Efficacy of fosaprepitant combined with tropisetron plus dexamethasone in preventing nausea and emesis during fractionated radiotherapy with weekly cisplatin chemotherapy: interim analysis of a randomized, prospective, clinical trial using competing risk analysis.

PURPOSE: There are no well-recognized guidelines for antiemesis during concurrent chemoradiotherapy (CCRT) for cervical cancer (CC) and nasopharyngeal cancer (NPC) until now. The study was designed to assess the efficacy and safety of fosaprepitant combined with tropisetron and dexamethasone in preventing nausea and vomiting during 5 weeks of fractionated radiotherapy and concomitant weekly low-dose cisplatin chemotherapy in patients with CC or NPC. METHODS: Patients with CC or NPC were scheduled to receive fractionated radiotherapy and weekly cisplatin (25-40 mg/m2) chemotherapy for at least 5 weeks. Patients stratified by tumor type and induction chemotherapy were 1:1 randomly assigned to receive fosaprepitant, tropisetron, and dexamethasone or tropisetron plus dexamethasone as an antiemetic regimen. Efficacy was assessed primarily by the cumulative incidence of emesis after 5 weeks of treatment, and safety by adverse events (AEs). RESULTS: Between July 2020 and July 2022, 116 patients consented to the study of whom 103 were included in this interim analysis (fosaprepitant group [N = 52] vs control group [N = 51]). The cumulative incidence of emesis at 5 weeks (competing risk analysis) was 25% (95% CI 14.2-37.4) for the fosaprepitant group compared with 59% (95% CI 43.9-71.0) for the control group. There was a significantly lower cumulative risk of emesis in the fosaprepitant group (HR 0.35 [95% CI 0.19-0.64]; p < 0.001). Fosaprepitant was well tolerated as the incidences of adverse events in the two groups were comparable. CONCLUSION: The addition of fosaprepitant to tropisetron plus dexamethasone significantly reduced the risk of nausea and vomiting during 5 weeks of CCRT in patients with CC or NPC, and fosaprepitant was well tolerated. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov on October 3, 2022, number NCT05564286.

The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep.

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.

Dietary Inflammatory Index and All-Cause Mortality in Older Adults with Hypertension: Results from NHANES.

Both diet and inflammation are strongly associated with hypertension. However, the relationship between the dietary inflammatory index (DII) and the prognosis of hypertensive patients over 65 years of age is unclear. The objective of this study is to investigate the correlation between DII and all-cause mortality in older adults with hypertension. Data were obtained from the 2011−2018 National Health and Nutrition Examination Survey (NHANES) and followed for survival through December 31, 2019. DII was calculated by the 24 h dietary history interview. Cox proportional hazards models were used to investigate the associations. A total of 2531 participants were finally included. During a median follow-up of 4.33 years, 471 participants were determined as all-cause mortality. After adjusting for confounding factors, DII was positively correlated with the risk of all-cause mortality (HR = 1.08, 95% CI = 1.01−1.16). Compared with the anti-inflammatory diet group (DII < 0), the pro-inflammatory diet group (DII > 0) had a 54% increased risk of all-cause death (HR = 1.54, 95% CI = 1.13−2.10). The results were robust in subgroup and sensitivity analyses. DII was positively correlated with the all-cause mortality of elderly hypertensive patients. The results provided an aid to dietary evaluation in the nonpharmacologic management of hypertension.

Association of systemic immune inflammatory index with all-cause and cause-specific mortality in hypertensive individuals: Results from NHANES.

