A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis.

BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. TRIAL REGISTRATION: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

The correlation between expression of synuclein-gamma, glucose transporter-1, and survival outcomes in endometrioid endometrial carcinoma.

PURPOSE: To evaluate the correlation between immunohistochemical expression of synuclein-gamma, glucose transporter-1, and survival outcomes in endometrioid endometrial carcinoma. MATERIALS AND METHODS: A tissue microarray was constructed using formalinfixed, paraffin-embedded tissue that included 23 early and 18 advanced cases. The intensity and area of the immunohistochemical reactions were evaluated using the semi-quantitative scoring system. RESULTS: Synuclein-y expression was higher in the advanced stage, although it was not statistically significant (p = 0.51). Glucose transporter-1 was overexpressed in the advanced stage (p = 0.01). Synuclein-gamma (score = 0 vs > 0) and glucose transporter-1 (score < or = 7 vs > 7) did not show any differences in overall survival (p = 0.54, p = 0.48) and disease-free survival (p = 0.61, p = 0.14). CONCLUSION: In this study the expression of synuclein-y and glucose transporter-1 were not considered to be a prognostic factor and were not related with survival outcomes in endometrioid endometrial carcinoma.

Use of red palm oil in local snacks can increase intake of provitamin A carotenoids in young aborigines children: a Malaysian experience.

INTRODUCTION: Carotenoid-rich red palm oil (RPO)-based snacks have been provided to children in impoverished communities to improve their vitamin A status. The non-availabilty of information on the acceptability of RPO-based snacks by Malaysian aborigines (Orang Asli) children forms the basis of this study. METHODS: Twenty-one Orang Asli children, majority of whom had normal body mass index for age (BMI-for-age) and aged 4.73 +/- 0.92 years in Sungai Tekir, Negeri Sembilan were provided with three freshly-prepared snacks (springroll, curry puff or doughnut) each containing one teaspoon or 5 ml of RPO per serving, on separate mornings. On the fourth morning, one serving each of all 3 different snacks was provided together on a plate to every child for consumption and preference for the snacks recorded. The children's habitual vitamin A intakes were assessed by a semi-quantitative food frequency questionnaire (FFQ) and carotenoid retention tests for the prepared snacks were performed by column chromatography. RESULTS: Fifty-four percent of the children did not meet their RNI for vitamin A. Based on acceptance criterion of consuming at least one-half serving of the snacks provided, springroll and curry puff recorded 100% acceptability while doughnut had 82% acceptability. Preference of snack was in the order, springroll (47%) > doughtnut (35%) > curry puff (18%), but a Z-test test for proportions showed no statistical significance. Carotenoid retention tests showed great variation between snacks namely, doughnut (100%) > springroll (84%) > curry puff (45%). CONCLUSION: The overall findings indicate that the RPO-based snacks are highly acceptable and can be used to improve the dietary intake of provitamin A carotenoids of Malaysian Orang Asli children.

A case of ovarian endometrioid adenocarcinoma with yolk sac tumor in a 35-year-old woman.

Ovarian yolk sac tumor (YST) is a malignant ovarian neoplasm differentiated from primordial germ cells that occur in young age, while endometrioid carcinoma (ECA) is a müllerian epithelial tumor that usually occurs in older patients. The coexistence of an ovarian ECA and YST component is very rare. Only 12 cases have been reported until now according to a Medline search of the English literatures. We present a case of a simultaneous ECA and a YST component in a 35-year-old woman. Exploratory laparotomy was performed. The parts of both ovaries that showed an endometrioid-like glandular pattern were positive for cytokeratin 7 and negative for AFP, but the YST component was negative for cytokeratin 7 and positive for AFP. After completion of four courses of BEP chemotherapy, two courses of taxane and carboplatin chemotherapy were added. The patient failed to respond and succumbed to the disease after 12 months of follow-up.

Fitz-Hugh-Curtis Syndrome: single centre experiences.

