The in vivo transport of elastic vesicles into human skin: effects of occlusion, volume and duration of application.

In the present study, several aspects of elastic vesicle transport into human skin were investigated in vivo. Surfactant-based elastic vesicles were applied onto human skin in vivo and subsequently a series of tape-strippings were performed, which were visualised by freeze fracture electron microscopy. Factors of investigation for non-occlusive treatment were the duration of application and the volume of application. In addition, occlusive vs. non-occlusive application was studied. The results have shown a fast penetration of intact elastic vesicles into the stratum corneum after non-occlusive treatment, frequently via channel-like regions. Intact vesicles could reach the ninth tape-strip after the 1-h non-occlusive treatment. After the 4-h treatment, vesicle material could be found in the 15th tape-strip. However, micrographs of the 4-h treatment showed extensive vesicle fusion, both at the skin surface as well as in the deeper layers of the stratum corneum. A higher volume of application resulted in an increase in the presence of vesicle material found in the deeper layers of the stratum corneum. Micrographs after occlusive treatment revealed very few intact vesicles in the deeper layers of the stratum corneum, but the presence of lipid plaques was frequently observed. Furthermore, we have proposed a hypothesis that the channel-like regions represent imperfections within the intercellular lipid lamellae in areas with highly undulating cornified envelopes.     

Impact of involved field radiotherapy in partial response after doxorubicin-based chemotherapy for advanced aggressive non-Hodgkin's lymphoma

PURPOSE: Whether salvage therapy in patients with advanced aggressive non-Hodgkin's lymphoma (NHL) in partial remission (PR) should consist of radiotherapy or autologous stem-cell transplantation (ASCT) is debatable. We evaluated the impact of radiotherapy on outcome in PR patients treated in four successive European Organization for Research and Treatment of Cancer trials for aggressive NHL. PATIENTS AND METHODS: Records of 974 patients (1980-1999) were reviewed regarding initial response, final outcome, and type and timing of salvage treatment. After 8 cycles of doxorubicin-based chemotherapy, 227 NHL patients were in PR and treated: 114 received involved field radiotherapy, 16 ASCT, 93 second-line chemotherapy, and 4 were operated. Overall survival (OS) and progression-free survival (PFS) after radiotherapy were estimated (Kaplan-Meier method) and compared with other treatments (log-rank). Impact on survival was evaluated by multivariate analysis (Cox proportional hazards model). RESULTS: The median PFS in PR patients was 4.2 years and 48% remained progression-free at 5 years. Half of the PR patients converted to a complete remission. After conversion, survival was comparable to patients directly in complete remission. Radiotherapy resulted in better OS and PFS compared with other treatments, especially in patients with low to intermediate International Prognostic Index score, bulky disease, or nodal disease only. Correction by multivariate analysis for prognostic factors such as stage, bulky disease, and number of extranodal locations showed that radiotherapy was clearly the most significant factor affecting both OS and PFS. CONCLUSION: This retrospective analysis demonstrates that radiotherapy can be effective for patients in PR after fully dosed chemotherapy; assessment in a randomized trial (radiotherapy vs. ASCT) is justified.     

Prevalence and content of written ethics policies on euthanasia in Catholic healthcare institutions in Belgium (Flanders)

BACKGROUND: Euthanasia is performed worldwide, regardless of the existence of laws governing it. Belgium became the second country in the world to enact a law on euthanasia in 2002. Healthcare institutions bear responsibility for guaranteeing the quality of care for patients at the end of life, and for ensuring support for caregivers involved. Therefore, institutional ethics policies on end-of-life decision-making, especially on euthanasia, may be useful. METHODS: A cross-sectional mail survey of general directors of Catholic hospitals and nursing homes in Belgium was used to describe the prevalence and content of written ethics policies for competent terminally ill, incompetent terminally ill, and non-terminally ill patients. RESULTS: Of the 298 targeted institutions, 81% of hospitals and 62% of nursing homes returned complete questionnaires. Of these, 79% of hospitals and 30% of nursing homes had a written ethics policy on euthanasia. Of hospitals 83% and of nursing homes 85% permitted euthanasia for competent terminally ill patients only in exceptional cases in accordance with legal due care criteria and provisions outlined by the palliative filter procedure. Euthanasia for incompetent terminally ill patients was prohibited by 27% of the hospitals and by 60% of the nursing homes. For non-terminally ill patients, these figures were 43 and 64%, respectively. CONCLUSIONS: Catholic healthcare institutions in Belgium (Flanders) made great efforts to develop written ethics policies on euthanasia. Only a small group of institutions completely prohibited euthanasia. Most of the institutions considered euthanasia to be an option if all possible alternatives (e.g., palliative filter procedure, which contains more rigorous criteria than those in the Belgian Euthanasia Act), have been thoroughly investigated.     

