Microfluidic fabrication of 6-methoxyethylamino numonafide-eluting magnetic microspheres.

Recently, 6-methoxyethylamino numonafide (MEAN) exhibited potent inhibition of hepatocellular carcinoma (HCC) cell growth and less systemic toxicity than amonafide. MEAN may serve as an ideal candidate for the treatment of HCC; however, liver-directed, selective infusion methods may be critical to maximize the MEAN dose delivered to the targeted tumors. This study describes the microfluidic fabrication of MEAN-eluting ultrasmall superparamagnetic iron oxide (USPIO) nanocluster-containing alginate microspheres (MEAN-magnetic microspheres) intended for selective transcatheter delivery to HCC. The resulting drug delivery platform was mono-disperse, microsphere sizes were readily controlled based on channel flow rates during synthesis procedures, and drug release rates from the microspheres could be readily controlled with the introduction of USPIO nanoclusters. The MR relaxivity properties of the microspheres suggest the feasibility of in vivo imaging after administration, and these microspheres exhibited potent therapeutic effects significantly inhibiting cell growth inducing apoptosis in hepatoma cells.

Bevacizumab for recurrent ependymoma.

BACKGROUND: Ependymoma is a rare type of glioma, representing 5% of all CNS malignancies. Radiotherapy (RT) is commonly administered, but there is no standard chemotherapy. At recurrence, ependymoma is notoriously refractory to therapy and the prognosis is poor. In recurrent glioblastoma, encouraging responses with bevacizumab have been observed. METHODS: In this Institutional Review Board-approved study, we retrospectively analyzed the records of 8 adult patients treated for recurrent ependymoma and anaplastic ependymoma with bevacizumab containing chemotherapy regimens. We determined radiographic response (Macdonald criteria), median time to progression (TTP), and median overall survival (OS; Kaplan-Meier method). RESULTS: There were 4 men and 4 women with a median age of 40 years (range, 20-65). Prior treatment included surgery (n = 8), RT (8), temozolomide (5), and carboplatin (4). Bevacizumab (5-15 mg/kg every 2-3 weeks) was administered alone (2) or concurrently with cytotoxic chemotherapy including irinotecan (3), carboplatin (2), or temozolomide (1). Six patients achieved a partial response (75%) and 1 remained stable for over 8 months. Median TTP was 6.4 months (95% confidence interval 1.4-7.4) and median OS was 9.4 months (95% confidence interval 7.0-not reached), with a median follow-up of 5.2 months among 5 surviving patients (63%). CONCLUSIONS: The radiographic response rate to bevacizumab-containing regimens is high. A prospective study is warranted.

Cryptogenic liver disease in HIV-seropositive men.

OBJECTIVES: In the era of highly active antiretroviral therapy (HAART), liver disease has become a leading cause of morbidity and mortality in HIV-seropositive individuals. Although liver disease is commonly caused by viral co-infection, it has also been described in patients without viral hepatitis. In this study, we determined clinical factors associated with the development of cryptogenic liver disease in HIV-infected individuals. METHODS: HIV-seropositive and -seronegative patients undergoing evaluation for liver transplantation were selected if they met clinical criteria for cryptogenic liver disease. Clinical data were collected retrospectively, and radiological and histological data were reviewed separately. RESULTS: Nine HIV-seropositive individuals were compared with 41 HIV-seronegative patients with cryptogenic liver disease. Only one HIV-seropositive patient (11%) had cirrhosis, compared to 39 HIV-seronegative patients (93%) (P<0.001). Three HIV-infected patients (33%) had histological evidence of nodular regenerative hyperplasia. HIV-seropositive patients had significantly lower body mass indices, and lower Child-Pugh-Turcotte and Model for Endstage Liver Disease scores than HIV-seronegative patients (P<0.05). CONCLUSIONS: Advanced cryptogenic liver disease in HIV-infected patients is infrequently caused by cirrhosis, and more frequently by nodular regenerative hyperplasia. This disease entity may become more common in the HAART era, and may contribute to an increased morbidity in HIV-infected individuals.

Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience.

OBJECTIVE: Bevacizumab has been shown to be effective in the treatment of recurrent glioblastoma in combination with chemotherapy compared with historic controls but not in randomized trials. METHODS: We conducted a retrospective analysis of patients treated for recurrent glioblastoma with bevacizumab vs a control group of patients, comparing progression-free survival (PFS) and overall survival (OS) between the two groups, and performed subgroup analysis based on age and performance status. Expression of vascular endothelial growth factor (VEGF) based on age was examined using DNA microarray analysis. We also evaluated the impact of bevacizumab on quality of life. RESULTS: We identified 44 patients who received bevacizumab and 79 patients who had not been treated with bevacizumab. There was a significant improvement in PFS and OS in the bevacizumab-treated group. Patients of older age (> or =55 years) and poor performance status (Karnofsky Performance Status < or =80) had significantly better PFS when treated with bevacizumab, and bevacizumab-treated older patients had significantly increased OS. VEGF expression was significantly higher in older glioblastoma patients (aged > or =55 years). Patients treated with bevacizumab also required less dexamethasone use and maintained their functional status longer than the control group. CONCLUSIONS: Bevacizumab in combination with chemotherapy may be a more effective treatment for recurrent glioblastoma and warrants further randomized prospective studies to determine its effect on survival. Bevacizumab also has more effect in those with older age and might reflect biologic differences in glioblastoma in different age groups as seen with the expression of vascular endothelial growth factor.

Embryo as epiphenomenon: some cultural, social and economic forces driving the stem cell debate.

Our human embryonic stem cell debates are not simply about good or bad ethical arguments. The fetus and the embryo have instead become symbols for a larger set of value conflicts occasioned by social and cultural changes. Beneath our stem cell debates lie conflicts between those who would privilege scientific progress and individual choice and others who favour the sanctity of family life and traditional family roles. Also at work, on both the national and international levels, is the use of the embryo by newly emergent social groups to express resentment against cultural elites. The organisational needs of religious groups have also played a role, with the issue of protection of the embryo and fetus serving as a useful means of rallying organisational allegiance in the Roman Catholic and evangelical communities. Because the epiphenomenal moral positions on the status and use of the embryo are driven by the powerful social, cultural or economic forces beneath them, they will most likely change only with shifts in the underlying forces that sustain them.

Outcome for adult contacts of smear-positive pulmonary tuberculosis in the absence of X-ray follow-up: 2000-03.

The effects of the policy change in X-ray follow-up of adult tuberculin-positive close contacts of sputum microscopy positive pulmonary tuberculosis made by the Joint Tuberculosis Committee of the British Thoracic Society in 2000 were monitored prospectively from late 2000 until the end of 2003. No cases in contacts that could have been detected by interval X-rays at three and 12 months were found. The data, on 291 cases, support the abandonment of X-ray follow-up in favour of an 'inform and advise' strategy after an initial normal chest X-ray in this category of tuberculosis contact.

Inhibiting mild steel corrosion from sulfate-reducing bacteria using antimicrobial-producing biofilms in Three-Mile-Island process water.

Biofilms were used to produce gramicidin S (a cyclic decapeptide) to inhibit corrosion-causing, sulfate-reducing bacteria (SRB). In laboratory studies these biofilms protected mild steel 1010 continuously from corrosion in the aggressive, cooling service water of the AmerGen Three-Mile-Island (TMI) nuclear plant, which was augmented with reference SRB. The growth of both reference SRB (Gram-positive Desulfosporosinus orientis and Gram-negative Desulfovibrio vulgaris) was shown to be inhibited by supernatants of the gramicidin-S-producing bacteria as well as by purified gramicidin S. Electrochemical impedance spectroscopy and mass loss measurements showed that the protective biofilms decreased the corrosion rate of mild steel by 2- to 10-fold when challenged with the natural SRB of the TMI process water supplemented with D. orientis or D. vulgaris. The relative corrosion inhibition efficiency was 50-90% in continuous reactors, compared to a biofilm control which did not produce the antimicrobial gramicidin S. Scanning electron microscope and reactor images also revealed that SRB attack was thwarted by protective biofilms that secrete gramicidin S. A consortium of beneficial bacteria (GGPST consortium, producing gramicidin S and other antimicrobials) also protected the mild steel.

