Immunoglobulin G/immunoglobulin M autoantibody ratios in incomplete systemic lupus erythematosus.

OBJECTIVE: Immunoglobulin G (IgG) autoantibodies in systemic lupus erythematosus (SLE) are considered pathogenic, whereas immunoglobulin M (IgM) autoantibodies may have protective effects. The aim of this study was to identify whether IgG/IgM autoantibody ratios differ between patients with incomplete systemic lupus erythematosus (iSLE), patients with SLE, and healthy controls (HCs), and whether IgG/IgM autoantibody ratios relate to progression from iSLE to SLE. METHOD: This prospective cohort study included 34 iSLE patients, 41 SLE patients, and 11 HCs. IgG and IgM anti-dsDNA, anti-Ro52, and anti-Ro60 were measured by fluoro-enzyme immunoassay in serum samples obtained at baseline in all groups and in follow-up samples of up to 5 years for iSLE patients. Correlations between IgG/IgM autoantibody ratios, interferon signature, and clinical parameters were also assessed. RESULTS: At baseline, IgG anti-dsDNA, anti-Ro52, anti-Ro60, and IgM anti-dsDNA were elevated in iSLE and SLE patients. IgG/IgM anti-dsDNA and anti-Ro52 ratios were similar between groups, while IgG/IgM anti-Ro60 ratios were significantly elevated in iSLE and SLE patients compared to HCs. IgG/IgM autoantibody ratios were not correlated with interferon signature or clinical parameters. IgG/IgM ratios at baseline were similar and remained relatively stable during a median follow-up of 18 months in non-progressors and six iSLE patients who progressed to SLE. CONCLUSION: IgG anti-dsDNA, anti-Ro52, anti-Ro60, and IgM anti-dsDNA were elevated in iSLE and SLE patients, which was not apparent from the respective IgG/IgM ratios only. IgG/IgM autoantibody ratios remained relatively stable over up to 5 years in iSLE non-progressors and six patients who progressed to SLE.

Adjuvant Use of PlasmaJet Device During Cytoreductive Surgery for Advanced-Stage Ovarian Cancer: Results of the PlaComOv-study, a Randomized Controlled Trial in The Netherlands.

OBJECTIVE: Standard surgical treatment of advanced-stage ovarian carcinoma with electrosurgery cannot always result in complete cytoreductive surgery (CRS), especially when many small metastases are found on the mesentery and intestinal surface. We investigated whether adjuvant use of a neutral argon plasma device can help increase the complete cytoreduction rate. PATIENTS AND METHODS: 327 patients with FIGO stage IIIB-IV epithelial ovarian cancer (EOC) who underwent primary or interval CRS were randomized to either surgery with neutral argon plasma (PlasmaJet) (intervention) or without PlasmaJet (control group). The primary outcome was the percentage of complete CRS. The secondary outcomes were duration of surgery, blood loss, number of bowel resections and colostomies, hospitalization, 30-day morbidity, and quality of life (QoL). RESULTS: Complete CRS was achieved in 119 patients (75.8%) in the intervention group and 115 patients (67.6%) in the control group (risk difference (RD) 8.2%, 95% confidence interval (CI) -0.021 to 0.181; P = 0.131). In a per-protocol analysis excluding patients with unresectable disease, complete CRS was obtained in 85.6% in the intervention group and 71.5% in the control group (RD 14.1%, 95% CI 0.042 to 0.235; P = 0.005). Patient-reported QoL at 6 months after surgery differed between groups in favor of PlasmaJet surgery (95% CI 0.455-8.350; P = 0.029). Other secondary outcomes did not differ significantly. CONCLUSIONS: Adjuvant use of PlasmaJet during CRS for advanced-stage ovarian cancer resulted in a significantly higher proportion of complete CRS in patients with resectable disease and higher QoL at 6 months after surgery. (Funded by ZonMw, Trial Register NL62035.078.17.) TRIAL REGISTRATION: Approved by the Medical Ethics Review Board of the Erasmus University Medical Center Rotterdam, the Netherlands, NL62035.078.17 on 20-11-2017. Recruitment started on 30-1-2018.

