An inflammatory response is instrumental in the physiological process of parturition but the upstream signals initiating inflammation are undefined. Because endogenous ligands for Toll-like receptor 4 (TLR4) are released in late gestation, we hypothesized that on-time labor requires TLR4 signaling, to trigger a cytokine and leukocyte response and accelerate the parturition cascade. In pregnant TLR4-deficient (Tlr4-/-) mice, average gestation length was extended by 13 hours and increased perinatal mortality was seen compared with wild-type controls. Quantification of cytokine and uterine activation gene expression showed that late gestation induction of Il1b, Il6, Il12b, and Tnf expression seen in control placenta and fetal membranes was disrupted in Tlr4-/- mice, and accompanied by a transient delay in expression of uterine activation genes, including prostaglandin F receptor, oxytocin receptor, and connexin-43. Leukocyte populations were altered before birth in TLR4-deficient females, with fewer neutrophils and macrophages in the placenta, and fewer dendritic cells and more regulatory T cells in the myometrium. Administration of TLR4 ligand lipopolysaccharide to pregnant wild-type mice induced cytokine expression and fetal loss, whereas Tlr4-/- pregnancies were protected. The small molecule TLR4 antagonist (+)-naloxone increased mean duration of gestation by 16 hours in wild-type mice. Collectively, these data demonstrate that TLR4 is a key upstream regulator of the inflammatory response acting to drive uterine activation and control the timing of labor. Because causal pathways for term and preterm labor converge with TLR4, interventions to manipulate TLR4 signaling may have therapeutic utility for women at risk of preterm labor, or in postterm pregnancy.
Inflammatory activation, a major driver of preterm birth and subsequent neonatal morbidity, is an attractive pharmacological target for new preterm birth therapeutics. Inflammation elicited by intraamniotic infection is causally associated with preterm birth, particularly in infants delivered ≤34 weeks' gestation. However, sterile triggers of PTB, including placental ischaemic injury, uterine distention, cervical disease, or imbalance in the immune response, also act through inflammatory mediators released in response to tissue damage. Toll-like Receptors (TLRs) are critical upstream gate-keepers controlling the inflammatory activation that precedes preterm delivery, as well as in normal term labour. In particular, TLR4 is implicated for its capacity to sense and integrate a range of disparate infectious and sterile pro-inflammatory triggers, and so acts as a point-ofconvergence through which a range of infectious and sterile agents can activate and accelerate the parturition cascade. Recent studies point to the TLR4 signalling complex as a tractable target for the inhibition of fetal, placental & intraamniotic inflammatory cytokine production. Moreover, studies on mice show that novel small molecule antagonists of TLR4 signalling are highly effective in preventing preterm birth induced by bacterial mimetic LPS, heat-killed E. coli or the TLR4-dependent pro-inflammatory lipid, Platelet Activating Factor (PAF). In this review, we discuss the role of TLR4 in regulating the timing of birth and the potential utility of TLR4 antagonists as novel therapeutics for preterm delivery.
Introduction: Microbial and sterile triggers of inflammation can activate Toll-like receptors (TLR) to initiate synthesis of pro-inflammatory cytokines that in turn drive the parturition cascade leading to preterm delivery (PTD). Platelet activating factor (PAF) has been identified as a key endogenous sterile inflammatory trigger that is elevated in the amniotic fluid in both normal and PTD in human. Intrauterine administration of PAF in mice results in PTD. We investigated the role of TLR4 in PAF-induced PTD. Materials and Methods: BALB/c females were administered PAF or vehicle i.p on gestational day (gd) 16.5, followed by treatment with the small molecule TLR4 antagonist, (+)-Naltrexone, or vehicle control. Mice were observed for PTD, and in the absence of PTD mice were killed on gd 18.5 and implantation sites, fetal viability and fetal and placental weights were determined. Results: PAF administration lead to PTD in 64% (9/14 mice), with reduced numbers of viable fetuses compared to vehicle controls. (+)- Naltrexone administration to mice given PAF was able to prevent PAF-induced PTD and viable fetuses were comparable in number to control groups. Secondly, wildtype and Tlr4-/- BALB/c female mice were mated to males of the same genotype, and were challenged with PAF or vehicle on gd 16.5. Tlr4-/- females had 17% (2/12 mice) of PTD, with the number of viable fetuses similar to wildtype females when administered with PAF, suggesting that PAF may activate TLR4- independent pathways to drive fetal inflammatory injury. Conclusion: PAF is a clear mediator of inflammation-driven PTD, through TLR4-dependent and TLR4- independent pathways.
