Development and Validation of a Nomogram to Predict Frailty Progression in Nonfrail Chinese Community-Living Older Adults.

OBJECTIVE: Frailty state progression is common among older adults, so it is necessary to identify predictors to implement individualized interventions. We aimed to develop and validate a nomogram to predict frailty progression in community-living older adults. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 3170 Chinese community-living people aged ≥60 years were randomly assigned to a training set or validation set at a ratio of 6:4. METHODS: Candidate predictors (demographic, lifestyle, and medical characteristics) were used to predict frailty state progression as measured with the Fried frailty phenotype at a 4-year follow-up, and multivariate logistic regression analysis was conducted to develop a nomogram, which was validated internally with 1000 bootstrap resamples and externally with the use of a validation set. The C index and calibration plot were used to assess discrimination and calibration of the nomogram, respectively. RESULTS: After a follow-up period of 4 years, 64.1% (917/1430) of the participants in the robust group and 26.0% (453/1740) in the prefrail group experienced frailty progression, which included 9.1% and 21.0%, respectively, who progressed to frailty. Predictors in the final nomogram were age, marital status, physical exercise, baseline frailty state, and diabetes. Based on this nomogram, an online calculator was also developed for easy use. The discriminative ability was good in the training set (C index = 0.861) and was validated using both the internal bootstrap method (C index = 0.861) and an external validation set (C index = 0.853). The calibration plots showed good agreement in both the training and validation sets. CONCLUSIONS AND IMPLICATIONS: An easy-to-use nomogram was developed with good apparent performance using 5 readily available variables to help physicians and public health practitioners to identify older adults at high risk for frailty progression and implement medical interventions.

Prognostic value of EUS combined with MSCT in predicting the recurrence and metastasis of patients with gastric cancer.

OBJECTIVE: This study aims to explore the prognostic value of endoscopic ultrasonography combined with multi-slice spiral computed tomography in predicting the recurrence and metastasis of gastric cancer, as well as investigate the correlation of fragile histidine triad protein expression with the tumor-node-metastasis stage of gastric cancer patients. METHODS: A total of 81 gastric cancer patients were selected in our study. All patients were examined by endoscopic ultrasonography and multi-slice spiral computed tomography before operation, and gastric cancer tissues and adjacent normal tissues were obtained after operation. Immunohistochemistry was performed to detect fragile histidine triad expression. All patients were followed up for 3 years after operation. Univariate and multivariate analysis of risk factors were conducted for the prognosis of gastric cancer patients. RESULTS: Endoscopic ultrasonography combined with multi-slice spiral computed tomography could increase the accuracy of preoperative tumor-node-metastasis stage of gastric cancer patients. In gastric cancer tissues, fragile histidine triad expression was mostly weakly positive with a positive rate of 60.5%. In gastric cancer adjacent normal tissues, the positive fragile histidine triad expression was mostly moderate with a positive rate of 79.0%. The fragile histidine triad expression was negatively correlated with tumor-node-metastasis stage of gastric cancer patients. The fragile histidine triad expression decreased along with the increase of T-stage, N-stage and M-stage of gastric cancer patients. Univariate and multivariate analysis showed that T-stage and N-stage were risk factors for the recurrence/metastasis and 3-year mortality of gastric cancer patients, while fragile histidine triad expression was a protective factor. CONCLUSION: Our study demonstrated that endoscopic ultrasonography combined with multi-slice spiral computed tomography may be more accurate in assessing the preoperative tumor-node-metastasis stage of gastric cancer patients.

The effects of general anesthesia on whole body and regional pharmacokinetics of local anesthetics at toxic doses.