The frictional layer in the observed momentum budget of the trades.

Profiles of eddy momentum flux divergence are calculated as the residual in the momentum budget constructed from airborne circular dropsonde arrays ( ∼ 220 km) for 13 days during the EUREC 4 A/ATOMIC field campaign. The observed dynamical forcing averaged over all flights agrees broadly with European Centre for Medium-Range Weather Forecasts (ECMWF) Integrated Forecasting System (IFS) forecasts. In the direction of the flow, a mean flux divergence (friction) exists over a 1.5-km deep Ekman layer, and a mean flux convergence (acceleration) is present near cloud tops. The friction is countergradient between 1 and 1.5 km, where vertical wind shear exceeds the observed thermal wind. From the frictional profile, a 10-m momentum flux of ∼ 0.1 N · m - 2 is derived, in line with Saildrone turbulence measurements. A momentum flux divergence in the cross-wind direction is pronounced near the surface and acts to veer the wind, opposing the friction-induced cross-isobaric wind turning. Weaker friction and upper-level acceleration of easterly flow are observed when stronger winds and more vigorous convection prevail. Turbulence measurements on board the SAFIRE ATR-42 aircraft and the Uncrewed Aircraft System (UAS) RAAVEN reveal pronounced spatial variability of momentum fluxes, with a non-negligible contribution of mesoscales (5-30 km). The findings highlight the nontrivial impact of turbulence, convection, and mesoscale flows in the presence of diverse cloud fields on the depth and strength of the frictional layer.

The LeVe CPAP System for Oxygen-Efficient CPAP Respiratory Support: Development and Pilot Evaluation.

Background: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has placed a significant demand on healthcare providers (HCPs) to provide respiratory support for patients with moderate to severe symptoms. Continuous Positive Airway Pressure (CPAP) non-invasive ventilation can help patients with moderate symptoms to avoid the need for invasive ventilation in intensive care. However, existing CPAP systems can be complex (and thus expensive) or require high levels of oxygen, limiting their use in resource-stretched environments. Technical Development + Testing: The LeVe ("Light") CPAP system was developed using principles of frugal innovation to produce a solution of low complexity and high resource efficiency. The LeVe system exploits the air flow dynamics of electric fan blowers which are inherently suited to delivery of positive pressure at appropriate flow rates for CPAP. Laboratory evaluation demonstrated that performance of the LeVe system was equivalent to other commercially available systems used to deliver CPAP, achieving a 10 cm H2O target pressure within 2.4% RMS error and 50-70% FiO2 dependent with 10 L/min oxygen from a commercial concentrator. Pilot Evaluation: The LeVe CPAP system was tested to evaluate safety and acceptability in a group of ten healthy volunteers at Mengo Hospital in Kampala, Uganda. The study demonstrated that the system can be used safely without inducing hypoxia or hypercapnia and that its use was well-tolerated by users, with no adverse events reported. Conclusions: To provide respiratory support for the high patient numbers associated with the COVID-19 pandemic, healthcare providers require resource efficient solutions. We have shown that this can be achieved through frugal engineering of a CPAP ventilation system, in a system which is safe for use and well-tolerated in healthy volunteers. This approach may also benefit other respiratory conditions which often go unaddressed in Low and Middle Income Countries (LMICs) for want of context-appropriate technology designed for the limited oxygen resources available.

[Elderly patients with an abdominal aortic aneurysm; preoperative frailty-screening and a multidisciplinary approach]. / Ouderen met een aneurysma van de abdominale aorta.

Aneurysm of the abdominal aorta is common and can be treated with endovascular repair, open surgical repair or conservative treatment. Risk-stratification and treatment decision-making can be complex in frail patients and depends largely on anatomy, life-expectancy and functional capacity. Currently, risk-stratification in the Netherlands is primarily based on comorbidities and age. Insight in a patient's resilience could provide important additional information. For this reason, St. Antonius hospital has implemented an Anaesthesia Geriatric Evaluation (AGE) to screen for frailty in high risk vascular surgery patients. Results of frailty-screening are discussed in a multi-disciplinary team (MDT) to assess perioperative risk and compose a personal treatment plan. This paper presents a case-series of three patients to illustrate the additional value of MDT care and frailty-screening in a high-risk vascular surgery population.