Approximately 18% of pregnant women are colonized with Group B streptococcus (GBS), which are β-hemolytic, gram-positive bacteria. GBS conversion from the asymptomatic commensal in the vagina to an invasive pathogen predisposes the pregnant women to ascending intrauterine infection that tiggers preterm birth and initiate fetal and neonatal infections. Here, we review the prevalence of colonizing GBS serotypes and sequence types (STs) in different geographical regions. Maternal components including demographical and obstetric factors that increase the risk for GBS colonization during pregnancy are also further elucidated. The prevalence of colonizing GBS serotypes and sequence types (STs) are elucidated in this review in addition to the maternal components including demographical and obstetric factors that increase the risk for GBS colonization during pregnancy. Investigating the epidemiology is crucial for the development of new therapeutic and preventive measures to reduce the burden of invasive GBS disease worldwide including risk-factor based screening protocols.
Vaginal colonization with Group B streptococcus (GBS) or Streptococcus agalactiae can potentially cause ascending intrauterine infection among pregnant women, and hence it is known as one of the risk factors for preterm delivery. Ascending intrauterine infection may also cause the transmission of GBS to the fetus in utero and the newborn during delivery, leading to the development of early onset of neonatal infection. GBS are β-hemolytic, gram-positive bacteria that are opportunistic commensal of the gastrointestinal and urogenital tract of approximately 18% of pregnant women globally. Intrapartum antibiotic prophylaxis (IAP) only reduces the rate of early onset neonatal infection, but not the late onset neonatal infection. Thus, the development of GBS vaccine is thought to be important to decrease the rate of preterm delivery and neonatal infections particularly in low-and-middle income countries where IAP program is not feasible. Vaccination can also be cost-effective for the healthcare system when executed together with IAP program. The aim of the current review is to summarize the mechanisms on how the GBS virulence factors interact with host immune components in the gestational tissues, leading to cervicovaginal colonization and ascending intrauterine infection. The elucidation of these mechanisms is essential for expediting the development of vaccines and novel therapeutic measures targeting these GBS virulence factors that will hamper the vaginal colonization, ascending intrauterine infection and conceptus tissue invasion by GBS. These strategies are crucial to potentially reduce the rate of preterm delivery and subsequent serious complications in the newborn.
Introduction: With the arise of the COVID-19 pandemic, higher institutions are forced to change the method of delivery for bedside teaching sessions from face-to-face to online learning. However, online learning was found not effective in delivering practical knowledge and skills to students. Hence, the objective of this study was to determine the association between level of knowledge gained, confidence, motivation and flexibility on types of learning for bedside teaching sessions among clinical students in four Malaysian medical schools during COVID-19 pandemic. Methods: A cross-sectional study involving medical students from Universiti Putra Malaysia (UPM), Universiti Sains Islam Malaysia (USIM), Universiti Islam Antarabangsa (UIA) and Universiti Sains Malaysia (USM) were conducted from 1st March 2021 until 6th June 2021. An online questionnaire was distributed and it consisted of 5 sections which cover sociodemographic information, level of knowledge gained, confidence, motivation, and flexibility from bedside teaching session. The data was analysed by using SPSS software program. Results: There is a significant association between the level of knowledge gained, level of confidence, level of motivation and level of flexibility with the type of learning (online or face-to-face) during bedside teaching sessions. Results revealed that students gained a higher level of knowledge (84.9%), higher level of confidence in physical examination (93.3%), higher motivation (82.2%) and higher flexibility (64.1%) during face-to-face bedside teaching sessions compared to online learning. Conclusion: Most of the medical students in four Malaysian medical schools prefer face-to-face learning compared to online learning for bedside teaching sessions.
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