The impact of transforming growth factor-beta1 gene polymorphism on end-stage renal failure after heart transplantation

BACKGROUND: Nephrotoxicity is a major side effect of calcineurin inhibitors (CNI). Earlier we reported 8% of our heart transplant recipients reaching end-stage renal failure (ESRF). Now, with an extended follow up of 20 years, we re-evaluated the development of ESRF and studied its influence on survival and the impact of polymorphisms in codon 10 and 25 of the promoter region of transforming growth factor (TGF)-beta on the risk of ESRF. METHODS: In all, 465 patients were transplanted between June 1984 and June 2005. All were on maintenance CNI treatment. Development of ESRF was studied in 402/465 (86.5%) patients surviving at least one year. Their median follow up was eight years, total observation time of 3,414 years. TGF-beta polymorphisms in codon 10 (Leu to Pro) and codon 25 (Arg to Pro) were analyzed with real-time polymerase chain reaction in a cohort of 237 patients, with an observation time of 2,329 years. RESULTS: Ten-year survival of patients surviving at least one year was 58.5%. Seventy-three patients (18.2%) developed ESRF. Dialysis-free survival was 60% at 15 years. The relative risk for ESRF in Pro carriers was 2.9 (CI 1.5-5.8) compared to patients with the Leu/Leu genotype (P = 0.002), while Pro carriers had a RR of 2.6 (CI 1.4-4.8) compared to the Arg/Arg25 genotype (P = 0.002). Survival of patients with ESRF was 1.5 years (median). CONCLUSION: We found a highly significant association between TGF-beta polymorphisms and CNI induced ESRF after heart transplantation (HTx). Pro carriers of either codon 10 or 25 had a 2.6 to 2.9 times increased risk of developing ESRF. As ESRF after HTx results in high mortality rates these patients should no longer receive CNI-based immunosuppression.     

High pretransplant parathyroid hormone levels increase the risk for graft failure after renal transplantation

BACKGROUND: Calcium (Ca), phosphate (P), and parathyroid hormone (PTH) are important variables influencing the risk for cardiovascular disease in dialysis patients. We studied the influence of long-standing Ca-P disregulation on renal transplant survival. METHODS: Pretransplant PTH, Ca, P, total protein (TP), albumin, and alkaline phosphatase (AP) values were gathered in all 407 patients that received a renal transplant in our center between January 1, 2000 and July 1, 2004. Other variables expected to influence the risks were included. RESULTS. In the Cox proportional hazards analysis the risk for graft failure censored for death was significantly influenced by pretransplant PTH concentration (P = 0.008) and donor type (P < 0.001). The influence of PTH on the risk for patient death was not significant. The risk for acute rejection was studied but PTH level did not have a significant influence on this risk (P = 0.055). The risk for delayed graft function was not influenced by PTH level. CONCLUSION: Serum PTH levels have an independent influence on the risk for graft failure censored for death. Efforts to improve calcium-phosphate-PTH homeostasis in patients on the waiting list for renal transplantation should be encouraged also to improve graft survival.     

