Driving and Parkinson's Disease: A Survey of the Patient's Perspective.

BACKGROUND: Parkinson's disease (PD) is a multi-system disorder that can impact on driving ability. Little is known about how these changes in driving ability affect people with PD, making it difficult for clinicians and carers to offer appropriate support. OBJECTIVE: To assess patient views concerning the effect of PD on their driving ability, the impact of these changes and how they manage them. METHOD: An online survey was created by a team of clinicians, people with PD, their carers, and representatives from Parkinson's UK. People with PD throughout the United Kingdom were invited to participate through Parkinson's UK's website, newsletter and Parkinson's Excellence Network email list. RESULTS: 805 people with PD took part in the survey. We found that the loss of a driving licence had an adverse impact on employment, socialisation, travel costs and spontaneous lifestyle choices. Multiple changes in driving ability related to PD were described, including that impulse control disorders can have an adverse impact on driving. Changes in driving ability caused people to change their driving practices including taking shorter journeys and being less likely to drive at night. Participants advised managing changes in driving ability through planning, vehicle adaptions, maintaining skills and self-assessment. CONCLUSION: This study demonstrates the impact that changes in driving ability can have on the lifestyle of people with PD and reveals the strategies that individuals adopt to manage these changes.

Highlighting the goals for Parkinson's care: commentary on NICE Guidelines for Parkinson's in Adults (NG71).

Parkinson's disease is a chronic multi-system disease that can cause motor and non-motor symptoms, cognitive changes and variably effective medications. Optimal management of the condition requires a multi-disciplinary team of healthcare professionals to work closely with the patient and their carers. The National Institute for Health and Care Excellence published updated guidelines on managing Parkinson's disease in adults in 2017. Here we discuss the implications of this guidance to current healthcare professionals involved in the care of people with Parkinson's disease. The guidance highlights the importance of clear communication with people with Parkinson's disease. We discuss examples of this, including providing a point of contact with specialist services for people with Parkinson's disease and ensuring information about the risks of impulse control disorders are given to people on dopaminergic therapy. The breadth of services required by people with Parkinson's disease is also described, including the need for access to physiotherapy, occupational therapy and speech and language therapy as well as treatment monitoring services for Clozapine. In addition, we emphasise the continued importance of ensuring people with Parkinson's disease receive their medications on time when in hospital or a care home.

Why geriatric medicine? A survey of UK specialist trainees in geriatric medicine.

Background: there is concern that there are insufficient numbers of geriatricians to meet the needs of the ageing population. A 2005 survey described factors that influenced why UK geriatricians had chosen to specialise in the field-in the decade since, UK postgraduate training has undergone a fundamental restructure. Objective: to explore whether the reasons for choosing a career in geriatric medicine in the UK had changed over time, with the goal of using this knowledge to inform recruitment and training initiatives. Design: an online survey was sent to all UK higher medical trainees in geriatric medicine. Methods: survey questions that produced categorical data were analysed with simple descriptive statistics. For the survey questions that produced free-text responses, an inductive, iterative approach to analysis, in keeping with the principles of framework analysis, was employed. Results: two hundred and sixty-nine responses were received out of 641 eligible respondents. Compared with the previous survey, a substantially larger number of respondents regarded geriatric medicine to be their first-choice specialty and a smaller number regretted their career decision. A greater number chose geriatric medicine early in their medical careers. Commitments to the general medical rota and the burden of service provision were considered important downsides to the specialty. Conclusions: there are reasons to be optimistic about recruitment to geriatric medicine. Future attempts to drive up recruitment might legitimately focus on the role of the medical registrar and perceptions that geriatricians shoulder a disproportionate burden of service commitments and obligations to the acute medical take.

12 tips for developing trainee-led initiatives to promote recruitment to training in shortage specialties.