An assessment of sleep disturbance in patients before and after total hip arthroplasty.

Patients with osteoarthritis commonly complain of sleep disturbance that may be due to pain. Osteoarthritic hip pain is commonly alleviated by total hip arthroplasty (THA). Forty-eight patients waiting for THA completed a sleep questionnaire and were monitored using actigraphy and sleep diaries for 4 to 5 nights, 1 month before and 3 months after surgery. For the group as a whole, significant improvements were seen in subjective and objective measures of sleep after THA. In this study, 75% of participants reported that their sleep was never or rarely disturbed by hip pain after surgery. Actigraphy indicated significant reductions in time in bed and activity during sleep, more efficient sleep and less fragmented (restless) sleep. Differences between patients aged < 65 and > or = 65 years were observed. These findings support the hypothesis that relief from the pain of osteoarthritis as a result of THA improves sleep quality. Improvements in sleep contribute to the improved quality of life and day-to-day functioning seen after THA.

Determining access to assisted reproductive technology: reactions of clinic directors to ethically complex case scenarios.

BACKGROUND: Our aim was to increase understanding of how patient selection is handled by assisted reproductive technology (ART) clinicians. METHODS: Ethically complex case scenarios were evaluated by the directors of USA ART clinics. Scenarios included using a son as sperm donor for his father, sex selection without associated disease, treatment of morally irresponsible couples, and a dispute over embryo disposition. Respondents reviewed eight scenarios and gave their opinions on whether to offer treatment. Reasons given for these decisions were placed into one of 13 categories. RESULTS: Survey response rate was 57%. Between 3 and 50% of respondents would treat in each case. Of reasons given, 'conditional' responses (requiring counselling, blood tests or agreement to other 'conditions') were common (31.4%). Non-maleficence (risk) accounted for 29.4% of responses, philosophy of medicine 18.9%, respect for patient autonomy 5.9% and legal concerns 4.6%. Discrimination and threats were each significant in one case. Reasons evoking absolutist beliefs, personal discomfort, commitment to justice, religion and ethical relativism were rare. CONCLUSIONS: Clinicians felt conflict between a desire to respect patient autonomy and their discomfort over the risk associated with the procedure. They raised concerns about misuse of medical technology. Attempts to resolve complex issues through negotiation and compromise were common.

Hepatic canalicular membrane transport of bile salt in C57L/J and AKR/J mice: implications for cholesterol gallstone formation.

C57L/J (gallstone-susceptible) and AKR/J (gallstone-resistant) mice have been utilized for quantitative trait loci (QTL) analysis to identify the Lith 1 locus for cholelithiasis. Abcb11 encodes for the liver canalicular membrane bile salt export pump (BSEP), which maps to this QTL and is a candidate gene for Lith 1. We investigated the transmembrane transport of taurocholate in canalicular liver membrane vesicles isolated from these murine strains. Canalicular liver plasma membranes (cLPM) and RNA were isolated from C57L/J and AKR/J mice livers, and were utilized for Northern and Western blot analysis and functional (3)H-taurocholate uptake studies. ATP-dependent (3)H-taurocholate uptake was significantly higher in AKR/J, compared to C57L/J mice. V(max) was 127 vs. 42 pmol TC/mg/s in the murine strains, respectively, while K(m) was unchanged. In contrast, gene and protein expression of hepatic Abcb11 was increased three-fold in C57L/J, compared to AKR/J mice. Thus, Abcb11 bile salt transport activity per unit protein was reduced nine-fold in the C57L/J, compared to AKR/J mice. In contrast, canalicular membrane cholesterol:phospholipid content was also significantly higher in the C57L/J mice. We conclude that gallstone-susceptible C57L/J mice demonstrate increased gene and canalicular membrane expression of Abcb11, however, taurocholate transport is functionally diminished. The latter may be due to the increased cholesterol membrane content of the cLPM in C57L/J mice. These findings may be important for the pathogenesis of gallstone formation.