BACKGROUND: Local anesthetic toxicity is often studied experimentally in anesthetized subjects, but clinical toxicity usually occurs in conscious patients. In this study, we determined the influence of general anesthesia on the pharmacokinetics of six local anesthetics administered i.v. at approximately the highest recommended doses. METHODS: Chronically instrumented ewes (approximately 45-50 kg, n = 18) were infused over 3 min with (base doses as HCl salts) bupivacaine (100 mg), levobupivacaine (125 mg), ropivacaine (150 mg), lidocaine (350 mg), mepivacaine (350 mg), or prilocaine (350 mg), on separate occasions when conscious and halothane anesthetized. Serial arterial, heart, and brain venous blood drug concentrations were measured by achiral/chiral high-performance liquid chromatography, as relevant. Whole body pharmacokinetics were assessed by noncompartmental analysis; heart and brain pharmacokinetics were assessed by mass balance. Drug blood binding, in the absence and presence of halothane, was assessed by equilibrium dialysis in vitro. RESULTS: Blood local anesthetic concentrations were doubled with anesthesia because of decreased whole body distribution and clearance (respectively, to 33% and 52% of values when conscious). Heart and brain net drug uptake were greater under anesthesia, reflecting slower efflux from both regions. Clearances of R-bupivacaine > S-bupivacaine and R-prilocaine > S-prilocaine, but, mepivacaine clearance was not enantioselective. Halothane did not influence blood binding of the local anesthetics. CONCLUSIONS: General anesthesia significantly changed whole body and regional pharmacokinetics of each local anesthetic as well as the systemic effects. General anesthesia is thus an important but frequently overlooked factor in studies of local anesthetic toxicity.

The effects of general anesthesia on the central nervous and cardiovascular system toxicity of local anesthetics.

BACKGROUND: Local anesthetic toxicity is often studied experimentally in acutely prepared, anesthetized laboratory animals. We determined the influence of halothane/O(2) anesthesia on cardiovascular and central nervous system (CNS) toxic responses to six amide-type local anesthetics administered i.v.. METHODS: Behavioral, cardiovascular, and pharmacokinetic responses were determined in previously instrumented ewes (approximately 45-50 kg, n = 18), on separate occasions when conscious and anesthetized, to bupivacaine (100 mg), levobupivacaine (125 mg), ropivacaine (150 mg), lidocaine (350 mg), mepivacaine (350 mg), prilocaine (350 mg), and saline (control) infused i.v. over 3 min. RESULTS: The local anesthetics caused convulsions in conscious sheep, but no overt CNS effects in anesthetized sheep. Negative inotropy and slight bradycardia without changes in arterial blood pressure occurred initially in conscious sheep, followed by positive inotropy, tachycardia, and hypertension at the abrupt onset of CNS excitotoxicity, along with widening of QRS complexes. Fatal cardiac arrhythmias occurred in, respectively, 3 of 11, 2 of 12, and 2 of 13 conscious sheep infused with bupivacaine, levobupivacaine, and ropivacaine; in 1 of 9 with prilocaine, electromechanical dissociation (followed by polymorphic ventricular tachycardia) caused death. In anesthetized sheep, cardiovascular depression, preexisting from the general anesthesia, was exacerbated by all local anesthetics, and increased QRS width was prolonged; concurrent blood local anesthetic concentrations were doubled. Nevertheless, all anesthetized animals survived. CONCLUSIONS: General anesthesia produced physiological perturbations, exacerbated local anesthetic-induced cardiovascular depression, and changed the pharmacokinetics of toxic doses of local anesthetics. However, cardiovascular fatalities from local anesthetics occurred only in conscious animals.

Enhancement of cisplatin efficacy by thalidomide in a 9L rat gliosarcoma model.