This article was migrated. The article was marked as recommended. The healthcare needs of the global population are changing, leaving many medical specialties facing ballooning demand in the context of under-filled specialty training programmes. In this paper we draw on a synthesis of existing literature and our experiences of developing a series of initiatives to tackle the challenge of recruitment to specialty training in geriatric medicine in the UK. We propose a set of strategies that can contribute to the development and success of such initiatives and commend these to healthcare professionals, both junior and senior, who are working in so-called 'shortage' specialities facing recruitment challenges. A common theme throughout the twelve tips is the need to empower trainees to deliver such initiatives. Trainees' unique insight into training programmes, coupled with their burgeoning enthusiasm for their chosen specialty, ought to be harnessed, as it offers a ripe source of potential ideas and solutions to tackle recruitment problems.

Synergistic growth inhibitory effects of the dual endothelin-1 receptor antagonist bosentan on pancreatic stellate and cancer cells.

Pancreatic stellate cells (PSC) play a key role in pancreatic fibrosis. Activation of PSC occurs in response to pro-fibrogenic stimuli and is maintained by autocrine loops of mediators, such as endothelin (ET)-1. Here, we have evaluated effects of the dual ET receptor antagonist bosentan in models of pancreatic fibrogenesis and cancer. Cell culture studies revealed that PSC and DSL6A pancreatic cancer cells expressed both ET-1 and ET receptors. Bosentan efficiently inhibited proliferation of both cell types and collagen synthesis in PSC. Expression of the myofibroblastic marker alpha-smooth muscle actin, connective tissue growth factor, and ET-1 itself in PSC was reduced, while expression of matrix metalloproteinase-9 was enhanced. Like PSC, DSL6A cells secrete less ET-1 when cultured with bosentan. In a rat model of pancreatic fibrosis, chronic pancreatitis induced by dibutyltin dichloride, a tendency towards a diminished disease progression was observed in a subgroup of rats with less severe disease. Together, our results indicate that bosentan exerts antifibrotic and antitumor effects in vitro. Its efficiency in vivo warrants further investigation.

Molecular insights into connective tissue growth factor action in rat pancreatic stellate cells.

Pancreatic fibrosis, a key feature of chronic pancreatitis and pancreatic cancer, is mediated by activated pancreatic stellate cells (PSC). Connective tissue growth factor (CTGF) has been suggested to play a major role in fibrogenesis by enhancing PSC activation after binding to alpha5beta1 integrin. Here, we have focussed on molecular determinants of CTGF action. Inhibition of CTGF expression in PSC by siRNA was associated with decreased proliferation, while application of exogenous CTGF stimulated both cell growth and collagen synthesis. Real-time PCR studies revealed that CTGF target genes in PSC not only include mediators of matrix remodelling but also the proinflammatory cytokines interleukin (IL)-1beta and IL-6. CTGF stimulated binding of NF-kappaB to the IL-6 promoter, and siRNA targeting the NF-kappaB subunit RelA interfered with CTGF-induced IL-6 expression, implicating the NF-kappaB pathway in the mediation of the CTGF effect. In further studies, we have analyzed regulation of CTGF expression in PSC. Transforming growth factor-beta1, activin A and tumor necrosis factor-alpha enhanced expression of the CTGF gene, while interferon-gamma displayed the opposite effect. The region from -74 to -125 of the CTGF promoter was revealed to be critical for its activity in PSC as well as for the inhibitory effect of interferon-gamma. Taken together, our results indicate a tight control of CTGF expression in PSC at the transcriptional level. CTGF promotes fibrogenesis both directly by enhancing PSC proliferation and matrix protein synthesis, and indirectly through the release of proinflammatory cytokines that may accelerate the process of chronic inflammation.

Leukocytapheresis (LCAP) in the management of chronic active ulcerative colitis--results of a randomized pilot trial.

Recent studies suggest that leukocytapheresis with Cellsorba is a valuable therapy for ulcerative colitis after failure of conventional treatment. In this study the potential of leukocytapheresis to induce remission in refractory chronic colitis under the conditions of European treatment guidelines was investigated. The therapeutic benefit of leukocytapheresis in the maintenance of remission was additionally elucidated. Twenty patients were treated weekly for 5 weeks. A significant decrease in the activity index was observed. Fourteen patients achieved clinical remission, and mucosal healing was observed endoscopically in six patients. After randomization these 14 patients in remission entered a second period of either monthly leukocytapheresis or no further treatment. In both groups steroids were tapered down. After 6 months, only one patient in the control group remained in remission, in contrast to five of eight patients in the leukocytapheresis group. In conclusion, leukocytapheresis may offer a therapeutic option in the induction and the maintenance of remission in chronic active ulcerative colitis.