Evaluation of effectiveness of the PlasmaJet surgical device in the treatment of advanced stage ovarian cancer (PlaComOv-study): study protocol of a randomized controlled trial in the Netherlands.

BACKGROUND: The most important goal for survival benefit of advanced stage ovarian cancer is to surgically remove all visible tumour, because complete cytoreductive surgery (CCS) has been shown to be associated with prolonged survival. In a remarkable number of women, CCS is very challenging. Especially in women with many small metastases on the peritoneum and intestinal surface, conventional CCS with electrosurgery is not able to be "complete" in removing safely all visible tumour. In this randomized controlled trail (RCT) we investigate whether the use of the PlasmaJet Surgical Device increases the rate of CCS, and whether this indeed leads to a longer progression free and overall survival. The main research question is: does the use of the PlasmaJet Surgical Device in surgery for advanced stage ovarian cancer result in an increased number of complete cytoreductive surgeries when compared with conventional surgical techniques. Secondary study objectives are: 30-day morbidity, duration of surgery, blood loss, length of hospitalisation, Quality of Life, disease-free survival, overall survival, percentage colostomy, cost-effectiveness. METHODS: The study design is a multicentre single-blinded superiority RCT in two university and nine non-university hospitals in The Netherlands. Three hundred and thirty women undergoing cytoreductive surgery for advanced stage ovarian carcinoma (FIGO Stage IIIB-IV) will be randomized into two arms: use of the PlasmaJet (intervention group) versus the use of standard surgical instruments combined with electrocoagulation (control group). The primary outcome is the rate of complete cytoreductive surgery in both groups. Secondary study objectives are: 30-day morbidity, duration of surgery, blood loss, length of hospitalisation, Quality of Life, disease-free survival, overall survival, percentage colostomy, cost-effectiveness. Quality of life will be evaluated using validated questionnaires at baseline, at 1 and 6 months after surgery and at 1, 2, 3 and 4 years after surgery. DISCUSSION: We hypothesize the additional value of the use of the PlasmaJet in CCS for advanced stage epithelial ovarian cancer. More knowledge about efficacy, side effects, recurrence rates, cost effectiveness and pathology findings after using the PlasmaJet Device is advocated. This RCT may aid in this void. TRIAL REGISTRATION: Dutch Trial Register NTR6624 . Registered 18 August 2017. Medical Ethical Committee approval number: NL62035.078.17 (Medical Ethical Committee Erasmus Medical Centre Rotterdam).

Nomogram for 30-day morbidity after primary cytoreductive surgery for advanced stage ovarian cancer.

PURPOSE OF INVESTIGATION: Extensive surgical procedures to achieve maximal cytoreduction in patients with advanced stage epithelial ovarian cancer (EOC) are inevitably associated with postoperative morbidity and mortality. This study aimed to identify preoperative predictors of 30-day morbidity after primary cytoreductive surgery for advanced stage EOC and to develop a nomogram for individual risk assessment. MATERIALS AND METHODS: Patients in The Netherlands who underwent primary cytoreductive surgery for advanced stage EOC between January 2004 and December 2007. All peri- and postoperative complications within 30 days after surgery were registered and classified. To investigate predictors of 30-day morbidity, a Cox proportional hazard model with backward stepwise elimination was utilized. The identified predictors were entered into a nomogram. The main outcome was to identify parameters that predict operative risk. RESULTS: 293 patients entered the study protocol. Optimal cytoreduction was achieved in 136 (46%) patients. Thirty-day morbidity was seen in 99 (34%) patients. Morbidity could be predicted by age (p = 0.033; OR 1.024), preoperative hemoglobin (p = 0.194; OR 0.843), and WHO performance status (p = 0.015; OR 1.821) with a optimism-corrected c-statistic of 0.62. Determinants co-morbidity status, serum CA125 level, platelet count, and presence of ascites were comparable in both groups. CONCLUSIONS: Thirty-day morbidity after primary cytoreductive surgery for advanced stage EOC could be predicted by age, hemoglobin, and WHO performance status. The generated nomogram could be valuable for predicting operative risk in the individual patient.

