Assessing the impact of mRNA vaccination in chronic inflammatory murine model.

The implications of administration of mRNA vaccines to individuals with chronic inflammatory diseases, including myocarditis, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD), are unclear. We investigated mRNA vaccine effects in a chronic inflammation mouse model implanted with an LPS pump, focusing on toxicity and immunogenicity. Under chronic inflammation, mRNA vaccines exacerbated cardiac damage and myocarditis, inducing mild heart inflammation with heightened pro-inflammatory cytokine production and inflammatory cell infiltration in the heart. Concurrently, significant muscle damage occurred, with disturbances in mitochondrial fusion and fission factors signaling impaired muscle repair. However, chronic inflammation did not adversely affect muscles at the vaccination site or humoral immune responses; nevertheless, it partially reduced the cell-mediated immune response, particularly T-cell activation. These findings underscore the importance of addressing mRNA vaccine toxicity and immunogenicity in the context of chronic inflammation, ensuring their safe and effective utilization, particularly among vulnerable populations with immune-mediated inflammatory diseases.

mRNA-HPV vaccine encoding E6 and E7 improves therapeutic potential for HPV-mediated cancers via subcutaneous immunization.

The E6 and E7 proteins of specific subtypes of human papillomavirus (HPV), including HPV 16 and 18, are highly associated with cervical cancer as they modulate cell cycle regulation. The aim of this study was to investigate the potential antitumor effects of a messenger RNA-HPV therapeutic vaccine (mHTV) containing nononcogenic E6 and E7 proteins. To achieve this, C57BL/6j mice were injected with the vaccine via both intramuscular and subcutaneous routes, and the resulting effects were evaluated. mHTV immunization markedly induced robust T cell-mediated immune responses and significantly suppressed tumor growth in both subcutaneous and orthotopic tumor-implanted mouse model, with a significant infiltration of immune cells into tumor tissues. Tumor retransplantation at day 62 postprimary vaccination completely halted progression in all mHTV-treated mice. Furthermore, tumor expansion was significantly reduced upon TC-1 transplantation 160 days after the last immunization. Immunization of rhesus monkeys with mHTV elicited promising immune responses. The immunogenicity of mHTV in nonhuman primates provides strong evidence for clinical application against HPV-related cancers in humans. All data suggest that mHTV can be used as both a therapeutic and prophylactic vaccine.

Intravenous, oral, and the combination of intravenous and oral ramosetron for the prevention of nausea and vomiting after laparoscopic cholecystectomy: a randomized, double-blind, controlled trial.

BACKGROUND: Patients undergoing general anesthesia for laparoscopic cholecystectomy have a high risk of postoperative nausea and vomiting (PONV) with incidences up to 75%. Ramosetron, a serotonin subtype 3 (5-HT(3)) antagonist, has been shown to be effective as an antiemetic after chemotherapy and surgery. Consensus guidelines recommend a combination of antiemetic therapies in high-risk groups. Until now, no published data have been available on the use of combination oral plus intravenous ramosetron. OBJECTIVE: The goal of this prospective, randomized, double-blind study was to compare the efficacy and tolerability of intravenous, oral, and the combination of oral and intravenous ramosetron for PONV prophylaxis in patients undergoing laparoscopic cholecystectomy. METHODS: Patients scheduled for laparoscopic cholecystectomy were double-randomly allocated to 1 of 3 groups. Patients were randomly allocated to receive either 0.3 mg of intravenous ramosetron (group A), 0.1 mg of oral ramosetron (group B), or the combination of 0.1 mg of oral ramosetron and 0.3 mg of intravenous ramosetron (group C). All patients received standardized balanced anesthesia with desflurane and remifentanil. Postoperative nausea, retching, vomiting, pain, and adverse effects were assessed at 0 to 2, 2 to 24, and 24 to 48 hours after surgery. RESULTS: A total of 124 Korean patients (67 women, 57 men; age range, 25-65 years) were randomized to 1 of 3 study groups (42 in group A [mean age, 49.8 years], 41 in group B [mean age, 47.4 years], and 41 in group C [mean age, 48.9 years]). No statistical differences were observed among the 3 groups with regard to patient characteristics and information on surgery and anesthesia. During postoperative period 0 to 2 hours, complete response occurred in 31 (74%) patients in group A, 27 (66%) in group B, and 37 (90%) in group C. During the postoperative period of 2 to 24 hours, complete response was observed in 36 (86%), 33 (80%), and 40 (98%) patients in groups A, B, and C, respectively; there was a statistically significant difference in group C compared with group A or group B. During the postoperative period of 0 to 48 hours, incidences of rescue antiemetic use were 13 (31%), 14 (34%), and 3 (7%) in groups A, B and C, respectively. Common adverse effects (headache, dizziness, and drowsiness) were observed, but there was no significant difference in the incidences of adverse effects among the 3 groups (P > 0.05). CONCLUSIONS: The combination of 0.1-mg oral and 0.3-mg intravenous ramosetron was more effective than either 0.3-mg intravenous ramosetron or 0.1-mg oral ramosetron alone for the prophylaxis of nausea and vomiting after laparoscopic cholecystectomy during the first 24 hours after surgery. In addition, differences did not reach the level of statistical significance between 0.1 mg of oral ramosetron and 0.3 mg of intravenous ramosetron for the prevention of PONV in this patient population. Oral, intravenous, and combined oral and intravenous ramosetron appears well tolerated in the population studied. ClinicalTrials.gov identifier: NCT 01041183.

Identification of patients with childhood moyamoya diseases showing temporary hypertension after anesthesia by preoperative multifractal Hurst analysis of heart rate variability.

OBJECTIVE: This study was performed to determine whether the preoperative multifractal Hurst analysis of heart rate variability might identify and characterize childhood patients with moyamoya disease (MMD) who showed temporary postoperative hypertension. METHODS: We studied 59 childhood patients with MMD. Thirty were classified as hypertensive group when the mean arterial pressure in the postoperative recovery room was 120% or greater than that during the preoperative period and 29 were classified as normotensive group. The 2 groups were compared with respect to preoperative indices of heart rate variability including frequency-domain measures, approximate entropy, and very short-term multifractal Hurst exponents of RR intervals (RRI). Using preoperative indices that showed significant differences, discriminant analysis was performed to identify postoperative hypertensive patients. RESULTS: Only exponents of the order > or =3 (H3alpha, H4alpha, and H5alpha) were significantly lower in the hypertensive group than in the normotensive group. Frequency-domain measures, approximate entropy, and the exponents of the order < or =2 were not significantly different in the 2 groups. Discriminant analysis using all of the three exponents correctly identified 27/30 (90%) of the postoperative hypertensive patients. CONCLUSIONS: Preoperative very short-term multifractal Hurst analysis of RRI variability identified 90% of childhood MMD patients who developed postoperative hypertension. The preoperative characteristic of RRI variability was the reduced smoothness at the 8-second-long, local RRI regions within which a very large change of RRI occurs.