Anti-emetic drugs such as the tachykinin NK
1 receptor antagonists are useful to control emesis induced by diverse challenges. Evidence suggests pungent capsaicin-like TRPV1 activators also have ...broad inhibitory anti-emetic activity. However, pungent compounds are associated with undesirable effects including adverse actions on the cardiovascular system and on temperature homeostasis. In the present investigations using the ferret, we examine if the non-pungent vanilloid, olvanil, has useful anti-emetic properties without adversely affecting behaviour, blood pressure or temperature control. Olvanil (0.05–5 mg/kg, s.c.) was compared to the pungent vanilloid, resiniferatoxin (RTX; 0.1 mg/kg, s.c.), and to the anandamide reuptake inhibitor, AM404 (10 mg/kg, s.c.), for a potential to inhibit emesis induced by apomorphine (0.25 mg/kg, s.c.), copper sulphate (50 mg/kg, intragastric), and cisplatin (10 mg/kg, i.p.). Changes in blood pressure and temperature were also recorded using radiotelemetry implants.
In peripheral administration studies, RTX caused transient hypertension, hypothermia and reduced food and water intake, but also significantly inhibited emesis induced by apomorphine, copper sulphate, or cisplatin. Olvanil did not have a similar adverse profile, and antagonised apomorphine- and cisplatin-induced emesis but not that induced by copper sulphate. AM404 reduced only emesis induced by cisplatin without affecting other parameters measured. Following intracerebral administration only olvanil antagonised cisplatin-induced emesis, but this was associated with transient hypothermia. In conclusion, olvanil demonstrated clear anti-emetic activity in the absence of overt cardiovascular, homeostatic, or behavioural effects associated with the pungent vanilloid, RTX. Our studies indicate that non-pungent vanilloids may have a useful spectrum of anti-emetic properties via central and/or peripheral mechanisms after peripheral administration.
Summary Objective To investigate the safe displacement range of the foramen of Monro (FM) during single burr hole rigid endoscopic third ventriculostomy (ETV) and endoscopic tumor biopsy (ETB). ...Methods Eleven patients who received ETV/ETB for third ventricular and pineal region tumor were reviewed. The burr-hole location, the size, and the virtual displacement of FM were measured using neuronavigation software. Results Hydrocephalus was resolved, and no subsequent cerebrospinal fluid (CSF) shunting was required in all cases. Histological diagnosis was established in 11 patients. Ten cases received instrumental cognitive and memory assessment postoperatively. The results were within the normal range for eight cases. The mean burr-hole location was 1.7 cm anterior to coronal suture and 3 cm from the midline. The mean diameters of FM measured on the axial, coronal, sagittal, and views were 5.7, 7.8, and 5.6 mm, respectively. The mean virtual displacements of the FM were 1.9 ± 2.0 mm (range = 0–4.8) for ETV and 2.4 ± 2.1 mm (range = 0–5.5) for ETB. The maximum displacements were 4.8 mm anteriorly for ETV and 5.5 mm posteriorly for ETB. Conclusion Single burr hole rigid ETV/ETB is likely to be safe within maximum FM displacements of 4.8 mm anterior for ETV and 5.5 mm posterior for ETB. Preoperative trajectory planning using neuronavigation software is recommended.
Patients with metastatic esophageal squamous cell carcinoma (ESCC) have a grave prognosis with limited life expectancy. Here, a phase II clinical trial was conducted to investigate the effect of ...Andrographis paniculata (AP) on the palliative care of patients with metastatic ESCC. Patients with metastatic or locally advanced ESCC deemed unfit for surgery, and who have already completed palliative chemotherapy or chemoradiotherapy or are not fit for these treatments, were recruited. These patients were prescribed AP concentrated granules for 4 months. They also received clinical and quality of life assessments for clinical response, as well as positron emission tomography–computed tomography at 3 and 6 months after AP treatment for the assessment of tumor volume. Furthermore, the change in gut microbiota composition after AP treatment was studied. From the results, among the 30 recruited patients, 10 completed the entire course of AP treatment, while 20 received partial AP treatment. Patients who completed the AP treatment achieved significantly longer overall survival periods with the maintenance of the quality of life during the survival period when compared to those who could not complete AP treatment. The treatment effect of AP also contributed to the shift of the overall structure of gut microbiota for ESCC patients towards those of healthy individuals. The significance of this study is the establishment of AP as a safe and effective palliative treatment for patients with squamous cell carcinoma of the esophagus. To the best of our knowledge, this is the first clinical trial of AP water extract in esophageal cancer patients demonstrating its new medicinal use.