Outcome of the treatment of culture negative tuberculosis (respiratory and non-respiratory): Blackburn 1996-2000.

OBJECTIVE: To determine the outcome of treating patients without culture confirmation of tuberculosis, with a regimen of two months of isoniazid, rifampicin, pyrazinamide and ethambutol followed by four months of isoniazid and rifampicin (2HRZE/4HR) in a setting with a rate of isoniazid resistance of 7.5% in culture confirmed cases. SETTING: Tuberculosis patients treated in the Blackburn, Hyndburn and Ribble Valley districts of the UK between 1996 and 2000 inclusive. METHODS: Patients from a detailed prospective clinical and epidemiological data base for all tuberculosis patients were studied for the years 1996-2000. RESULTS: One hundred and fourteen cases, all but two of Indian subcontinent ethnic origin, without culture confirmation had received 2HRZE/4HR. Twenty had pulmonary, 55 other respiratory and 39 non-respiratory tuberculosis. There was no bacteriologically confirmed relapse, 1 case was retreated as a clinical relapse. CONCLUSION: The treatment of tuberculosis cases without culture confirmation with a regimen of 2HRZE/4HR gives highly acceptable results. The clinical relapse rate was 0.85% (1/114), and the cure rate 99.15%.

Tuberculosis treatment outcome monitoring: Blackburn 1988-2000.

SETTING: All cases of tuberculosis in a high prevalence district (population 269,000) of England. OBJECTIVE: To analyse the tuberculosis programme outcome for confirmed pulmonary tuberculosis, and all other categories of cases for 1988-2000 inclusive. DESIGN: The outcome of all cases treated during the period 1988-2000 inclusive was assessed by agreed European outcome criteria, retrospectively for 1988-1998 and prospectively for 1999-2000. RESULTS: A total of 729 tuberculosis cases were notified, with 209 definite (culture-positive) pulmonary cases. Of the 205 definite pulmonary cases treated in life, 182 received self-administered treatment (SAT) and 23 directly observed treatment (DOT), with an 88% cure/completion rate and a 12% death rate. The relapse rate for SAT was 1/182 (0.5%) and 1/23 for DOT (4.3%). The cure/completion rate for all patients together was 94.3%, with a relapse rate of 0.8%. CONCLUSION: In this resource-rich setting, treatment largely by SAT, but carefully monitored, gives a very high cure/completion rate. Universal rather than selective DOT would make little additional impact on patient outcome. These outcomes are not likely to be reproducible, however, with SAT in a resource-poor setting.

Double Z-pinch hohlraum drive with excellent temperature balance for symmetric inertial confinement fusion capsule implosions.

A double Z pinch driving a cylindrical secondary hohlraum from each end has been developed which can indirectly drive intertial confinement fusion capsule implosions with time-averaged radiation fields uniform to 2%-4%. 2D time-dependent view factor and 2D radiation hydrodynamic simulations using the measured primary hohlraum temperatures show that capsule convergence ratios of at least 10 with average distortions from sphericity of /r200 MJ.

An empirical quantitative framework for the seasonal population dynamics of the tick Ixodes ricinus.