Prediction of 30-day morbidity after primary cytoreductive surgery for advanced stage ovarian cancer.

OBJECTIVE: Treatment in advanced stage epithelial ovarian cancer (EOC) is based on primary cytoreductive surgery followed by platinum-based chemotherapy. Successful cytoreduction to minimal residual tumour burden is the most important determinant of prognosis. However, extensive surgical procedures to achieve maximal debulking are inevitably associated with postoperative morbidity and mortality. The objective of this study is to determine predictors of 30-day morbidity after primary cytoreductive surgery for advanced stage EOC. METHODS: All patients in the South Western part of the Netherlands who underwent primary cytoreductive surgery for advanced stage EOC between January 2004 and December 2007 were identified from the Rotterdam Cancer Registry database. All peri- and postoperative complications within 30 days after surgery were registered and classified according to the definitions of the National Surgical Quality Improvement Programme (NSQIP). To investigate independent predictors of 30-day morbidity, a Cox proportional hazards model with backward stepwise elimination was utilised. The identified predictors were entered into a nomogram. RESULTS: Two hundred and ninety-three patients entered the study protocol. Optimal cytoreduction was achieved in 136 (46%) patients. 30-day morbidity was seen in 99 (34%) patients. Postoperative morbidity could be predicted by age (P=0.007; odds ratio [OR] 1.034), WHO performance status (P=0.046; OR 1.757), extent of surgery (P=0.1308; OR=2.101), and operative time (P=0.017; OR 1.007) with an optimism corrected c-statistic of 0.68. CONCLUSION: 30-day morbidity could be predicted by age, WHO performance status, operative time and extent of surgery. The generated nomogram could be valuable for predicting operative risk in the individual patient.

Combining multiple optical trapping with microflow manipulation for the rapid bioanalytics on microparticles in a chip.

An array of four independent laser traps is combined with a polydimethylsiloxane microfluidic chip to form a very compact system allowing parallel processing of biological objects. Strong three dimensional trapping allows holding objects such as functionalized beads in flows at speeds near 1 mm/s, enabling rapid processing. By pressure control of the inlet flows, the trapped objects can be put in contact with different solutions for analysis purpose. This setup, including a fluorescence excitation-detection scheme, offers the potential to perform complex biochemical manipulations on an ensemble of microparticles.

Gene transfer to the spinal cord neural scar with lentiviral vectors: predominant transgene expression in astrocytes but not in meningeal cells.

Viral vector-mediated overexpression of neurotrophins in cells constituting the neural scar may represent a powerful approach to rendering scar tissue of a central nervous system (CNS) lesion permissive for neuronal regrowth. In this study a lentiviral vector encoding green fluorescent protein (LV-GFP) was injected in and around the neural scar 2 weeks after a dorsal column lesion in the rat spinal cord in order to analyze transduction characteristics of the neural scar after 4, 7, and 14 days. GFP expression was found at all points after injection and increased from 4 to 7 days, with no apparent difference observed between 7 and 14 days. The core of the lesion was virtually devoid of GFP signal despite direct vector injections in this area. The colocalization of GFP with specific cell markers (GFAP, vimentin, Raldh2, NeuN, OX-42, ED-1, and NG-2) indicated that the predominant cells transduced in the rim of the lesion were astrocytes, with neurons, microglia, oligodendrocyte precursors, and macrophages transduced to a lesser extent. None of the Raldh2-positive meningeal cells, present in the core of the scar, expressed GFP. In vitro meningeal cells were readily transduced, indicating that in vivo the formation of an extracellular matrix might prevent LV particles from transducing cells in the core of the scar. Because astrocytes are important cellular constituents of the glial scar after CNS injury, transduction of astrocytes with LV vectors encoding neurotrophic factors like BDNF or NT-3 may be used to enhance regeneration of severed axonal tracts through or along boundaries of a CNS lesion.