Gut microbiota have long attracted the interest of scientists due to their profound impact on the well-being of animals. A non-random pattern of microbial assembly that results in a parallelism ...between host phylogeny and microbial similarity is described as phylosymbiosis. Phylosymbiosis has been consistently observed in different clades of animal hosts, but there have been no studies on crustaceans. In this study, we investigated whether host phylogeny has an impact on the gut microbiota assemblages in decapod shrimps. We examined the gut microbial communities in 20 shrimp species from three families inhabiting distinct environments, using metabarcoding analyses of the V1–V3 hypervariable region of the 16S rRNA gene. Gut microbial communities varied within each shrimp group but were generally dominated by Proteobacteria. A prevalent phylosymbiotic pattern in shrimps was evidenced for the first time by the observations of (1) the distinguishability of microbial communities among species within each group, (2) a significantly lower intraspecific than interspecific gut microbial beta diversity across shrimp groups, (3) topological congruence between host phylogenetic trees and gut microbiota dendrograms, and (4) a correlation between host genetic distances and microbial dissimilarities. Consistent signals of phylosymbiosis were observed across all groups in dendrograms based on the unweighted UniFrac distances at 99% operational taxonomic units (OTUs) level and in Mantel tests based on the weighted UniFrac distances based on 97% OTUs and amplicon sequence variants. Penaeids exhibited phylosymbiosis in most tests, while phylosymbiotic signals in atyids and pandalids were only detected in fewer than half of the tests. A weak phylogenetic signal was detected in the predicted functions of the penaeid gut microbiota. However, the functional diversities of the two caridean groups were not significantly related to host phylogeny. Our observations of a parallelism in the taxonomy of the gut microbiota with host phylogeny for all shrimp groups examined and in the predicted functions for the penaeid shrimps indicate a tight host-microbial relationship during evolution.
Background:
Pure oral arsenic trioxide (oral-ATO) solution (Arsenol ®) was first formulated in Hong Kong. It achieves a bioavailability comparable with that of intravenous ATO (i.v.-ATO). Oral-ATO ...combined with all-trans retinoic acid (ATRA) and ascorbic acid (the AAA regimen) combined with chemotherapy is highly efficacious in relapsed and newly-diagnosed APL. To reduce treatment-related toxicities and long-term risks of second primary cancers, a chemotherapy-free approach is increasingly favoured.
Aims:
The objectives of this prospective multicentre study in newly diagnosed APL patients were: 1. to evaluate the efficacy and safety of an entirely oral AAA-induction in a risk-adapted strategy; 2. to evaluate the molecular responses during oral-AAA-based induction/consolidation/maintenance.
Methods:
Newly-diagnosed APL patients were stratified by presentation leucocyte count into standard-risk (≤ 10 x 10 9/L) and high-risk (> 10 x 10 9/L) groups. Standard-risk patients and high-risk patients ≥ 65 years old received AAA induction comprising oral-ATO (Arsenol ®, Jacobson Pharma Corporation, Hong Kong) (10 mg/day, or 0.16 mg/kg in patients < 18 years old, days 1-42), ATRA (45 mg/m 2/day, or 25 mg/m 2/day in patients <18 years old, in 2 divided doses, days 1-42), and oral ascorbic acid (1 g/day, or 15mg/kg/day in patients <18 years old, days 1-42). High-risk patients < 65 years old received in addition daunorubicin (50 mg/m 2/day i.v. for 3 days). On reaching first complete remission (CR1), consolidation with AAA (days 1-14) every 28 days for 2 cycles was given, followed by maintenance with AAA (days 1-14) every 8 weeks for 12 cycles. Real-time quantitative polymerase chain reaction for PML:: RARA with a sensitivity of 10 -5 was performed (weekly during induction, every 4 weeks during consolidation, every 8 weeks during maintenance and thereafter every 12 weeks for 2 years). For molecular response, the normalized copy number ratio was defined as PML::RARA copy number/ ABL copy number. Primary outcomes were overall survival (OS, time from presentation to death or last follow-up), and relapse-free survival (RFS, time from CR1 to molecular or haematological relapse, death or last follow-up), and safety (according to the Common Toxicity Criteria for Adverse Events (AE) version 5.0). The secondary outcome was molecular response. Data were censored on July 22, 2023.
