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1.
Physiol Meas ; 41(5): 054002, 2020 06 19.
Article in English | MEDLINE | ID: mdl-32259798

ABSTRACT

OBJECTIVE: Smartphone devices may enable out-of-clinic assessments in chronic neurological diseases. We describe the Draw a Shape (DaS) Test, a smartphone-based and remotely administered test of Upper Extremity (UE) function developed for people with multiple sclerosis (PwMS). This work introduces DaS-related features that characterise UE function and impairment, and aims to demonstrate how multivariate modelling of these metrics can reliably predict the 9-Hole Peg Test (9HPT), a clinician-administered UE assessment in PwMS. APPROACH: The DaS Test instructed PwMS and healthy controls (HC) to trace predefined shapes on a smartphone screen. A total of 93 subjects (HC, n = 22; PwMS, n = 71) contributed both dominant and non-dominant handed DaS tests. PwMS subjects were characterised as those with normal (nPwMS, n = 50) and abnormal UE function (aPwMS, n = 21) with respect to their average 9HPT time (≤ or > 22.7 (s), respectively). L 1-regularization techniques, combined with linear least squares (OLS, IRLS), or non-linear support vector (SVR) or random forest (RFR) regression were investigated as functions to map relevant DaS features to 9HPT times. MAIN RESULTS: It was observed that average non-dominant handed 9HPT times were more accurately predicted by DaS features (r 2 = 0.41, [Formula: see text] 0.05; MAE: 2.08 ± 0.34 (s)) than average dominant handed 9HPTs (r 2 = 0.39, [Formula: see text] 0.05; MAE: 2.32 ± 0.43 (s)), using simple linear IRLS ([Formula: see text] 0.01). Moreover, it was found that the Mean absolute error (MAE) in predicted 9HPTs was comparable to the variability of actual 9HPT times within HC, nPwMS and aPwMS groups respectively. The 9HPT however exhibited large heteroscedasticity resulting in less stable predictions of longer 9HPT times. SIGNIFICANCE: This study demonstrates the potential of the smartphone-based DaS Test to reliably predict 9HPT times and remotely monitor UE function in PwMS.


Subject(s)
Diagnostic Techniques and Procedures/instrumentation , Multiple Sclerosis/diagnosis , Multiple Sclerosis/physiopathology , Smartphone , Upper Extremity/physiopathology , Adult , Female , Humans , Male , Regression Analysis
2.
Sleep Med X ; 2: 100027, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33870178

ABSTRACT

OBJECTIVE/BACKGROUND: The benefit of Continuous Positive Airway Pressure (CPAP) treatment following ischemic stroke in patients with obstructive sleep-disordered breathing (SDB) is unclear. We set out to investigate this open question in a randomized controlled trial as part of the SAS-CARE study. PATIENTS/METHODS: Non-sleepy patients (ESS < 10) with ischemic stroke or transient ischemic attack (TIA) and obstructive SDB (AHI ≥ 20) 3 months post-stroke were randomized 1:1 to CPAP treatment (CPAP+) or standard care. Primary outcome was the occurrence of vascular events (TIA/stroke, myocardial infarction/revascularization, hospitalization for heart failure or unstable angina) or death within 24 months post-stroke. Secondary outcomes included Modified Rankin Scale (mRS) and Barthel Index. RESULTS: Among 238 SAS-CARE patients 41 (17%) non-sleepy obstructive SDB patients were randomized to CPAP (n = 19) or standard care (n = 22). Most patients (80%) had stroke and were males (78%), mean age was 64 ± 7 years and mean NIHSS score 0.6 ± 1.0 (range: 0-5). The primary endpoint was met by one patient in the standard care arm (a new stroke). In an intent-to treat analysis disregarding adherence, this corresponds to an absolute risk difference of 4.5% or an NNT = 22. mRS and Barthel Index were stable and similar between arms. CPAP adherence was sufficient in 60% of evaluable patients at month 24. CONCLUSION: No benefit of CPAP started three months post-stroke was found in terms of new cardio- and cerebrovascular events over 2 years. This may be related to the small size of this study, the mild stoke severity, the exclusion of sleepy patients, the delayed start of treatment, and the overall low event rate.