The wide geographic and climatic range of the tick Ixodes ricinus, and the consequent marked variation in its seasonal population dynamics, have a direct impact on the transmission dynamics of the many pathogens vectored by this tick species. We use long-term observations on the seasonal abundance and fat contents (a marker of physiological ageing) of ticks, and contemporaneous microclimate at three field sites in the UK, to establish a simple quantitative framework for the phenology (i.e. seasonal cycle of development) of I. ricinus as a foundation for a generic population model. An hour-degree tick inter-stadial development model, driven by soil temperature and including diapause, predicts the recruitment (i.e. emergence from the previous stage) of a single cohort of each stage of ticks each year in the autumn. The timing of predicted emergence coincides exactly with the new appearance of high-fat nymphs and adults in the autumn. Thereafter, fat contents declined steadily until unfed ticks with very low energy reserves disappeared from the questing population within about 1 year from their recruitment. Very few newly emerged ticks were counted on the vegetation in the autumn, but they appeared in increasing numbers through the following spring. Larger ticks became active and subsequently left the questing population before smaller ones. Questing tick population dynamics are determined by seasonal patterns of tick behaviour, host-contact rates and mortality rates, superimposed on a basal phenology that is much less complex than has hitherto been portrayed.

Diagnosis and management of the "difficult" abdominal aortic aneurysm: pararenal aneurysms, inflammatory aneurysms, and horseshoe kidney.

All "difficult" abdominal aortic aneurysms-whether pararenal or inflammatory or associated with abnormal renal parenchymal anatomy-often best are approached with some combination of retroperitoneal exposure and supraceliac clamping. Preoperative recognition that an unusual case may exist, complete and appropriate imaging and formulation of a sensible plan before operation are absolutely critical to success. Following such a plan can convert a relatively complex situation into a relatively simple one.

Safety and efficacy of limited-dose tissue plasminogen activator in acute vascular occlusion.

OBJECTIVE: The purposes of this study were to evaluate the safety and efficacy of limited-dose tissue plasminogen activator (t-PA) in patients with acute vascular occlusion and to compare these results with those obtained in equivalent patients receiving urokinase. METHODS: We compared the results of 60 patients receiving catheter-directed urokinase from November 1997 to November 1998 (240,000 units/h x 4 h, 120,000 units/h thereafter for a maximum of 48 h) with those of 45 patients receiving catheter-directed t-PA from November 1998 to August 2000 (2 mg/h, total dose < or =100 mg) for acute arterial occlusion (AAO) and acute venous occlusion (AVO). Interventional approaches such as cross-catheter and coaxial techniques were used to reduce the dose of lytic agent needed to achieve pre-lysis-treatment goals (eg, complete lysis of all thrombus/unmasking graft stenosis or establishing outflow target). Statistical analysis was performed using Student t test and Fisher exact test. RESULTS: The urokinase and t-PA groups were comparable with regard to age, comorbidities (coronary artery disease, hypertension, diabetes, renal insufficiency, smoking), duration of ischemic or occlusive symptoms, location of occlusive process, pretreatment with warfarin, and thrombotic versus embolic and native versus graft occlusion in patients with AAO. In patients with AAO and in those with AVO, t-PA was equivalent to or better than urokinase with regard to percent of clot lysis, incidence of major bleeding complications, limb salvage, and mortality. Achievement of pretreatment goals (arterial patients only) was 50% for urokinase patients and 76% for t-PA patients (P =.02). Analysis of success in individual pretreatment-goal achievement showed urokinase and t-PA to be equivalent in unmasking stenoses (85% and 84%, respectively; P = NS), whereas t-PA was superior to urokinase in the more critical task of establishing run-off (39% versus 81% for urokinase and t-PA, respectively; P =.001). Additional interventions, either endovascular or surgical, were required in 60% and 51% (P = NS) of patients receiving urokinase and t-PA, respectively, for AAO, and in 54% and 62% (P = NS) of patients receiving urokinase and t-PA, respectively, for AVO. CONCLUSIONS: Limited-dose t-PA is a safe and effective therapy for AAO and AVO when administered by experienced teams using innovative but well-established interventional techniques.

What does it mean to use someone as "a means only": rereading Kant.

Debates about commodification in bioethics frequently appeal to Kant's famous second formulation of the categorical imperative, the formula requiring us to treat the rational (human) being as "an end in itself" and "never as a means only." In the course of her own treatment of commodification, Margaret Jane Radin observes that Kant's application of this formula "does not generate noncontroversial particular consequences." This is so, I argue, because Kant offers three different--and largely incompatible--interpretations of the formula. One focuses on the obligation to preserve rational willing; the second stresses respect for human (physical) dignity and integrity; the third views respect for others as "ends in themselves" as primarily involving a willingness to govern one's conduct by a procedure of impartial co-legislation. Only the third of these interpretations, I conclude, offers a reasonable and coherent approach to moral judgment about the limits of commodification.

