Computer-aided design of dry powder inhalers using computational fluid dynamics to assess performance

Dry powder inhalers (DPIs) are gaining popularity for the delivery of drugs. A cost effective and efficient delivery device is necessary. Developing new DPIs by modifying an existing device may be the simplest way to improve the performance of the devices. The aim of this research was to produce a new DPIs using computational fluid dynamics (CFD). The new DPIs took advantages of the Cyclohaler® and the Rotahaler®. We chose a combination of the capsule chamber of the Cyclohaler® and the mouthpiece and grid of the Rotahaler®. Computer-aided design models of the devices were created and evaluated using CFD. Prototype models were created and tested with the DPI dispersion experiments. The proposed model 3 device had a high turbulence with a good degree of deagglomeration in the CFD and the experiment data. The %fine particle fraction (FPF) was around 50% at 60?L/min. The mass median aerodynamic diameter was around 2.8–4?μm. The FPF were strongly correlated to the CFD-predicted turbulence and the mechanical impaction parameters. The drug retention in the capsule was only 5–7%. In summary, a simple modification of the Cyclohaler® and Rotahaler® could produce a better performing inhaler using the CFD-assisted design.     

Measurement of xenon diffusing capacity in the rat lung by hyperpolarized 129Xe MRI and dynamic spectroscopy in a single breath-hold.

We used the dual capability of hyperpolarized 129Xe for spectroscopy and imaging to develop new measures of xenon diffusing capacity in the rat lung that (analogously to the diffusing capacity of carbon monoxide or DLCO) are calculated as a product of total lung volume and gas transfer rate constants divided by the pressure gradient. Under conditions of known constant pressure breath-hold, the volume is measured by hyperpolarized 129Xe MRI, and the transfer rate is measured by dynamic spectroscopy. The new quantities (xenon diffusing capacity in lung parenchyma (DLXeLP)), xenon diffusing capacity in RBCs (DLXeRBC), and total lung xenon diffusing capacity (DLXe)) were measured in six normal rats and six rats with lung inflammation induced by instillation of fungal spores of Stachybotrys chartarum. DLXeLP, DLXeRBC, and DLXe were 56 +/- 10 ml/min/mmHg, 64 +/- 35 ml/min/mmHg, and 29 +/- 9 ml/min/mmHg, respectively, for normal rats, and 27 +/- 9 ml/min/mmHg, 42 +/- 27 ml/min/mmHg, and 16 +/- 7 ml/min/mmHg, respectively, for diseased rats. Lung volumes and gas transfer times for LP (TtrLP) were 16 +/- 2 ml and 22 +/- 3 ms, respectively, for normal rats and 12 +/- 2 ml and 35 +/- 8 ms, respectively, for diseased rats. Xenon diffusing capacities may be useful for measuring changes in gas exchange associated with inflammation and other lung diseases.     

细胞间黏附分子-1在实验性自身免疫性脑脊髓炎大鼠中表达的动态变化及作用

目的探讨细胞间黏附分子-1(ICAM-1)在实验性自身免疫性脑脊髓炎(EAE)大鼠中表达的动态变化及其作用。方法分别取免疫后第4、6、8、10、12、14、16、18、20天EAE大鼠脑和脊髓制成石蜡切片,行HE染色和ICAM-1半定量免疫组化分析。结果免疫后第8天ICAM-1表达即出现明显上调,早于临床症状的发生;随免疫后时间的延长,ICAM-1表达呈逐渐增高后缓慢下降的变化趋势,并且与EAE大鼠病情评分呈显著正相关(r=0.57,P=0.003)。结论ICAM-1的表达上调可能在EAE发病中具重要作用。     

Outcome of conservative treatment of primary vesicoureteral reflux in 87 Thai children in a single center