This study was conducted to report 10 cases of Fitz-Hugh-Curtis Syndrome (FHCS) diagnosed with CT and 101 cases of FHCS-like lesion that suggested perihepatitis during laparoscopic surgery. We reviewed retrospectively the images of 3,674 laparoscopies for obstetrical and gynaecological diseases and analysed 10 cases of FHCS diagnosed by clinical patterns and CT. All the 10 cases showed liver capsular enhancement on CT. Among the 3,674 laparoscopies, we found 101 cases (2.7%) with FHCS like lesion. Among them, 23 cases were during laparoscopic procedure for endometriosis, 16 for gynaecological malignant tumours, 16 for benign adnexal diseases excluding endometriosis, 13 for uterine leiomyoma, 7 for pelvic inflammatory disease, 2 had peritoneal tuberculosis and 21 for other gynaecological diseases. Further consideration should be given for the causes of FHCS other than N. gonorrhoeae and C. trachomatis. Because FHCS may represent various clinical phases, other considerations and clinical classifications are necessary for treatment.

Phosphodiesterase inhibition by naloxone augments the inotropic actions of beta-adrenergic stimulation.

BACKGROUND: In a shock state, naloxone generates the cardiovascular pressor effect by displacing the endogenous opiate-like peptide beta-endorphin, resulting in restoration of the normal response to catecholamines. In addition to this opioid antagonistic effect, the non-opiate receptor-mediated effect has also been proposed. The aim of this study was to define the mechanism of non-opiate receptor-mediated action of naloxone. METHODS: In guinea-pig ventricular tissues, cumulative concentration-response curves for isoproterenol as well as for forskolin and 3-isobutylmethylxanthine (IBMX) were obtained by increasing the concentration stepwise. To assess the effect on the phosphodiesterase (PDE), the effects of naloxone on contractile forces induced by isoproterenol (0.05 microM) in the presence of IBMX, cilostamide (a PDE III inhibitor), or rolipram (a PDE IV inhibitor) were observed. Naloxone-induced changes in cAMP production by isoproterenol both in the absence and in the presence of IBMX were measured. Naloxone-induced changes in cAMP production by forskolin in the presence of IBMX were also measured. RESULTS: Naloxone (30 microM) produced a leftward shift of the isoproterenol concentration-response curve (0.01-2 microM) without changing the maximal response. Forskolin (0.5-10 microM) produced a concentration-dependent increase in contractile forces. Naloxone increased the maximal inotropic response of forskolin. Naloxone showed no effect on the IBMX concentration-response curve. In the presence of IBMX (200 microM), naloxone did not alter the contractions evoked by isoproterenol or forskolin. Whereas naloxone increased contractile forces significantly (approximately 25%) more than that of isoproterenol in the presence of rolipram, no alteration of contractile forces in the cilostamide-incubated muscles was observed. Naloxone caused a concentration-related increase of cAMP in the absence of IBMX, but caused no change in its presence. CONCLUSIONS: The enhancement of myocardial contractility by naloxone in the presence of stimulation of adenylyl cyclase activity appears to be mediated by inhibition of PDE, specifically PDE III.

Chest computed tomography before evacuation of hydatidiform mole.

PURPOSE OF INVESTIGATION: To evaluate the usefulness of chest CT for assessing pulmonary micrometastasis in hydatidiform moles. METHOD: We retrospectively evaluated 48 cases diagnosed with hydatidiform moles. We collected and compared data between the pulmonary micrometastatic and non-metastatic groups based on several factors. The non-parametric, Mann-Whitney, Kaplan-Meier and log-rank tests were used. RESULTS: Of 14 patients who underwent chest CT at their initial evaluation, 57% had pulmonary micrometastasis. The time to remission of serum beta-hCG after evacuation, serum beta-hCG before evacuation and the largest diameter of the uterus were statistically significant. Persistent GTD developed in 38% of the metastatic group, but in only 25% of the nonmetastatic group. Micrometastasis was missed by chest X-ray in 64% of 11 patients suspected of having micrometastasis. CONCLUSION: The chest X-ray was suspected of being ineffective in the diagnosis of pulmonary micrometastasis, but the use of chest CT should be considered during the initial evaluation of hydatidiform moles.