Background: The relationship between the systemic immune inflammatory index (SII) and the prognosis of hypertensive patients is unclear. This study aims to explore the association of SII with all-cause and cause-specific mortality in patients with hypertension. Methods: This study included 8524 adults with hypertension from the National Health and Nutritional Examination Surveys (NHANES) 2011-2018, and followed for survival through December 31, 2019. Cox proportional hazards models were used to investigate the associations between SII and mortality from all causes, cardiovascular disease (CVD), and cancer. Restricted cubic spline, piecewise linear regression, subgroup and sensitivity analyses were also used. Results: During a median follow-up of 4.58 years, 872 all-cause deaths occurred. After adjusting for covariates, higher SII was significantly associated with an elevated risk of CVD mortality. There was a 102% increased risk of CVD mortality per one-unit increment in natural log-transformed SII (lnSII) (P < 0.001). Consistent results were also observed when SII was examined as categorical variable (quartiles). The associations of SII with all-cause and cancer mortality were detected as U-shaped with threshold values of 5.97 and 6.18 for lnSII respectively. Below thresholds, higher SII was significantly associated with lower all-cause mortality (HR=0.79, 95%CI=0.64-0.97) and cancer mortality (HR=0.73, 95%CI=0.53-1.00). Above thresholds, SII was significantly positive associated with all-cause mortality (HR=1.93, 95%CI=1.55-2.40) and cancer mortality (HR=1.93, 95%CI=1.22-3.05). The results were robust in subgroup and sensitivity analyses. Conclusion: Higher SII (either as a continuous or categorical variable) were significantly associated with a higher risk of CVD mortality. The U-shaped associations were observed between SII and all-cause and cancer mortality.

Chronic modafinil therapy ameliorates depressive-like behavior, spatial memory and hippocampal plasticity impairments, and sleep-wake changes in a surgical mouse model of menopause.

Depression, cognitive deficits, and sleep disturbances are common and often severe in menopausal women. Hormone replacement cannot effectively alleviate these symptoms and sometimes elicits life-threatening adverse reactions. Exploring effective therapies to target psychological problems is urgently needed. In this work, we developed a mouse model of menopause by bilateral ovariectomies (OVXs) and investigated whether menopausal mental symptoms can be ameliorated by psychostimulant modafinil (MOD) as well as explored the underlying mechanisms. At ~3 weeks after OVXs, mice got daily intraperitoneal administrations of MOD at the beginning of the active phase. Several behavioral tests and electroencephalogram (EEG) recordings were conducted. Electrophysiological and immunohistochemical experiments were carried out to evaluate the synaptic plasticity and neurogenesis, respectively. We found that chronic MOD administration in OVX mice significantly decreased immobility time. The spatial memory performance of OVX mice improved significantly in response to MOD administration in the Morris water-maze test. The OVX mice were characterized by an attenuation of hippocampal synaptic transmission and synaptic long-term potentiation and had fewer 5-ethynyl-2'-deoxyuridine-labeled cells in the dentate gyrus, which were restored after MOD administration. Antagonists of dopamine D1 and D2 receptors and GABAA receptor agonists were involved in MOD-exerted anti-depressant actions and augments of hippocampal neurogenesis in OVX mice. Moreover, night-dosed MOD therapy significantly promoted the night-time delta-band EEG power during wakefulness and the day-time rapid eye movement sleep amount, which were significantly reduced by OVXs. Collectively, these findings suggest that MOD is a promising therapeutic candidate for menopausal women.

The Rostromedial Tegmental Nucleus: Anatomical Studies and Roles in Sleep and Substance Addictions in Rats and Mice.

The rostromedial tegmental nucleus (RMTg), a brake of the dopamine system, is specifically activated by aversive stimuli, such as foot shock. It is principally composed of gamma-aminobutyric acid neurons. However, there is no exact location of the RMTg on the brain stereotaxic atlas. The RMTg can be defined by c-Fos staining elicited by psychostimulants, the position of retrograde-labeled neurons stained by injections into the ventral tegmental area (VTA), the terminal field formed by axons from the lateral habenula, and some molecular markers identified as specifically expressed in the RMTg such as FoxP1. The RMTg receives a broad range of inputs and produces diverse outputs, which indicates that the RMTg has multiple functions. First, the RMTg plays an essential role for non-rapid eye movement sleep. Additionally, the RMTg serves a vital role in response to addiction. Opiates increase the firing rates of dopaminergic neurons in the VTA by acting on µ-opioid receptors on RMTg neurons and their terminals inside the VTA. In this review, we summarize the recent research advances on the anatomical location of the RMTg in rats and mice, its projections, and its regulation of sleep-wake behavior and addiction.