Inhibitory effects of interferon-gamma on activation of rat pancreatic stellate cells are mediated by STAT1 and involve down-regulation of CTGF expression.

Pancreatic stellate cells (PSCs) are the main source of extracellular matrix proteins in pancreatic fibrosis, a pathological feature of chronic pancreatitis and pancreatic cancer. Interferon-gamma (IFN-gamma) is an antifibrotic cytokine, but how precisely it exerts its effects on PSCs is largely unknown. Here, we have focussed on the role of STAT1 as well as target genes of IFN-gamma signalling. Our data indicate that IFN-gamma regulates the expression of two autocrine mediators of PSC activation, connective tissue growth factor and endothelin-1, in a transforming growth factor-beta1-antagonistic manner. STAT1 overexpression under the control of a tetracycline-dependent promoter revealed a close correlation between STAT1 expression and activation, the biological effects of IFN-gamma (growth inhibition, induction of apoptosis), and target gene expression. Our data further support the hypothesis that IFN-gamma interferes with stellate cell activation in the pancreas and suggest activated STAT1 as an inductor of a quiescent PSC phenotype.

Adenovirus-mediated gene transfer of interleukin-4 into pancreatic stellate cells promotes interleukin-10 expression.

Pancreatic stellate cells (PSC) are crucially involved in the development of fibrosis, a hallmark of chronic pancreatitis. Therefore, PSC represent an attractive target for the modulation of cellular functions providing the prerequisite for the establishment of novel therapeutic strategies like transfer of genetic material to the cells. Based on recent studies suggesting that the chronic course of pancreatitis is associated with immune deviation towards a Th1 cytokine profile, we have investigated the applicability of primary PSC to an adenovirus-mediated transfer of the cDNA encoding the Th2 cytokine interleukin (IL) 4 and the autocrine-acting effects of IL 4 on the cells in vitro. The transduction of primary PSC with a replication-incompetent adenovirus type 5 vector carrying the cDNA encoding rat IL- 4 resulted in a distinct expression of the cytokine on mRNA and protein level for two weeks. Similar to recombinant IL 4, effects of the endogenously synthesized cytokine were mediated by the signal transducer and activator of transcription (STAT)6. Interestingly, beside the increase of PSC proliferation, IL 4 transduction was accompanied by an up-regulation in the endogenous expression of the anti-inflammatory cytokine IL 10. In summary, our data suggest that PSC are suitable targets for gene therapy modulating cellular interactions in the pancreas.

Delayed response toward activation stimuli in pancreatic stellate cells.

OBJECTIVES: Pancreatic stellate cells (PSCs) are known to be crucially involved in the development of pancreatic fibrosis, a characteristic feature of chronic pancreatitis and pancreatic cancer. The key event in the pathogenesis of fibrosis represents a transition process of quiescent PSCs into a myofibroblastlike phenotype associated with cell activation in terms of proliferation and synthesis of profibrogenic substances. There is little information available regarding the dynamics of the complex processes initiated by an activating stimulus in quiescent stellate cells. METHODS: Using microarray analysis, we characterized the expression profiles during PSC activation caused by in vitro cultivation on days 2, 4, 7, and 14 after cell isolation. Activation status has been identified by the expression of the activation marker alpha-smooth muscle actin. Genes of interest were subjected to reverse transcription-polymerase chain reaction. To test biologic functions, the responsiveness of stellate cells toward the activators activin A and transforming growth factor-beta1 was investigated in dependence on the cell transition status. RESULTS: Our results revealed that freshly isolated (=quiescent) PSCs were refractory to stimuli for several days, a phenomenon that we referred to as delay phase. CONCLUSION: The retarded response could be considered a protection mechanism to prevent inappropriate stellate cell activation.

Peroxisome proliferator-activated receptor gamma overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells.