Aminoguanidine prevents arterial stiffening in a new rat model of type 2 diabetes.

BACKGROUND: Formation of advanced glycation end-products (AGEs) on collagen within the arterial wall may be responsible for the development of diabetic vascular injury. This study focused on investigating the role of aminoguanidine (AG), an inhibitor of AGE formation, in the prevention of noninsulin-dependent diabetes mellitus (NIDDM)-derived arterial stiffening and cardiac hypertrophy in rats. MATERIALS AND METHODS: The NIDDM was induced in male Wistar rats, which were administered intraperitoneally with 180 mg kg(-1) nicotinamide (NA) 30 min before an intravenous injection of 50 mg kg(-1) streptozotocin (STZ). After induction of diabetes mellitus type 2, animals receiving daily peritoneal injections with 50 mg kg(-1) AG for 8 weeks were compared with the age-matched, untreated, diabetic controls. RESULTS: After exposure to AG, the STZ-NA diabetic rats had improved aortic distensibility, as evidenced by 18.8% reduction of aortic characteristic impedance (P < 0.05). Treatment of the experimental syndrome with AG also resulted in a significant increase in wave transit time (+23.7%, P < 0.05) and a decrease in wave reflection factor (-26.6%, P < 0.05), suggesting that AG may prevent the NIDDM-induced augmentation in systolic load of the left ventricle. Also, the glycation-derived modification on aortic collagen was found to be retarded by AG. The diminished ratio of left ventricular weight to body weight suggested that prevention of the diabetes-related cardiac hypertrophy by AG may correspond to the drug-induced decline in aortic stiffening. CONCLUSIONS: Long-term administration of AG to the STZ-NA diabetic rats imparts significant protection against the NIDDM-derived impairment in vascular dynamics, at least partly through inhibition of the AGE accumulation on collagen in the arterial wall.

Arterial stiffening and cardiac hypertrophy in a new rat model of type 2 diabetes.

BACKGROUND: We determined the effects of NIDDM on haemodynamic parameters describing arterial wall elasticity and cardiac hypertrophy in rats administered streptozotocin (STZ) and nicotinamide (NA), using the aortic impedance analysis. METHODS: Male Wistar rats at 2 months were administered intraperitoneally 180 mg kg(-1) of NA, 30 min before an intravenous injection of 50 mg kg(-1) STZ, to induce type 2 diabetes. The STZ-NA rats were divided into two groups, 4 weeks and 8 weeks after induction of diabetes, and compared with untreated age-matched controls. Pulsatile aortic pressure and flow signals were measured by a high-fidelity pressure sensor and electromagnetic flow probe, respectively, and were then subjected to Fourier transformation for the analysis of aortic input impedance. RESULTS: In each diabetic group, the experimental syndrome was characterized by a moderate and stable hyperglycaemia and a relative deficiency of insulin secretion. However, the 8-week but not the 4-week STZ-NA diabetic rats showed a decrease in cardiac output in the absence of any significant changes in mean aortic pressure, having increased total peripheral resistance. The diabetic syndrome at 8 weeks also contributed to an increase in aortic characteristic impedance, from 1.49 +/- 0.33 (mean +/- SD) to 1.95 +/- 0.28 mmHg s mL(-1) (P < 0.05), suggesting a detriment to the aortic distensibility in NIDDM. Meanwhile, the STZ-NA diabetic animals after 8 weeks had an increased wave reflection factor (0.46 +/- 0.09 vs. 0.61 +/- 0.13, P < 0.05) and decreased wave transit time (25.8 +/- 3.8 vs. 20.6 +/- 2.8 ms, P < 0.05). Ratio of the left ventricular weight to body weight was also enhanced in the 8-week STZ-NA diabetic rats. CONCLUSION: The heavy intensity with early return of the pulse wave reflection may augment systolic load of the left ventricle coupled to the arterial system, leading to cardiac hypertrophy in the rats at 8 weeks after following STZ and NA administration.

Anti-cancer effect of adenovirus p53 on human cervical cancer cell growth in vitro and in vivo.