AIM: To evaluate the outcome of primary vesicoureteral reflux (VUR) using conservative treatment. METHODS: Eighty-seven children with primary VUR who had been treated with a conservative medical regimen and monitored through a yearly cystogram were recruited for the study. The study was conducted at the Pediatric Nephrology Clinic in Songklanagarind Hospital, the major tertiary care center in southern Thailand. Statistical analyses using Kaplan-Meier survival curves, chi-squared test, Fisher's exact test and multivariate analysis with Cox regression were performed. RESULTS: The study group consisted of 41 boys and 46 girls, with a total of 133 VUR. The age of the boys was significantly lower than that of the girls (P < 0.001). Resolution of the low grades (grades I-III) of VUR was significantly more frequent than that of the high grades (grades IV-V) (68/95, 72%vs 14/38, 37%; P < 0.001). Using the Kaplan-Meier survival analysis and log-rank test, the resolutions of VUR in boys versus girls, and age <1 years versus >or=1 years were not significantly different (P = 0.2252 and 0.4756, respectively). Low-grade VUR and unilateral VUR had significantly higher probabilities of resolution than high-grade VUR and bilateral VUR, respectively (P = 0.0041 and 0.0467, respectively). Multivariate Cox regression analysis indicated that among low-grade VUR, boys and unilateral VUR had significantly higher probabilities of resolution. Among the high-grade VUR, neither sex nor laterality had a significant effect on the probabilities of VUR resolution. CONCLUSION: This study offers more evidence that children with low-grade VUR have a higher chance of reflux resolution if they are boys and have only unilateral VUR. There is still no good guide for resolution of reflux in children with high-grade VUR.     

Optimal control of a revenue management system with dynamic pricing facing linear demand

This paper considers a dynamic pricing problem over a finite horizon where demand for a product is a time‐varying linear function of price. It is assumed that at the start of the horizon there is a fixed amount of the product available. The decision problem is to determine the optimal price at each time period in order to maximize the total revenue generated from the sale of the product. In order to obtain structural results we formulate the decision problem as an optimal control problem and solve it using Pontryagin's principle. For those problems which are not easily solvable when formulated as an optimal control problem, we present a simple convergent algorithm based on Pontryagin's principle that involves solving a sequence of very small quadratic programming (QP) problems. We also consider the case where the initial inventory of the product is a decision variable. We then analyse the two‐product version of the problem where the linear demand functions are defined in the sense of Bertrand and we again solve the problem using Pontryagin's principle. A special case of the optimal control problem is solved by transforming it into a linear complementarity problem. For the two‐product problem we again present a simple algorithm that involves solving a sequence of small QP problems and also consider the case where the initial inventory levels are decision variables. Copyright © 2006 John Wiley & Sons, Ltd.     

On the Limitations of Therapy Manuals

While the benefits of training manuals can hardly be questioned, they are exceedingly limited in reducing variability attributed to the "therapist factor." We propose that manuals provide a useful outline of the general principles of a therapeutic approach, but can only reduce therapist variability at the expense of other essential therapeutic phenomena. Manuals cannot adequately convey, for example, how the effective therapist functions as a model of adult living and as a person who provides guidance. We suggest that such an experience cannot readily be packaged in manualized form, though manuals may serve as a useful beginning. Recommendations for therapist manualized training include greater attention to the subtleties of human relationships and adequately conveying that any technique is effective only when catalysed by a living, relational process.     

Muscle mass index in haemodialysis patients: a comparison of indices obtained by routine clinical examinations.

BACKGROUND: Measurement of muscle mass is useful for evaluating protein nutritional status. Various methods for estimating muscle mass in haemodialysis patients have recently been developed. METHODS: The validity of the estimate of creatinine production calculated with the creatinine kinetic model (CKM) was examined in 46 haemodialysis patients by comparing it with the actual creatinine production, this being determined from the sum of creatinine appearing in the dialysate and the estimated metabolic degradation. The correlation of various other muscle mass indices with creatinine production was also investigated in these patients. RESULTS: The estimate of creatinine production using CKM was significantly correlated with creatinine production calculated from the spent dialysate plus an estimate for the extra-renal creatinine degradation (r=0.90, P<0.001). A Bland-Altman analysis revealed that the mean prediction error for the estimate of creatinine production by CKM was +0.10 g/day and the limits of agreement were +0.34 to -0.14 g/day. The cross-sectional area of the thigh muscle measured by computed tomography (CT) was also significantly correlated with creatinine production (r=-0.86, P<0.01). In contrast, the correlations of 3-methylhistidine production measured in the spent dialysate, the mid-upper arm muscle circumference and the skeletal muscle mass estimated by an anthropometric prediction model with creatinine production were lower (r<0.82). CONCLUSION: Creatinine production calculated using CKM and CT measurement of thigh muscle area are valid methods for estimating muscle mass during routine clinical examinations of haemodialysis patients.     