Results:
Between January 1, 2018 to July 22, 2023, 5 paediatric/adolescent patients (male, N=2; female, N=3) at a median age of 12 (3-15) years and 116 adult (> 18 years old) patients (male, N=47 ; female, N=69) at a median age of 49 (19-91) years were accrued (standard risk: paediatric/adolescent, N=3; adults, N=87; high-risk: paediatric/adolescent, N=2; adults, N=29). Seven patients (all high-risk adults) died at presentation before induction (intracranial haemorrhage, N=6; severe APL differentiation syndrome, DS, with leucocyte >100 x10 9/L, N=1). One-hundred and fourteen patients received oral-AAA-based induction (AAA alone, N=90; AAA+daunorubicin, N=24), all achieving CR1. For PML:: RARA normalized copy number, all treated patients at week 8 achieved a ratio of <0.01; and on completion of AAA maintenance, all evaluable patients (N=56) achieved a ratio of <0.0001. The median follow-up was 29 (IQR: 8-47) months, with 56 patients (49%) having completed 2 years of AAA maintenance. There was only one relapse, occurring in an adult patient 12 months after completion of AAA maintenance. Molecular analysis showed a PML B2 domain A216V mutation that conferred resistance to ATO. One adult patient died of an unrelated gastrointestinal bleeding while in CR1. The 3-year OS was 99.1% (paediatric/adolescent: 100%; adult: 99%). The 3-year RFS was 97.9% (paediatric/adolescent: 100%; adult: 97.9%). The most common non-haematological AEs (all grade 1-2) were transaminitis (N=54, 47.3%) and headache (N=32, 28%) Notably, no cardiotoxicity (arrhythmias/cardiac failure) was observed. APL-DS occurred in 67 patients (58.7%) after initiation of AAA, all responding fully to intravenous dexamethasone. There were no treatment discontinuations.
Conclusion:
The use of an entirely oral AAA-based induction in a risk-adapted strategy that minimized chemotherapy was highly effective and safe in newly-diagnosed APL of all risk categories and age groups. Early deaths remained an obstacle to realizing a cure-for-all in APL.
In addition to regulating growth hormone release from the pituitary, ghrelin receptors also influence cell proliferation and apoptosis. By studying mitogen-activated protein kinase activity in human ...embryonic kidney 293 cells over-expressing ghrelin receptors, we aimed to identify the specific cell signalling pathways used by ghrelin receptors, and to determine if the truncated ghrelin receptor polypeptide had any influence on the functional activity of ghrelin receptors. We found that ghrelin activated extracellular signal-regulated kinases 1/2 with an EC50 value of 10nM, and that this response was inhibited by the ghrelin receptor antagonists d-Lys(3)-GHRP-6 and d-Arg1,d-Phe5,d-Trp7,9,Leu11-substance P. Ghrelin had little or no effect on the activity of c-Jun N-terminal kinase, p38 kinase or Akt. Ghrelin appeared to activate extracellular signal-regulated kinases 1/2 through a calcium-independent novel protein kinase C isoform which may utilize diacylglycerol derived from hydrolysis of phosphatidylcholine rather than from phosphatidylinositol. Ghrelin-stimulated extracellular signal-regulated kinases 1/2 activity was independent of transactivation of epidermal growth factor receptors, and even when ghrelin receptor internalization was blocked by concanavalin A or a β-arrestin mutant, there was no decrease in phosphorylated extracellular signal-regulated kinases 1/2, suggesting this is a G protein-dependent process. The truncated ghrelin receptor polypeptide had no effect on ghrelin receptor signalling to extracellular signal-regulated kinases 1/2, but decreased the constitutive activation of phosphatidylinositol-specific phospholipase C by ghrelin receptors. In conclusion, our results suggest that any up-regulation of the truncated ghrelin receptor polypeptide might preferentially attenuate functional activity dependent on the constitutive activation of ghrelin receptors, while leaving ghrelin-dependent signalling unaffected.
