day periods (RI, 1.52; 95% CI, 0.88-2.63; and (RI, 1.70; 95% CI, 0.73-3.8, respectively). There was no significant increased risk of TTS after BNT162b2 in any period. Increased risks of TTS following a positive SARS-CoV-2 test occurred across all age groups and exposure periods. Conclusions: We demonstrate an increased risk of TTS in the 4 to 27 days following COVID-19 vaccination, particularly for ChAdOx1. These risks were lower than following SARS-CoV-2 infection. An alternative vaccine may be preferable in younger age groups in whom the risk of postvaccine TTS is greatest.

Adipocytes in both brown and white adipose tissue of adult mice are functionally connected via gap junctions: implications for Chagas disease.

Adipose tissue serves as a host reservoir for the protozoan Trypanosoma cruzi, the causative organism in Chagas disease. Gap junctions interconnect cells of most tissues, serving to synchronize cell activities including secretion in glandular tissue, and we have previously demonstrated that gap junctions are altered in various tissues and cells infected with T. cruzi. Herein, we examined the gap junction protein connexin 43 (Cx43) expression in infected adipose tissues. Adipose tissue is the largest endocrine organ of the body and is also involved in other physiological functions. In mammals, it is primarily composed of white adipocytes. Although gap junctions are a prominent feature of brown adipocytes, they have not been explored extensively in white adipocytes, especially in the setting of infection. Thus, we examined functional coupling in both white and brown adipocytes in mice. Injection of electrical current or the dye Lucifer Yellow into adipocytes within fat tissue spread to adjacent cells, which was reduced by treatment with agents known to block gap junctions. Moreover, Cx43 was detected in both brown and white fat tissue. At thirty and ninety days post-infection, Cx43 was downregulated in brown adipocytes and upregulated in white adipocytes. Gap junction-mediated intercellular communication likely contributes to hormone secretion and other functions in white adipose tissue and to nonshivering thermogenesis in brown fat, and modulation of the coupling by T. cruzi infection is expected to impact these functions.

The actions of hyperthermia on the autonomic nervous system: central and peripheral mechanisms and clinical implications.

Hyperthermia is defined as an elevated body temperature due to failed thermoregulation. It can occur under physiological conditions such as intense exercise or due to pathology such as malignant hyperthermia and heat stroke. It has also been implicated as a cause for sudden infant death syndrome. High temperatures are also used in medical interventions - hyperthermic chemotherapy or radiofrequency ablation, for example, which have serious side effects. The effect of hyperthermia on the central nervous system has not been fully researched, but even less is known on the effects of hyperthermia on the peripheral autonomic nervous system. In this review we discuss how conditions such as malignant or therapeutic hyperthermia affect the central and peripheral components of the autonomic nervous system, smooth muscle, skeletal muscle and cardiac muscle. We conclude that there is sufficient evidence for the detrimental effect of hyperthermia on central nerves, and that these effects are long lasting, although the major mechanism for this remains unknown. Similarly, the direct damage of hyperthermia to the enteric nerves also seems to be long lasting. In contrast, the reduced contractility of cardiac muscle and gastrointestinal smooth muscle when exposed to hyperthermia is short-lived. The consensus is that inadequate calcium handling is the mechanism of heat damage to cardiac and skeletal muscle. There is no such consensus when dealing with smooth muscle. The mechanism of hyperthermic damage to autonomic end organs such as the gastrointestinal tract has yet to be elucidated and further research into both central and peripheral hyperthermia is necessary.

Differential effect of hyperthermia on nerves and smooth muscle of the mouse ileum.

BACKGROUND AND OBJECTIVES: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) gained wide acceptance as the treatment of choice for selected patients with peritoneal surface malignancies. Patients tend to suffer from prolonged ileus following CRS + HIPEC, complicating their recovery. We studied the effects of hyperthermia on the intestine to gain insight into mechanisms of ileus post-HIPEC. METHODS: Segments of mouse ileum were incubated at 36°C. Electrical field stimulation (EFS) was applied, stimulating nerves, and the resultant muscle contraction was measured. The response was measured at varying temperatures (38-43°C) at exposure times of up to 120 min. We also stimulated the tissues with 10(-6) M carbachol, a muscarinic receptor agonist, which acts directly on smooth muscle. RESULTS: Response to EFS decreased at high temperatures, especially above 41°C. This effect was irreversible for 120 min after decreasing temperature. When stimulating with carbachol, both transient and plateau responses decreased at 43°C (plateau more than transient) but the effect reversed on returning to 36°C. CONCLUSION: The irreversible decline in responses to nerve stimulation when exposed to high temperatures was not seen with direct muscle stimulation. This indicates that smooth muscle is resilient and that the main effect of hyperthermia is on nerves. These results have significance for HIPEC.