A new HBsAg screening assay designed for sensitive detection of HBsAg subtypes and variants.

The design of a new HBsAg screening assay, the Hepanostika HBsAg Ultra is based on the use of monoclonal antibodies raised against native wild-type HBsAg and reactive with HBsAg in which the common 'a'-determinant is modified by site-directed mutagenesis of four of the cysteine moieties. The design was checked using the same cysteine variants and samples from patients known to be infected with HBsAg variants. The results found were compared with other state-of-the-art commercial screening assays. The design of the Hepanostika HBsAg Ultra enabled detection of all variant HBsAg-positive samples in contrast to the other commercial assays. An additional 980 samples were tested to assess the specificity and sensitivity of the Hepanostika HBsAg Ultra. Screening of presumed negative serum and plasma samples resulted in a specificity of 100%. This makes the Hepanostika HBsAg Ultra the first screening assay with a design able to detect HBsAg variants with high sensitivity and specificity.

[Comments on the Dutch Institute for Health Care Improvement's standard code of practice entitled, "Donation of fetal tissue"]. / Opmerkingen bij het CBO-modelreglement 'Terbeschikkingstelling van foetaal weefsel'.

Under the auspices of the Kwaliteitsinstituut voor de Gezondheidszorg CBO [Dutch Institute for Healthcare Improvement] a standard code of practice was developed as a template for local institutional codes to implement the Law on Foetal Tissue. It is a useful model code, but arguments should have been outlined more explicitly, notably in instances where the code adopts a somewhat stricter position than the Law. The following remarks pertain to the model code: 1. It may be argued that the inclusion or exclusion of 12-15-year-old pregnant girls should be relative to the privacy-related sensitivity of the use of foetal tissue. 2. Transplantation requires additional tests for the safety of the recipient, including testing for HIV/AIDS. A pregnant woman's permission for such testing should not be taken for granted. 3. The abortion technique may be modified in view of the subsequent use of foetal tissue if the woman consents to the modification, with the prerequisites that the modification does not harm the woman and that any potential sensation of pain by the foetus must be minimised.

Adeno-associated viral vector-mediated neurotrophin gene transfer in the injured adult rat spinal cord improves hind-limb function.

To foster axonal growth from a Schwann cell bridge into the caudal spinal cord, spinal cells caudal to the implant were transduced with adeno-associated viral (AAV) vectors encoding for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (AAV-NT-3). Control rats received AAV vectors encoding for green fluorescent protein or saline. AAV-BDNF- and AAV-NT-3-transduced 293 human kidney cells produced and secreted BDNF or NT-3, respectively, in vitro. The secreted neurotrophins were biologically active; they both promoted outgrowth of sensory neurites in vitro. In vivo, transgene expression was observed predominantly in neurons for at least 16 weeks after injection. Compared with controls, a modest though significant improvement in hind-limb function was found in rats that received AAV-BDNF and AAV-NT-3. Retrograde tracing demonstrated that twice as many neurons with processes extending toward the Schwann cell graft were present in the second lumbar cord segment of AAV-BDNF- and AAV-NT-3-injected animals compared with controls. We found no evidence, however, for growth of regenerated axons from the Schwann cell implant into the caudal cord. Our results suggest that AAV vector-mediated overexpression of BDNF and NT-3 in the cord caudal to a Schwann cell bridge modified the local lumbar axonal circuitry, which was beneficial for locomotor function.

Vincristine induced apoptosis in acute lymphoblastic leukaemia cells: a mitochondrial controlled pathway regulated by reactive oxygen species?