To evaluate anti-tumor effects of recombinant adenovirus p53, time-course p53, E6 expression, and cell growth inhibition were investigated in vitro and in vivo using cervical cancer cell lines such as CaSki, SiHa, HeLa, HeLaS3, C33A, and HT3. The cell growth inhibition was studied via cell count assay, MTT assay and neutral red assay. After transfecting AdCMVp53 into SiHa cells-xenografted nude mice, the transduction efficiency and anti-tumor effect were investigated for a month. The results showed that adenoviral p53 expression induced significant growth suppression on the cancer cells, in which E6 transcript was strongly repressed, and that the expression of p53 and E6 were remarkably dependent on each cell type. The transduction efficiency was highly maintained in vivo as well as in vitro, and the size of tumor was remarkably decreased in comparison with AdCMVLacZ control. The results suggest that the adenovirus-mediated p53 gene transfection was done very effectively in vitro and in vivo experiment, and the cell growth was suppressed via p53-dependent apoptotic cell death, and that the anti-tumor effect could be related to E6 and p53 expression pattern.

Reperfusion pulmonary edema after pulmonary endarterectomy.

Pulmonary artery thromboendarterectomy is a potentially curative procedure in chronic, major vessel thromboembolic pulmonary hypertension. However, persistent pulmonary hypertension and unrelenting reperfusion edema have serious complications, often requiring prolonged mechanical ventilation. A 50-year-old man who was diagnosed with a thromboembolism in both pulmonary arteries underwent a bilateral pulmonary endarterectomy. He received O2-isoflurane-fentanyl anesthesia. When the lungs were reperfused with CPB weaning, massive hemorrhage occurred in the left lung. After the operation, the patient was taken to the intensive care unit. Mechanical ventilation was performed immediately and then both inhaled NO and i.v. furosemide therapies were administered. The patient was discharged from ICU 15 days postoperation.

Uremic pruritus: roles of parathyroid hormone and substance P.

BACKGROUND: Most patients receiving maintenance hemodialysis have pruritus, but its underlying mechanism remains unknown. Secondary hyperparathyroidism is another common problem in these patients, but its role in uremic pruritus is controversial. Capsaicin can deplete substance P from the peripheral neurons and is known to be effective in the treatment of pain and itching. OBJECTIVE: Our purpose was to evaluate the role of parathyroid hormone (PTH) and substance P in uremic pruritus and to elucidate the underlying mechanisms. METHODS: The study contained two phases. In phase I, we analyzed the correlation between the intensity of itching and serum levels of intact PTH. In phase II, patients with moderate to severe pruritus were placed into two groups: one with high PTH levels and one with low levels. A double-blind, placebo-controlled study of capsaicin 0.025% cream was conducted in phase II. RESULTS: Serum levels of intact PTH did not correlate with the intensity of pruritus and did not significantly change during treatment with capsaicin or placebo. Capsaicin was significantly more effective in alleviating uremic pruritus than the placebo, and no serious side effects were noted. CONCLUSION: Uremic pruritus is not related to PTH. Substance P may act as a neurotransmitter in uremic pruritus and topical capsaicin can be used in the treatment of localized pruritus.

Hemodialysis-related pruritus: a double-blind, placebo-controlled, crossover study of capsaicin 0.025% cream.