Sildenafil relieves symptoms and normalizes motility in patients with oesophageal spasm: a report of two cases

Oesophageal spasm presents with dysphagia and chest pain. Current treatments are limited by poor efficacy and side effects. Studies in health and oesophageal dysmotility show that sildenafil reduces peristaltic pressure and velocity; however the clinical efficacy and tolerability in symptomatic oesophageal spasm remains uncertain. We provided open-label sildenafil treatment to two patients with severe, treatment resistant symptoms associated with oesophageal spasm. The effects of sildenafil on oesophageal function and symptoms were documented by high resolution manometry (HRM). Patients were followed up to assess the efficacy of maintenance treatment with sildenafil b.i.d. HRM revealed focal and diffuse spasm in the smooth muscle oesophagus that were associated with symptoms in both cases, especially on swallowing solids. Lower oesophageal sphincter function was normal. A therapeutic trial of 25-50 mg sildenafil suppressed oesophageal contraction almost completely for water swallows; however effective, coordinated peristalsis returned with reduced frequency of spasm for solid swallows. Dysphagia and chest pain resolved during the therapeutic trial and efficacy was maintained on maintenance treatment with 25-50 mg sildenafil b.i.d. without troublesome side effects. This report shows that sildenafil can improve oesophageal function and relieve dysphagia and chest pain in patients with oesophageal spasm in whom other treatments have failed.     

Myocardial perfusion SPECT reconstruction: Receiver operating characteristic comparison of CAD detection accuracy of filtered backprojection reconstruction with all of the clinical imaging information available to readers and solely stress slices iteratively reconstructed with combined compensation

BACKGROUND: Past receiver operating characteristic (ROC) studies have demonstrated that single photon emission computed tomography (SPECT) perfusion imaging by use of iterative reconstruction with combined compensation for attenuation, scatter, and detector response leads to higher area under the ROC curve (A(z)) values for detection of coronary artery disease (CAD) in comparison to the use of filtered backprojection (FBP) with no compensations. A new ROC study was conducted to investigate whether this improvement still holds for iterative reconstruction when observers have available all of the imaging information normally presented to clinical interpreters when reading FBP SPECT perfusion slices. METHODS AND RESULTS: A total of 87 patient studies including 50 patients referred for angiography and 37 patients with a lower than 5% likelihood for CAD were included in the ROC study. The images from the two methods were read by 4 cardiology fellows and 3 attending nuclear cardiologists. Presented for the FBP readings were the short-axis, horizontal long-axis, and vertical long-axis slices for both the stress and rest images; cine images of both the stress and rest projection data; cine images of selected cardiac-gated slices; the CEQUAL-generated stress and rest polar maps; and an indication of patient gender. This was compared with reading solely the iterative reconstructed stress slices with combined compensation for attenuation, scatter, and resolution. With A(z) as the criterion, a 2-way analysis of variance showed a significant improvement in detection accuracy for CAD for the 7 observers (P = .018) for iterative reconstruction with combined compensation (A(z) of 0.895 +/- 0.016) over FBP even with the additional imaging information provided to the observers when scoring the FBP slices (A(z) of 0.869 +/- 0.030). When the groups of 3 attending physicians or 4 cardiology fellows were compared separately, the iterative technique was not statistically significantly better; however, the A(z) for each of the 7 observers individually was larger for iterative reconstruction than for FBP. Compared with results from our previous studies, the additional imaging information did increase the diagnostic accuracy of FBP for CAD but not enough to undo the statistically significantly higher diagnostic accuracy of iterative reconstruction with combined compensation. CONCLUSIONS: We have determined through an ROC investigation that included two classes of observers (experienced attending physicians and cardiology fellows in training) that iterative reconstruction with combined compensation provides statistically significantly better detection accuracy (larger A(z)) for CAD than FBP reconstructions even when the FBP studies were read with all of the extra clinical nuclear imaging information normally available.