Does Immigrant Generation Matter? Re-examining the Ethnic Density Effects on Mental Health of Ethnic Minorities in Britain.

Objectives: In this study, we extend previous research by re-examining the ethnic density effects on mental health of British ethnic minorities and exploring how the relationship varies across generations at a lower geographic scale Lower Super Output Areas (official census geographical classification designed for the consistent reporting of local statistics). Methods: We used random intercept logistic multilevel models to analyze the second wave (2010-2011) of the United Kingdom Household Longitudinal Study (UKHLS). Results: The results show that after controlling for neighborhood deprivation, respondents' socio-demographic characteristics, duration of stay in a neighborhood and moving preference, ethnic concentration has a detrimental effect on mental health for Pakistanis, Bangladeshis, black Caribbeans and black Africans. Moreover, the results show that the detrimental effects are particularly pronounced for the first-generation Pakistanis, Bangladeshis and Indians compared to their second-generation counterparts. Conclusions: Policy interventions to ameliorate ethnic disadvantages in mental health may need to be more targeted to first-generation South Asian minorities living in ethnically clustered areas, and that previous research overlooking migration generation may conceal important internal differences within British ethnic minorities.

Differential diagnosis of Helicobacter pylori-associated gastritis with the linked-color imaging score.

BACKGROUND: Helicobacter pylori (H. pylori) infection in gastric mucosa is the main risk factor for gastric cancer. The purpose of this study was to assess the value of the linked-color imaging (LCI) score for the identification of H. pylori-associated gastritis. METHODS: A total of 358 patients were enrolled in the study. H. pylori was positive in 127 cases and negative in 231 cases. Redness of fundus glands, granular erosion, purple mucus (+) and mucus lake turbidity were investigated by the LCI mode of endoscopy. Logistic regression was used to screen the observation indexes and their relative partial regression coefficients, which were helpful for the differential diagnosis of H. pylori infection. Then, each observation index was scored according to the partial regression coefficient. RESULTS: Using a total scores of 3.5 as the cut-off value, the sensitivity and specificity were 83.8% and 99.5%, respectively, for the differential diagnosis of H. pylori gastritis. The area under the curve was 95.3%. CONCLUSIONS: The LCI score showed high sensitivity and specificity for the differential diagnosis of H. pylori-associated gastritis and is an effective method for identifying H. pylori infection in gastric mucosa.

Crosstalk network among multiple inflammatory mediators in liver fibrosis.

Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.

[Construction of VEGF recombinant plasmid pcDNA/V and its expression in model rats with acute myocardial ischemia].

The cDNA encoding human Vascular Endothelial Growth Factor 165 (VEGF165) was amplified using RT-PCR from human tonsil tissue and cloned into eukaryotic expression vector pcDNA3.1 (+). The recombinant plasmid pcDNA/V was transferred into 293 cells mediated by liposome and the cells stably expressing VEGF were selected under the pressure of G418. ELISA and Western blotting demonstrated that the eukaryotic expression vector pcDNA/V was successfully constructed and its corresponding protein could be expressed efficiently in vitro. Chick Charioallantoic Membrane (CAM) bioassay showed that recombinant protein has biological activity of hVEGF. Model rats with acute myocardial ischemia were used to further study the expression of VEGFin vivo. The model rats were divided randomly into three groups: control group, pcDNA3.1 (+) group and pcDNA/V group. 50microL naked plasmid DNA or saline was intramyocardially injected at three sites into the border zone of infarction. The hearts of rats were excised and fixed histologically, then the infarction sizes were studied by immunohistochemical staining and electron microscope after four weeks. Immunohistochemical staining for VEGF appeared to be negative in control and pcDNA3.1 (+) groups. In pcDNA/V group, myocardial cells in infarction border zone showed positive staining for VEGF in cytoplasm. Ultrastructural anaylsis showed that there were visible hyperplasia of vascular endothilium in pcDNA/V group. The control and pcDNA3.1 (+) groups showed less capillary hyperplasia. In this study, VEGF165 gene was successfully cloned and its protein expressed in vitro and in vivo was of bioactivity, which provides a basis for the further study of biological functions of human VEGF.