Pungent transient receptor potential vanilloid (TRPV1) channel activators have been shown to have broad inhibitory anti-emetic activity against centrally- and peripherally acting challenges but only ...at doses that have adverse effects on the cardiovascular system and on temperature homeostasis. In the present studies, we investigated the anti-emetic potential of the non-pungent TRPV1 activator, olvanil (0.05–5
mg/kg, s.c., 3 times per day, for 3 days) to antagonise the acute and delayed emesis induced by cisplatin (5
mg/kg, i.p.) in ferrets that had been implanted with radiotelemetry devices to enable an analysis of heart rate and temperature. Cisplatin induced an acute (day 1: 48.0
±
18.3 retches
+
vomits) and delayed (day 2: 111.7
±
35.5; day 3: 147.5
±
20.2 retches
+
vomits) emetic response that was associated with reduced food (−98.7% at day 3,
P
<
0.001) and water consumption (−70.2% at day 3,
P
<
0.001) and progressive weight loss (−12.0% at day 3,
P
<
0.001). Olvanil did not prevent either emesis or the weight loss and negative effects on food and water consumption (
P
>
0.05); the effect on food consumption appeared potentiated by a further 21.2% at 0.05
mg/kg (
P
<
0.05) and 19.9% at 0.5
mg/kg (
P
<
0.05). Cisplatin did not alter body temperature (basal: 37.7
±
0.1
°C) or heart rate (basal: 233.7
±
5.5 beats per min (BPM);
P
>
0.05), but hypothermia (−1.6
°C) and increases in locomotor activity (50–90%) were recorded in animals concomitantly treated with olvanil (
P
<
0.05). These data indicate that non-pungent activators as exemplified by olvanil are unlikely to be useful clinically for the control of the gastrointestinal side effects induced by cisplatin.
This study aimed to evaluate the diagnostic utilities of monocyte HLA-DR as an infection marker in the identification of early-onset clinical infection and pneumonia in newborn infants.
Term newborns ...in whom infection was suspected when they were <72 h of age were eligible for enrollment in the study. C-reactive protein (CRP), monocyte HLA-DR and neutrophil CD64 expressions were quantitatively measured at the time of sepsis evaluation (0 h) and 24 h afterwards by flow cytometry and standard laboratory method.
A total of 288 infants with suspected sepsis were investigated, and 93 were found to be clinically infected. There were no significant differences in monocyte HLA-DR expression between the infected, non-infected and control groups at 0 h (median (interquartile range): 13,986 (10,994-18,544), 14,234 (12,045-17,474) and 18,441 (14,250-21,537) antibody phycoerythrin (PE) molecules bound/cell), and between infected and non-infected infants at 24 h (median (interquartile range): 17,772 (12,933-25,167) and 19,406 (14,885-24,225) antibody PE molecules bound/cell). The areas under the receiver operating characteristics (ROC) curves for HLA-DR, CD64 and CRP were 0.52-0.54, 0.88-0.94 and 0.75-0.77, respectively. We were unable to determine an optimal cutoff value for HLA-DR, as the diagnostic utilities of any cutoff point on the ROC curves were unable to satisfy the criteria (i.e. sensitivity and specificity >or=80%) for consideration as an useful diagnostic marker of infection.
Our findings did not support the use of monocyte HLA-DR alone or in combination with other infection markers in the diagnosis of early-onset clinical infection and pneumonia in term newborns.
Aim
Paraoesophageal hernia warrants surgical repair when it becomes symptomatic. Complex definitive surgical repair carries a high risk of complication and morbidity.
Patients and Methods
We present ...a case of paraoesophageal hernia in an elderly woman managed by minimally‐invasive method with laparoscopic‐assisted endoscopic reduction and gastropexy.
Results
The operation was done under general anaesthesia. The intrathoracic oesophagus and stomach were reduced with laparoscopic assistance, and the adhesion with the hernia sac was removed. Gastropexy was performed with two percutaneous endoscopic gastrostomies (PEG), and a feeding jejunostomy was placed via one of the PEG. The patient was initially started on jejunosotmy feeding, and oral feeding was gradually resumed. She was then discharged on postoperative day 20.
Conclusion
In patients who are considered high risk for definitive surgical repair or invasive procedure involving hiatal dissection, endoscopic reduction and fixation with laparoscopic assistance are an acceptable alternative.
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