Vincristine (VCR), a microtubule interfering anti-cancer agent, plays a key role in the treatment of childhood acute lymphoblastic leukaemia (ALL). The route of VCR induced apoptosis in ALL cells is not well defined. In this study we demonstrated caspase-9 and -3 activation in vivo in bone marrow leukaemic cells of a child with newly diagnosed ALL, after treatment with a single dose of VCR. We hypothesized that VCR induced apoptosis in ALL cells proceeds by a mitochondrial controlled pathway. We further studied the route of VCR induced apoptosis in Jurkat acute lymphoblastic leukaemia cells. First we showed that VCR induces activation of caspase-9 and -3 in Jurkat cells. With the caspase-9 inhibitor Z-LEHD-FMK we proved that caspase-9 was activated prior to caspase-3. Loss of mitochondrial transmembrane potential was independent of caspase-9 activation. To confirm the mitochondrial role in VCR induced apoptosis, the effect of blocking the mitochondrial route upstream of caspase-9 activation was investigated at two different levels: reactive oxygen species (ROS) scavenging and Bcl-2 overexpression. Generation of ROS was detected early in Jurkat cells during VCR exposure. Ascorbic acid, a ROS scavenger, inhibited ROS generation as well as caspase-9 and -3 activation and cell death induced by VCR. Furthermore, in Bcl-2 overexpressing Jurkat cells mitochondrial membrane potential changes, caspase-9 and -3 activation and cell death upon VCR exposure were decreased, in comparison to parental Jurkat cells. However, generation of ROS was not decreased in Jurkat cells with Bcl-2 overexpression. We concluded that ROS play a regulatory role in the initial phase of a mitochondrial controlled pathway of VCR induced apoptosis in Jurkat cells.

Intravitreal injection of adeno-associated viral vectors results in the transduction of different types of retinal neurons in neonatal and adult rats: a comparison with lentiviral vectors.

Replication-deficient viral vectors encoding the marker gene green fluorescent protein (GFP) were injected into the vitreous of newborn, juvenile (P14), and adult rats. We tested two different types of modified virus: adeno-associated viral-2-GFP (AAV-GFP) and lentiviral-GFP vectors (LV-GFP). The extent of retinal cell transduction in different-aged animals was compared 7, 21, and 70 days after eye injections. At all postinjection times, LV-GFP transduction was mostly limited to pigment epithelium and cells in sclera and choroid. In contrast, transduction of large numbers of neural retinal cells was seen 21 and 70 days after AAV-GFP injections. AAV-GFP predominantly transduced neurons, although GFP-positive Müller cells were seen. All neuronal classes were labeled, but the extent of transduction for a given class varied depending on injection age. After P0 injections about 50% of transduced cells were photoreceptors and 30-40% were amacrine or bipolar cells. After adult injections 60-70% of transduced cells were retinal ganglion cells. In adults many GFP-positive retinal axons were traced through the optic nerve/tract and terminal arbors were visualized in central targets.

[A European discussion about stem cells for therapeutic use]. / Een Europese discussie over stamcellen voor therapie.

Stem cells as a source material for growing cellular transplants to repair dysfunctional organs appear to be a new challenge for medical science. Though stem cells are also present in foetal and adult organs, embryonic stem cells from the pre-implantation embryo in particular have the potency to proliferate easily in vitro and the capacity to differentiate into all the body's organ-specific cells. Therefore, these are the ideal cells for developing new cell transplantation therapies for diseases such as Parkinson's disease, diabetes mellitus and heart failure. The use of spare in vitro fertilization (IVF) embryos or pre-implantation embryos specially created to harvest human embryonic stem cells is, however, controversial and an ethical problem. In a European discussion platform organised by the European Commission Research Directorate-General, the status quo of the progress was presented and subsequently commented upon and discussed in terms of medical-ethical, social, industrial and patient interests. The expectations of this new medical technology were high, but clinical trials seem only acceptable once the in vitro differentiation of stem cells can be adequately controlled and once it is known how in vitro prepared stem cells behave after implantation. The ethical justification of the use of in vitro pre-implantation embryos remains controversial. The prevailing view is that the interests of severely ill patients for whom no adequate therapy exists, surmounts the interest of protection of a human in vitro pre-implantation embryo, regardless of whether it was the result of IVF or of transplantation of a somatic cell nucleus of the patient in an enucleated donor egg cell (therapeutic cloning).

The role of serial free/total prostate-specific antigen ratios in a watchful observation protocol for men with localized prostate cancer.