Pruritus is a significant symptom among patients receiving hemodialysis. However, its underlying mechanisms remain obscure. Substance P, a neuropeptide, has been implicated in the mediation of pain and some itch sensations. Local application of capsaicin depletes the peripheral neurons of substance P and may block the conduction of pain or pruritus. This study aims to assess the efficacy and safety of capsaicin 0.025% cream in the treatment of hemodialysis-related pruritus and to further explore the underlying pathomechanism. Nineteen hemodialysis patients with idiopathic, moderate (n = 5) to severe (n = 14) pruritus were examined in a double-blind, placebo-controlled, crossover study and 17 of them completed the study. Topical agent of capsaicin or placebo base cream was applied to localized areas of pruritus 4 times a day. The severity of pruritus and treatment-related side effects (cutaneous burning/stinging sensations, dryness, or erythema) were evaluated weekly. The results showed (1) that 14 of 17 patients reported marked relief and 5 of these 14 patients had complete remission of pruritus during capsaicin treatment (Wilcoxon signed-ranks test, 2p < 0.001); (2) capsaicin was significantly more effective than placebo (Mann-Whitney rank sum test, 2p < 0.001) and a prolonged antipruritic effect was observed 8 weeks posttreatment; (3) no serious side effects were noted during the study and (4) there were no significant changes in serum concentrations of albumin, calcium, phosphorus, alkaline phosphatase, or intact parathyroid hormone during the treatment with either capsaicin or placebo. In summary, the present study indicates indirectly that idiopathic pruritus in some patients on maintenance hemodialysis may be transmitted by substance P from the peripheral sensory neurons to the central nervous system. Topical capsaicin with the unique pharmacological effect is demonstrated to markedly improve the pruritus of these patients.

Additive inhibition of RL95-2 endometrial carcinoma cell growth by carboplatin and 1,25 dihydroxyvitamin D3.

Responses of stage III/IV endometrial adenocarcinomas to cytotoxic agents have been partial and of short duration, results which indicate a need for new agents and therapeutic strategies. This study was undertaken to determine the effects of carboplatin and the active metabolite of vitamin D, 1,25 dihydroxyvitamin D3 (calcitriol), on the growth of RL95-2 endometrial carcinoma cells. Carboplatin is a second-generation platinum-based cytotoxic agent. Calcitriol is a biologic agent that has activity against multiple solid tumors, including ovarian carcinomas. Carboplatin inhibited the growth of RL95-2 cells in a concentration-dependent manner with maximal inhibition (78%) at 200 micrograms/ml. Calcitriol also inhibited RL95-2 growth in a concentration-dependent manner. Maximal inhibition (29%) was elicited by 80 nM calcitriol. Addition of 10-50 nM calcitriol to 5-20 micrograms/ml carboplatin resulted in improved growth inhibition. The degree of interaction between carboplatin and calcitriol was assessed using isobolographic analysis and was found to be additive at all drug concentrations and ratios examined. These results suggest that carboplatin and calcitriol each inhibit the growth of RL95-2 endometrial carcinoma cells and that the combination of these two agents acts additively to inhibit the growth of RL95-2 cells. These agents merit further investigation for their utility against endometrial carcinomas.

Combined effects of 1,25-dihydroxyvitamin D3 and platinum drugs on the growth of MCF-7 cells.

The effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and platinum treatments (both singly and combined) on the growth inhibition of MCF-7 cells, an epithelial cell line shown to possess specific receptors for 1,25(OH)2D3, were evaluated. The inhibitory effects of 1,25(OH)2D3 and platinum on MCF-7 cell proliferation in vitro were time and dose related. The data showed that 10 nM and 100 nM 1,25(OH)2D3 inhibited MCF-7 cell growth by 10.8 +/- 2.4% and 34.9 +/- 0.5% (mean +/- SE), respectively. The degrees of growth inhibition induced by 0.2 to 200 micrograms/ml of cis-diammine-1,1-cyclobutane dicarboxylatoplatinum(II) (carboplatin) were slightly less than those induced by 0.02 to 20 micrograms/ml of cis-diamminedichloroplatinum(II) (cisplatin). The combined administration of 10 nM and 100 nM 1,25(OH)2D3 with either carboplatin (200 to 0.2 micrograms/ml) or cisplatin (20 to 0.02 micrograms/ml) was evaluated. Addition of 1,25(OH)2D3 to the platinum resulted in marginal to marked enhancement of growth inhibition over that observed with either platinum alone. The strength of these interactions varied inversely with the dose of the platinum drugs. Evaluation of drug interactions with isobolograms showed that at near-serum levels, carboplatin or cisplatin interacted synergistically with 1,25(OH)2D3 to inhibit MCF-7 cell growth. Our findings suggest potential usefulness in combining 1,25(OH)2D3, a biological modifier, with cytotoxic agents for the treatment of malignant disease.