With the aim of improving the treatment of glioblastoma multiforme, we investigated the potential of thalidomide to enhance the effectiveness of cisplatin chemotherapy in a rat glioma model. Female F344 rats were implanted with 9L gliosarcoma tumors either intracranially or subcutaneously and treated with 1 mg/kg cisplatin injected i.p. or with 1% thalidomide in the food or with these treatments combined. Cisplatin in combination with thalidomide significantly reduced both the subcutaneous tumor volume at 30 days to 22 +/- 5% (mean +/- SEM, P < 0.001) and the intracranial tumor volume at 18 days to 44 +/- 15% (P < 0.05) of that with cisplatin alone. Thalidomide selectively increased the cisplatin concentration 10-fold in intracranial tumors (P < 0.05) and 2-fold in the subcutaneous tumors (P < 0.05) without increasing its concentration in major organs including brain and kidney. Cisplatin combined with thalidomide caused a significant decrease in vascular endothelial growth factor (VEGF) levels by 73% in intracranial tumors (P < 0.05) and by 50% in subcutaneous tumors (P < 0.05) and caused the level of active hepatic growth factor (a-HGF) to double in both the subcutaneous and intracranial tumors (P < 0.05), suggesting this treatment altered the vasculature in these tumors. We conclude the increased efficacy of cisplatin in the presence of thalidomide was due to the selective increase in cisplatin concentration within the tumors and speculate that this is the result of thalidomide or the cisplatin/thalidomide combination, selectively altering the tumor vasculature. Based on the selective effects of thalidomide on tumor cisplatin concentrations and the resulting increase in efficacy, thalidomide may also increase the efficacy of other drugs that are presently considered ineffective against glioma.

Enantioselectivity of thalidomide serum and tissue concentrations in a rat glioma model and effects of combination treatment with cisplatin and BCNU.

Thalidomide is currently under evaluation as an anti-angiogenic agent in cancer treatment, alone and in combination with cytotoxic agents. Thalidomide is a racemate with known pharmacologic and pharmacokinetic enantioselectivity. In a previous study with thalidomide combination chemotherapy, we found evidence of anti-tumour synergy. In this study, we examined whether the synergy involved altered pharmacokinetics of thalidomide enantiomers. Adult female F344 rats were implanted with 9L gliosarcoma tumours intracranially, subcutaneously (flank), or both. Effectiveness of oral thalidomide alone, and with intraperitoneal BCNU or cisplatin combination chemotherapy, was assessed after several weeks treatment. Presumed pseudo steady-state serum, tumour and other tissues, collected after treatment, were assayed for R- and S-thalidomide by chiral HPLC. Both serum and tissue concentrations of R-thalidomide were 40-50% greater than those of S-thalidomide. Co-administration of BCNU or cisplatin with thalidomide did not alter the concentration enantioselectivity. Poor correlation of concentration with subcutaneous anti-tumour effect was found for individual treatments, and with all treatments for intracranial tumours. The consistency of the enantiomer concentration ratios across treatments strongly suggests that the favourable antitumour outcomes from interactions between thalidomide and the cytotoxic agents BCNU and cisplatin did not have altered enantioselectivity of thalidomide pharmacokinetics as their basis.

Thalidomide enantiomers: determination in biological samples by HPLC and vancomycin-CSP.

Thalidomide is a racemate with potentially different pharmacokinetics and pharmacodynamics of the component (+)-(R)- and (-)-(S)-thalidomide enantiomers. As part of a project on the adjunctive effects of thalidomide and cytotoxic agents, a method for the chiral separation and quantitation of thalidomide was developed and validated. Thalidomide in relevant serum and tissue homogenate samples was stabilized by buffering with an equal volume of citrate-phosphate buffer (pH 2, 0.2M), and stored at -80 degrees C pending assay. The thalidomide enantiomers, extracted from the samples with diethyl ether, were well separated on a chiral HPLC column of vancomycin stationary phase and a mobile phase of 14% acetonitrile in 20 mM ammonium formate adjusted to pH 5.4; their concentrations were determined with phenacetin as internal standard at 220 nm detection. Over a thalidomide concentration range of 0.1-20 microg/ml, assay precision was 1-5% (CV) for both enantiomers, and calibration curves were linear with all correlation coefficients being >0.99. The estimated limit of quantification for both enantiomers was 0.05 microg/ml with 0.2-0.6 ml serum samples. Thalidomide in rat and human serum, acidified and stored as described above, was found to be chemically and chirally stable over 1 year. The method has been successfully applied to serum samples from human patients undergoing thalidomide treatment for mesothelioma, and to serum, blood and tissue samples from a laboratory rodent model using transplanted 9l gliosarcoma. Enantioselectivity in thalidomide pharmacokinetics has been found, thereby reinforcing the need for considering the relevance of chirality in thalidomide pharmacology.