An ontogenic study of receptor mechanisms by which acute administration of low-doses of methamphetamine suppresses DOI-induced 5-HT2A-receptor mediated head-twitch response in mice.

BACKGROUND: Methamphetamine (MA) is a non-selective monoamine releaser and thus releases serotonin (5-HT), norepinephrine (NE) and dopamine (DA) from corresponding nerve terminals into synapses. DOI ((±)-2, 5-dimethoxy-4-iodoamphetamine) is a direct-acting serotonergic 5-HT2A/C receptor agonist and induces the head-twitch response (HTR) via stimulation of 5-HT2A receptor in mice. While more selective serotonin releasers such as d-fenfluramine evoke the HTR, monoamine reuptake blockers (e.g., cocaine) suppress the DOI-evoked HTR via indirect stimulation of serotonergic 5-HT1A- and adrenergic ɑ2-receptors. Since the induction of HTR by DOI is age-dependent, we investigated whether: (1) during development MA can evoke the HTR by itself, and (2) acute pretreatment with either the selective 5-HT2A receptor antagonist EMD 281014 or low-doses of MA can: (i) modulate the DOI-induced HTR in mice across postnatal days 20, 30 and 60, and (ii) alter the DOI-induced c-fos expression in mice prefrontal cortex (PFC). To further explore the possible modulatory effect of MA on DOI-induced HTR, we investigated whether blockade of inhibitory serotonergic 5-HT1A- or adrenergic ɑ2-receptors by corresponding selective antagonists (WAY 100635 or RS 79948, respectively), can prevent the effect of MA on DOI-induced HTR during aging. RESULTS: Although neither EMD 281014 nor MA by themselves could evoke the HTR, acute pretreatment with either EMD 281014 (0.01, 0.05 and 0.1 mg/kg, i.p.) or MA (1, 2.5, 5 mg/kg, i.p.), dose-dependently suppressed the DOI-induced HTR across ages. While WAY 100635 significantly reversed the inhibitory effect of MA in 20- and 30-day old mice, RS 79948 failed to significantly counter MA's inhibitory effect. Moreover, DOI significantly increased c-fos expressions in several PFC regions. EMD 281014 prevented the DOI-induced increases in c-fos expression. Despite the inhibitory effect of MA on DOI-induced HTR, MA alone or in combination with DOI, significantly increased c-fos expression in several regions of the PFC. CONCLUSION: The suppressive effect of MA on the DOI-evoked HTR appears to be mainly due to functional interactions between the HTR-inducing 5-HT2A receptor and the inhibitory 5-HT1A receptor. The MA-induced increase in c-fos expression in different PFC regions may be due to MA-evoked increases in synaptic concentrations of 5-HT, NE and/or DA.

Ultra-low doses of the transient receptor potential vanilloid 1 agonist, resiniferatoxin, prevents vomiting evoked by diverse emetogens in the least shrew (Cryptotis parva).

Published studies have shown that the transient receptor potential vanilloid 1 (TRPV1) receptor agonist, resiniferatoxin (RTX), has pro and antiemetic effects. RTX can suppress vomiting evoked by a variety of nonselective emetogens such as copper sulfate and cisplatin in several vomit-competent species. In the least shrew, we have already demonstrated that combinations of ultra-low doses of RTX and low doses of the cannabinoid CB1/2 receptor agonist delta-9-tetrahydrocannabinol (Δ-THC) produce additive antiemetic effects against cisplatin-evoked vomiting. In the current study, we investigated the broad-spectrum antiemetic potential of very low nonemetic doses of RTX against a diverse group of specific emetogens including selective and nonselective agonists of serotonergic 5-hydroxytrptamine (5-HT3) receptor (5-HT and 2-Me-5-HT), dopaminergic D2 receptor (apomorphine and quinpirole), cholinergic M1 receptor (pilocarpine and McN-A-343), as well as the selective substance P neurokinin NK1 receptor agonist GR73632, the selective L-Type calcium channel agonist FPL64176, and the sarcoplasmic endoplasmic reticulum calcium ATPase (SERCA) inhibitor thapsigargin. When administered subcutaneously, ultra-low (0.01 µg/kg) to low (5.0 µg/kg) doses of RTX suppressed vomiting induced by the aforementioned emetogens in a dose-dependent fashion with 50% inhibitory dose values ranging from 0.01 to 1.26 µg/kg. This study is the first to demonstrate that low nanomolar nonemetic doses of RTX have the capacity to completely abolish vomiting caused by diverse receptor specific emetogens in the least shrew model of emesis.