OBJECTIVE: To examine the change in the free/total prostate specific antigen ratio (f/tPSA) with time and to assess the potential value of serial measurements of f/tPSA as a determinant of disease progression in untreated, low-to-intermediate grade prostate cancer (T1b-T2b N0M0, Gleason score < or = 7 and PSA < or = 15 ng/mL). PATIENTS AND METHODS: In a prospective single-arm cohort study from November 1995, patients were conservatively managed with watchful observation alone unless they met arbitrarily defined criteria (clinical, histological and biochemical) of disease progression. Patients were followed regularly and underwent blood tests including PSA and f/tPSA. The initial and mean f/tPSA and the rate of change of f/tPSA with time were evaluated against the rate constant for the PSA doubling time (PSATd). Correlation analyses were used to evaluate any association between baseline clinical variables and either the rate of change of f/tPSA or initial f/tPSA. RESULTS: As of December 2000, 161 of a total of 206 accrued patients had three or more f/tPSA measurements and formed the basis of the study (median age 70 years; median follow-up 2.7 years). The median initial f/tPSA was 0.16; there was a significant negative correlation between this value and the initial total PSA. The mean f/tPSA and rate of change of f/tPSA with time were significantly negatively correlated with the rate constant for PSATd. Also, the rate of change of f/tPSA correlated negatively with clinical T stage, but not with other baseline variables, including initial PSA, age and Gleason score. CONCLUSION: The f/tPSA in men with untreated, clinically localized prostate cancer varied widely. The negative correlation between the rate of change of f/tPSA with time and rate constant for PSATd suggests that both might provide valuable information to allow clinicians to develop a strategy for optimizing the timing of therapeutic intervention for those patients choosing watchful observation alone.

Ethical guidance on human embryonic and fetal tissue transplantation: a European overview.

This article presents an overview of regulations, guidelines and societal debates in eight member states of the EC about a) embryonic and fetal tissue transplantation (EFTT), and b) the use of human embryonic stem cells (hES cells) for research into cell therapy, including 'therapeutic' cloning. There appears to be a broad acceptance of EFTT in these countries. In most countries guidance has been developed. There is a 'strong' consensus about some of the central conditions for 'good clinical practice' regarding EFTT. International differences concern, amongst others, some of the informed consent issues involved, and the questions whether an intermediary organisation is necessary, whether the methods of abortion may be influenced by the possible use of EFT, and whether EFTT should only be used for the experimental treatment of rare disorders. The potential use of hES cells for research into cell therapy has given a new impetus to the debate about (human) embryo research. The therapeutic prospects with regard to the retrieval and research use of hES cells appear to function as a catalyst for the introduction of less restrictive regulations concerning research with spare embryos, at least in some European countries. It remains to be seen whether the prospect of treating patients suffering from serious disorders with transplants produced by therapeutic cloning will decrease the societal and moral resistance to allowing the generation of embryos for 'instrumental' use.

Viral vector-mediated gene expression in olfactory ensheathing glia implants in the lesioned rat spinal cord.

Implantation of olfactory ensheathing glia (OEG) is a promising strategy to augment long-distance regeneration in the injured spinal cord. In this study, implantation of OEG following unilateral hemisection of the dorsal cervical spinal cord was combined with ex vivo gene transfer techniques. We report, to our knowledge for the first time, that purified cultures of primary OEG are capable of expressing a foreign gene following adenoviral (AdV) and lentiviral (LV) vector-mediated gene transfer. OEG implants subjected to AdV vector-mediated gene transfer expressed high levels of transgenic protein in both intact and lesioned spinal cord at 7 days after implantation. However, the levels of transgene expression gradually declined between 7 and 30 days after implantation in lesioned spinal cord. Infection with LV vectors resulted in stable transduction of primary OEG cultures and transgene expression persisted for at least 4 months after implantation. Genetic engineering of OEG opens the possibility of expressing additional neurotrophic genes and create optimal 'bridging' substrates to support spinal axon regeneration. Furthermore, stable transduction of OEG allows us to reliably study the behaviour of implanted cells and to obtain better understanding of their regeneration supporting properties.