3.
Parkinsonism Relat Disord ; 64: 118-123, 2019 07.
Article in English | MEDLINE | ID: mdl-30935828

ABSTRACT

BACKGROUND: Pallidal deep brain stimulation (DBS) has shown to be beneficial in patients with advanced levodopa-responsive Parkinson's disease (PD) in several short-term studies. However, reported long-term outcomes of pallidal DBS for PD are limited and contradictory. METHODS: Eighteen consecutive PD patients were treated with unilateral or bilateral stimulation of the internal part of the globus pallidus (GPi). Assessments were carried out before and six months after neurosurgery, and annually thereafter for up to 16 years (mean follow-up time: 6 years). Primary outcomes included motor signs (Unified PD Rating Scale [UPDRS]-III), activities of daily living (ADL, UPDRS-II), and levodopa-induced motor complications (UPDRS-IV). RESULTS: The results show that GPi stimulation improves levodopa-responsive PD motor signs (UPDRS-III), levodopa-induced motor complications (UPDRS-IV), and ADL (UPDRS-II) in advanced PD. Among motor signs, tremor showed the best response to pallidal stimulation. Levodopa-induced motor complications and tremor showed improvements for more than 10 years after neurosurgery. CONCLUSIONS: The overall findings in our cohort demonstrate that pallidal stimulation is effective in reducing parkinsonian motor signs (UPDRS-III), particularly in the 'off'-medication state. Although the beneficial effects on bradykinesia, rigidity and ADL may be limited to 5-6 years, the follow up results indicate that the improvements of levodopa-induced motor complications (UPDRS-IV) and tremor can be sustained for more than 10 years.


Subject(s)
Deep Brain Stimulation/methods , Globus Pallidus , Parkinson Disease/therapy , Aged , Cohort Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Time , Treatment Outcome
4.
J Neurovirol ; 25(1): 133-136, 2019 02.
Article in English | MEDLINE | ID: mdl-30414049

ABSTRACT

Long-term treatment of multiple sclerosis with natalizumab (NTZ) carries the risk of a devastating complication in the form of an encephalopathy caused by a reactivation of a latent John Cunningham virus infection (progressive multifocal leucoencephalopathy, PML). Early diagnosis is associated with considerably better prognosis. Quantitative EEG as an objective, rater-independent technique provides high sensitivity (88%) and specificity (82%) for the diagnosis of NTZ-PML. Combination of diagnostic modalities addressing static morphological (brain MRI) as well as functional (EEG) pathologic changes may improve risk management programmes.


Subject(s)
Electroencephalography/methods , Immunologic Factors/adverse effects , JC Virus/drug effects , Leukoencephalopathy, Progressive Multifocal/diagnosis , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Natalizumab/adverse effects , Adult , Female , Humans , Immunologic Factors/administration & dosage , JC Virus/growth & development , JC Virus/pathogenicity , Leukoencephalopathy, Progressive Multifocal/chemically induced , Leukoencephalopathy, Progressive Multifocal/pathology , Leukoencephalopathy, Progressive Multifocal/virology , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/pathology , Natalizumab/administration & dosage , Prognosis , Retrospective Studies , Virus Activation/drug effects
6.
Am J Transplant ; 13(5): 1253-61, 2013 May.
Article in English | MEDLINE | ID: mdl-23480233

ABSTRACT

Therapeutic drug monitoring (TDM) for tacrolimus (Tac) is universally applied. However, the concentration-effect relationship for Tac is poorly defined. This study investigated whether Tac concentrations are associated with acute rejection in kidney transplant recipients. Data from three large trials were pooled. We used univariate and multivariate analysis to investigate the relationship between biopsy-proven acute rejection (BPAR) and Tac predose concentration at five time points (day 3, 10 and 14, and month 1 and 6 after transplantation). A total of 136/1304 patients experienced BPAR, giving an overall incidence of 10.4%. We did not find any significant correlations between Tac predose concentrations and the incidence of BPAR at the different time points. In the multivariate analysis, only delayed graft function (DGF) and the use of induction therapy were independently correlated with BPAR, with an odds ratio of 2.7 [95% CI: 1.8-4.0; p < 0.001] for DGF and 0.66 [95% CI: 0.44-0.99; p = 0.049] for induction therapy. The other variables, including the Tac predose concentrations, were not statistically significantly associated with BPAR. We did not find an association between the Tac predose concentrations measured at five time points after kidney transplantation and the incidence of acute rejection occurring thereafter. Based on this study it is not possible to define the optimal target concentrations for Tac.