Pancreatic stellate cells (PSCs) play a key role in the development of pancreatic fibrosis, a constant feature of chronic pancreatitis and pancreatic cancer. In response to pro-fibrogenic mediators, PSCs undergo an activation process that involves proliferation, enhanced production of extracellular matrix proteins and a phenotypic transition towards myofibroblasts. Ligands of the peroxisome proliferator-activated receptor gamma (PPARgamma), such as thiazolidinediones, are potent inhibitors of stellate cell activation and fibrogenesis in pancreas and liver. The effects of PPARgamma ligands, however, are at least in part mediated through PPARgamma-independent pathways. Here, we have chosen a different approach to study regulatory functions of PPARgamma in PSCs. Using immortalised rat PSCs, we have established a model of tetracycline (tet)-regulated PPARgamma overexpression. Induction of PPARgamma expression strongly inhibited proliferation and enhanced the rate of apoptotic cell death. Furthermore, PPARgamma-overexpressing cells synthesised less collagen than controls. To monitor effects of PPARgamma on PSC gene expression, we employed Affymetrix microarray technology. Using stringent selection criteria, we identified 21 up- and 19 down-regulated genes in PPARgamma-overexpressing cells. Most of the corresponding gene products are either involved in lipid metabolism, play a role in signal transduction, or are secreted molecules that regulate cell growth and differentiation. In conclusion, our data suggest an active role of PPARgamma in the induction of a quiescent PSC phenotype. PPARgamma-regulated genes in PSCs may serve as novel targets for the development of antifibrotic therapies.

Interleukin-4 gene transfer into rat pancreas by recombinant adenovirus.

OBJECTIVE: Adenovirus-mediated gene transfer technology may provide a novel approach in the treatment of pancreatic diseases. In the rat model of chronic pancreatitis induced by dibutyltin dichloride (DBTC), Th1 lymphocytes are known to be involved in the mediation of inflammation. We therefore investigated whether local expression of the Th2 cytokine interleukin (IL)-4 might modulate the inflammatory response. To address this question, we have established a protocol of efficient gene transfer into rat pancreas. MATERIAL AND METHODS: Recombinant adenovirus constructs carrying the Escherichia coli beta-galactosidase gene (Adbeta-gal) or the rat IL-4 gene (AdrIL-4) were injected into the left gastric artery of healthy LEW.1W rats. Expression of beta-Gal and IL-4 in pancreatic cells was analyzed by X-Gal staining and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. After optimization of the transduction protocol, effects of the IL-4 gene transfer on pancreatic inflammation and fibrosis were studied in DBTC-treated rats. RESULTS: Seven days after Adbeta-gal injection, beta-gal-positive cells were detectable in the rat pancreas. RT-PCR analysis using RNA from pancreata of AdrIL-4-treated rats indicated that IL-4 was expressed for at least 14 days after adenovirus application. Expression of the IL-4 transgene was accompanied by a transient increase of the IL-10 mRNA level in the pancreas. In DBTC-treated rats, adenovirus-mediated transfer of the IL-4 gene modified the pattern of infiltrating inflammatory cells in the pancreas. Importantly, a decrease of CD4+ helper cells was observed. CONCLUSIONS: Our data suggest that the injection of recombinant adenoviruses into the left gastric artery is a promising approach to achieving expression of therapeutic transgenes in the pancreas.

Inhibition of lymphocyte apoptosis by pancreatic stellate cells: impact of interleukin-15.

There is growing evidence that pancreatic stellate cells (PSCs) produce cytokines and take part in the regulation of inflammatory processes in the pancreas. IL-15 inhibits apoptosis of various cell populations. This study was performed to investigate whether PSCs produce IL-15 and thereby can affect lymphocytes. Primary PSCs were isolated from the rat pancreas using density gradient centrifugation. mRNA expression of IL-15 was demonstrated by RT-PCR, and IL-15 protein was analyzed by immunoblotting. Lymphocytes obtained from rat mesenterial lymph nodes were cocultured with in vitro activated PSCs. Apoptosis has been quantified by the binding of annexin V-FITC with a flow cytometer. Proliferation was monitored using [3H]thymidine incorporation. PSCs express two splice variants of IL-15. The protein was detectable only in cell lysates but not in the cell culture supernatant. Cocultivation of lymphocytes with PSCs and IL-15 inhibited spontaneous lymphocyte apoptosis, and this effect was reduced by an anti-IL-15 antibody. Lymphocytes induced vice versa the proliferation and collagen production of PSCs. The inhibition of spontaneous lymphocyte apoptosis in cocultures with PSCs was at least partially mediated by cell-bound IL-15. This effect and the stimulation of PSCs by lymphocytes may lead to a circulus vitiosus, resulting in the persistence of inflammatory processes and the development of fibrosis during chronic pancreatitis.