Drug resistance trends in M. tuberculosis: Blackburn 1990-1999.

SETTING: Blackburn, United Kingdom. OBJECTIVE: To describe the drug resistance data for Mycobacterium tuberculosis in white and Indian Subcontinent (ISC) ethnic patients in a high prevalence district in the United Kingdom (UK) over a 10-year period. DESIGN: Data from a detailed prospective clinical and epidemiological database of all notified patients were examined for the years 1990-1999 inclusive. RESULTS: Primary isoniazid resistance was found in 17/229 (7.4%) of ISC and 3/67 (4.5%) of white isolates. There was no statistical difference in the rates of drug resistance in those of ISC ethnic origin, whether they were ISC or UK born and whether or not they had made return visits to the ISC. CONCLUSION: The rate of primary isoniazid resistance remains between 5-10% in ISC patients in Blackburn, showing no fall from previous surveys. The rate of drug resistance was not lower in those born in the UK, irrespective of whether return visits had been made to the ISC. These data will need to be further monitored.

Mechanism of indinavir-induced hyperbilirubinemia.

Indinavir is a viral protease inhibitor used for the treatment of HIV infection. Unconjugated hyperbilirubinemia develops in up to 25% of patients receiving indinavir, prompting drug discontinuation and further clinical evaluation in some instances. We postulated that this side-effect is due to indinavir-mediated impairment of bilirubin UDP-glucuronosyltransferase (UGT) activity and would be most pronounced in individuals with reduced hepatic enzyme levels, as occurs in approximately 10% of the population manifesting Gilbert's syndrome. This hypothesis was tested in vitro, in the Gunn rat model of UGT deficiency, and in HIV-infected patients with and without the Gilbert's polymorphism. Indinavir was found to competitively inhibit UGT enzymatic activity (K(I) = 183 microM) while concomitantly inducing hepatic bilirubin UGT mRNA and protein expression. Although oral indinavir increased plasma bilirubin levels in wild-type and heterozygous Gunn rats, the mean rise was significantly greater in the latter group of animals. Similarly, serum bilirubin increased by a mean of 0.34 mg/dl in indinavir-treated HIV patients lacking the Gilbert's polymorphism versus 1.45 mg/dl in those who were either heterozygous or homozygous for the mutant allele. Whereas saquinavir also competitively inhibits UGT activity, this drug has not been associated with hyperbilirubinemia, most likely because of the higher K(I) (360 microM) and substantially lower therapeutic levels as compared with indinavir. Taken together, these findings indicate that elevations in serum-unconjugated bilirubin associated with indinavir treatment result from direct inhibition of bilirubin-conjugating activity.

Are there still effects on Indian Subcontinent ethnic tuberculosis of return visits?: a longitudinal study 1978-97.

OBJECTIVE: To assess whether return visits to the Indian Subcontinent (ISC) are associated with increased risks of developing clinical tuberculosis. METHODS: Descriptive analysis of epidemiological records over a period of 1978-97 inclusive in Blackburn, Hyndburn and Ribble Valley for individuals of ISC ethnic origin notified with tuberculosis. Those cases diagnosed through local contact tracing exercises were excluded. RESULTS: Of 1032 eligible individuals notified with tuberculosis, 228 (22.1%) reported prior visits to the ISC. Of these 151 (66%) reported having visits within 3 years of that notification, including 60% of the United Kingdom (U.K.) born without prior exposure to the ISC. CONCLUSION: The clinical observations are consistent with the hypothesis that return visits to the ISC carry a risk of acquiring tuberculosis. This cannot be confirmed, however, without information about the return visits in the ISC population as a whole. A case-control study may be required to confirm the hypothesis.