Immunotherapies: Exploiting the Immune System for Cancer Treatment.

Cancer is a condition that has plagued humanity for thousands of years, with the first depictions dating back to ancient Egyptian times. However, not until recent decades have biological therapeutics been developed and refined enough to safely and effectively combat cancer. Three unique immunotherapies have gained traction in recent decades: adoptive T cell transfer, checkpoint inhibitors, and bivalent antibodies. Each has led to clinically approved therapies, as well as to therapies in preclinical and ongoing clinical trials. In this review, we outline the method by which these 3 immunotherapies function as well as any major immunotherapeutic drugs developed for treating a variety of cancers.

Kielland's forceps: does it increase the risk of anal sphincter injuries? An observational study.

INTRODUCTION AND HYPOTHESIS: Rotational instrumental deliveries are thought to carry additional risks compared with non-rotational instrumental deliveries, including trauma to maternal tissues, and require specific expertise and training. We conducted a retrospective study to investigate the association between the type of forceps delivery and maternal perineal trauma, and in particular to investigate if Kielland's rotational forceps delivery increases obstetric anal sphincter injuries (OASIS). METHODS: This is a retrospective observational study of 1,515 women who attended a tertiary maternity unit over a period of 5 years and had operative vaginal deliveries primarily or completed by forceps. Data were obtained through the hospital's maternity reporting system. The severity of maternal perineal trauma, particularly third and fourth-degree tears in relation to the type of forceps delivery was explored. Multinomial logistic regression models were used to estimate the crude and the adjusted relative risks (RR) of sustaining third-degree tears compared with other types of vaginal tears. Univariate analyses explored the crude associations between relative risks and age, ethnicity, birth weight, type of instrumental delivery and operator's experience. A multivariate multinomial logistic regression model estimated the adjusted relative risks and included all the previous variables as independent covariates. RESULTS: Of the 1,492 women included in the study, 150 women (77 %) had sustained category 1 tears, 63 women (4 %) had sustained category 2 tears and 279 women (19 %) had sustained third-degree tears. There was no statistically significant association between the severity of maternal perineal trauma and the type of forceps delivery (failed ventouse vs Kielland's forceps RR 1.52, p = 0.159 CI 0.84-2.72, Wrigleys vs Kielland's RR 0.59, p = 0.249, CI 0.24-1.43; Andersons vs Kielland's RR 1.16, p = 0.603, CI 0.65-2.05) after adjusting for age, birth weight, BMI, ethnicity and operator experience (full list of covariates not included). CONCLUSIONS: The incidence of third- and fourth-degree tears following rotational Kielland's forceps delivery and other non-rotational forceps deliveries is comparable.

Sustaining improvement in surgical infection prevention measures for hysterectomy.

Studies have shown that administering prophylactic antibiotics within 60 minutes of a surgical incision decreases the chance of postoperative infection. A large women's hospital that performs 8,000 surgical procedures per year committed to preventing infection by participating in a study. The study participants were patients who had undergone an abdominal hysterectomy. For testing and implementing improvements, the Plan-Do-Study-Act cycle performance improvement method was used. In order to benchmark and to share best practices, the hospital joined the Surgical Infection Prevention Collaborative. The result of the study was antibiotic prophylactic delivery 60 minutes prior to incision in the abdominal hysterectomy population from a baseline of 10% to greater than 90% from 2003 to 2005. This result could not have been accomplished without the dedication and teamwork the hospital staff demonstrated. Quality improvement strategies, staff education, and communication of data have resulted in this sustained improvement.