Tissue response to partially in vitro predegraded poly-L-lactide implants

The in vivo local reaction of as-polymerized poly-L-lactide composed of 96% L-lactide and 4% D-lactide (PLA96) was investigated by histology at 2, 13 and 26 weeks after subcutaneous implantation in rats. In order to simulate possible end stage reactions the PLA96 was also predegraded in vitro until approximately 50% weight loss. The local reaction of predegraded PLA (PLA96(168)) was compared to the local reaction of polyethylene (PE) and non-predegraded PLA (PLA96). For PE and PLA96 a mild local reaction was observed at all time points consisting of a minimal layer of macrophage like cells with incidentally multinucleated giant cells at the implant interface, surrounded by a mild connective tissue capsule. For PLA96 at weeks 13 and 26 some minimal alterations in terms of degradation and ingrowth of cells was noted. The in vitro incubation (90 degrees C for 168 h) of PLA96(168) resulted for the thin 0.2 mm samples in complete degradation. Predegraded 0.5, 1.0 and 2.0 mm PLA96(168) samples were implanted and evaluated. The 1.0 and 2.0 mm samples could be evaluated for all time points investigated, but some 0.5 mm PLA96(168) samples were already completely resorbed at week 2 after implantation. In general, responses found for the predegraded PLA96(168) at weeks 2, 13 and 26 were similar with a pronounced macrophage infiltrate containing birefringent material, encapsulation of polymer fragments, and the presence of a debris area consisting of polymer and cellular remnants. In lymph nodes foamy macrophages with birefringent material were only observed in lymph nodes draining sites with predegraded PLA96(168). Immunohistochemistry was performed for further characterization of the cellular infiltrate. At the implant interface of the non-degrading PE and PLA96, ED1 and OX6 (MHC class II) positive cells were identified. In the capsule macrophage like cells expressed all three macrophage markers ED1, ED2, and ED3. CD4 and CD8 positive cells, indicating T helper and T supressor/cytotoxic cells, respectively, could be observed in low numbers, CD4 more than CD8. Both CD4 and CD8 were occasionally observed within the degrading PLA96(168) implant. Polymorphonuclear neutrophilic granulocytes were mainly observed at 2 weeks after implantation. We showed that predegradation could be used as a means to study late tissue reactions to polymers. Complete degradation may be studied with relatively thin implants, but this may lead to rather optimistic interpretation of resorption periods. When materials are intended to be used for screws and/or plates for bone fixation, implants of at least 1.0-2.0 mm thickness should be used as these may show a more realistic representation of the resorption characteristics of the material under investigation.     

Development and psychometric properties of a pain-related problem list for adolescents (PPL)

Instruments for measuring pain-related problems in adolescents with chronic pain are sparse, especially those based on the personal experiences of these adolescents. This study aimed to develop and test such an instrument, the pain-related problem list for adolescents (PPL). A sample of 129 adolescents with chronic pain without documented physiological etiology completed the 57-item problem list, which was based on interviews with a similar group of adolescents with chronic pain. Principal components analysis yielded four domains: problems related to (1) concentration; (2) mobility; (3) adaptability; and (4) mood. The questionnaire was shortened to 18 items and has good reliability (total alpha = 0.82; concentration alpha = 0.86; mobility alpha = 0.77; adaptability alpha = 0.71; and mood alpha = 0.78); the validity also proved to be adequate, especially in the general population sample. The PPL provides a tool to assess the impact of chronic pain in adolescents. Future research should focus on further validation of the PPL in a large clinical population and establishing its test-retest reliability.     

Compartmental Modeling of Transdermal Iontophoretic Transport II: <Emphasis Type="Italic">In Vivo</Emphasis> Model Derivation and Application

No HeadingPurpose. This study was aimed to develop a family of compartmental models to describe in a strictly quantitative manner the transdermal iontophoretic transport of drugs in vivo. The new models are based on previously proposed compartmental models for the transport in vitro.Methods. The novel in vivo model considers two separate models to describe the input into the systemic circulation: a) constant input and b) time-variant input. Analogous to the in vitro models, the in vivo models contain four parameters: 1) kinetic lag time (t_L), 2) steady-state flux during iontophoresis (J_ss), 3) skin release rate constant (K_R), and 4) passive flux in the post-iontophoretic period (J_pas). The elimination from the systemic circulation is described by a) the one-compartment and b) the two-compartment pharmacokinetic models. The models were applied to characterize the observed plasma concentration vs. time data following single-dose iontophoretic delivery of growth hormone-releasing factor (GRF) and R-apomorphine. Moreover, the models were also used to simulate the observed plasma concentration vs. time profiles following a two-dose transdermal iontophoretic administration of alniditan.Results. The time-variant input models were superior to the constant input models and appropriately converged to the observed data of GRF and R-apomorphine allowing the estimation of J_ss, K_R, and J_pas. In most cases, the values of t_L were negligible. The estimated J_ss and the in vivo flux profiles of GRF and R-apomorphine were similar to those obtained using the deconvolution method. The two-dose iontophoretic transport of alniditan was properly simulated using the proposed time-variant input model indicating the utility of the model to predict and to simulate the drug transport by a multiple-dose iontophoresis. Moreover, the use of the compartmental modeling approach to derive an in vitro-in vivo correlation for R-apomorphine was demonstrated. This approach was also used to identify the optimum in vitro model that closely mimics the in vivo iontophoretic transport of R-apomorphine.Conclusions. The developed in vivo models demonstrate their consistency and capability to describe the in vivo iontophoretic drug transport. This compartmental modeling approach provides a scientific basis to examine in vitro-in vivo correlations of drug transport by iontophoresis.