Regulation of pancreatic stellate cell function in vitro: biological and molecular effects of all-trans retinoic acid.

Pancreatic stellate cells (PSCs) are essentially involved in the development of pancreatic fibrosis, a constant feature of chronic pancreatitis and pancreatic cancer. Profibrogenic mediators, such as ethanol metabolites and cytokines, induce a PSC activation process that involves proliferation, enhanced production of extracellular matrix proteins and a phenotypic transition towards myofibroblasts which includes a loss of the characteristic retinoid-containing fat droplets. Here, we have analysed how exogenous all-trans retinoic acid (ATRA) affects activation of rat PSCs induced by sustained culture. Bromodeoxyuridine-incorporation assays indicated an ATRA-dependent inhibition of DNA synthesis. In contrast, ATRA did not affect expression of alpha-smooth muscle actin, a protein typical for myofibroblasts. Quantification of [3H]proline incorporation revealed a diminished collagen production in ATRA-treated PSCs. Furthermore, zymography experiments showed that supernatants of ATRA-exposed PSC cultures contained higher levels of matrix metalloproteinase-9 but not of matrix metalloproteinase-2 than untreated controls. At the level of intracellular signalling, ATRA had no effect on extracellular signal-regulated kinase activation after incubation of PSCs with the mitogen platelet-derived growth factor (PDGF). In addition, PDGF-induced DNA binding of activator protein-1 (AP-1) transcription factors was not inhibited by ATRA treatment. Luciferase reporter gene assays, however, revealed an ATRA-dependent transrepression of AP-1 in PDGF-stimulated PSCs. Together, the results indicate that exogenous ATRA displays inhibitory effects on PSC proliferation and collagen synthesis but does not block phenotypic transition towards myofibroblasts. We hypothesise that inhibition of AP-1 signalling may be involved in the mediation of biological effects of ATRA on PSCs.

Inhibition of pancreatic stellate cell activation by the hydroxymethylglutaryl coenzyme A reductase inhibitor lovastatin.

Pancreatic stellate cells (PSCs) play a key role in pancreatic fibrosis, a constant feature of chronic pancreatitis. PSC activation occurs in response to profibrogenic mediators such as cytokines and involves proliferation, transition towards a myofibroblastic phenotype and enhanced production of extracellular matrix proteins. Previously, we have shown that PSC activation correlates with the activity of the Ras-Raf-ERK (extracellular signal-regulated kinase) signalling cascade [Gut 51 (2002) 579]. Using a rat culture model of PSCs, we have now evaluated the effects of lovastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor that interferes with protein isoprenylation, on PSC viability and activation as well as on signalling through Ras proteins. Apoptotic cells were detected applying the TUNEL assay. Proliferation of PSCs was quantitated using the bromodeoxyuridine DNA incorporation assay. Expression of alpha-smooth muscle actin (an indicator of the myofibroblastic phenotype), ERK activation and membrane translocation of the Ras superfamily member RhoA were analysed by immunoblotting. Lovastatin inhibited serum- and platelet-derived growth factor-stimulated PSC proliferation in a dose-dependent manner. At drug concentrations above the level required for growth inhibition, a strong increase of apoptotic cells was observed. Furthermore, lovastatin inhibited induction of alpha-smooth muscle actin expression in the course of primary culture. Immunoblot experiments indicated that lovastatin suppressed both Ras-mediated ERK 1/2 activation and platelet-derived growth factor-induced membrane translocation of RhoA. Together, our data suggest that lovastatin, through the interruption of Ras signalling, interferes with PSC activation. The antifibrotic efficiency of statins should be tested in animal models of chronic pancreatitis.