Subject(s)
Graft Rejection/metabolism , Kidney Transplantation , Tacrolimus/pharmacokinetics , Acute Disease , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Graft Rejection/drug therapy , Graft Rejection/epidemiology , Humans , Immunosuppressive Agents/administration & dosage , Incidence , Male , Middle Aged , Netherlands/epidemiology , Prognosis , Tacrolimus/administration & dosage , Time Factors
7.
Lett Appl Microbiol ; 50(6): 571-7, 2010 Jun 01.
Article in English | MEDLINE | ID: mdl-20337928

ABSTRACT

AIMS: The aim of our study was to investigate indoor air quality (IAQ) by comparing pyrogen concentration and microbiological contamination in offices in public buildings. METHODS AND RESULTS: Air samples were collected during cold and warm seasons in 39 offices in four European cities. Pyrogens were measured by the in vitro pyrogen test (IPT), moulds and bacteria by classical microbiology. In 92% of the investigated offices, pyrogen and microbial contaminations were below 150 EEU m(-3) and 10(3) CFU m(-3), respectively, whilst in 75%, moulds did not exceed 10(2) CFU m(-3). CONCLUSIONS: The IPT is a rapid, reliable tool for measuring pyrogens that could be used as an 'early warning' indicator of IAQ. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study on pyrogenic compound detection in offices using IPT, which could serve for developing future indoor air guidelines.


Subject(s)
Aerosols/analysis , Air Microbiology , Air Pollution, Indoor/analysis , Bacteria/isolation & purification , Fungi/isolation & purification , Pyrogens/isolation & purification , Bacteria/classification , Environmental Monitoring , Fungi/classification , Pilot Projects , Pyrogens/classification
8.
Eur J Clin Invest ; 39(11): 1010-6, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19807782

ABSTRACT

BACKGROUND: Endonasal blood volume depends on autonomous nervous system activation and ultimately vascular reactivity. It can be measured by optical rhinometry, a simple- to-use, subject-compliance independent method. We investigated endonasal perfusion following postural change to determine predictors of vascular response. MATERIALS AND METHODS: Optical rhinometry was performed in 52 healthy subjects (25 women) with an age range of 21-80 years. Subjects were placed in supine position after 5 min of standing. Optical density (OD) as marker of endonasal blood volume was continuously measured for 30 min after postural change. In addition to age, data on other risk factors for impaired vascular reactivity, such as gender, smoking, level of physical activity, resting heart rate and blood pressure were obtained. To evaluate raw-data curves, integrals over defined time-periods were calculated. RESULTS: The OD initially increased following the intervention (t(max) at 207 +/- 12 s, mean +/- SEM). Thereafter, a gradual return to baseline levels was observed in young but not in elderly subjects. In multivariate models, age was the most influential parameter for vascular response followed by body mass index. The defined integrals as indicators of curve structure were all significantly influenced by age (P < 0.01 for each interval). Other measured risk factors had no effect on curve characteristics. CONCLUSIONS: Age is an important predictor of endonasal perfusion. Evaluation of optical rhinometry needs to take age-dependency of results into account. Studies in patients with cardiovascular disease are needed to show if optical rhinometry can provide information about vascular responsiveness as a predictor of cardiovascular morbidity.


Subject(s)
Aging/physiology , Autonomic Nervous System/physiopathology , Blood Volume/physiology , Cardiovascular Diseases/physiopathology , Nasal Mucosa/pathology , Rhinometry, Acoustic/methods , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Nasal Cavity , Predictive Value of Tests , Prevalence , Prospective Studies , Young Adult
9.
Am J Transplant ; 9(8): 1876-85, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19563339

ABSTRACT

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: -0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 +/- 23.8 ml/min vs. 65.9 +/- 26.2 ml/min in the standard-dose cyclosporine, 64.0 +/- 23.1 ml/min in the low-dose cyclosporine and 65.3 +/- 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Calcineurin Inhibitors , Cyclosporine/therapeutic use , Graft Rejection/prevention & control , Immunoglobulin G/therapeutic use , Kidney Transplantation/immunology , Mycophenolic Acid/analogs & derivatives , Tacrolimus/therapeutic use , Adolescent , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Cyclosporine/adverse effects , Daclizumab , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Follow-Up Studies , Graft Rejection/epidemiology , Graft Rejection/immunology , Humans , Immunoglobulin G/adverse effects , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Incidence , Kaplan-Meier Estimate , Kidney Failure, Chronic/surgery , Male , Middle Aged , Mycophenolic Acid/adverse effects , Mycophenolic Acid/therapeutic use , Prospective Studies , Tacrolimus/adverse effects , Treatment Outcome , Young Adult
10.
Dis Aquat Organ ; 81(3): 241-7, 2008 Sep 24.
Article in English | MEDLINE | ID: mdl-18998588

ABSTRACT

Immune defence in creel-caught and trawled Nephrops norvegicus was investigated to assess a possible relationship between phenoloxidase (PO) activation and the total haemocyte count (THC). Capture, capture method and emersion evoked physiological and immunological responses that may have implications for the ability of N. norvegicus to survive the effects of such stressors. Haemolymph THC was always negatively related to PO activity in the trawled samples, suggesting a decreased level of the plasma serine proteinase inhibitors which reportedly regulate the ProPO system (Le Moullac et al. 1998; Fish shellfish Immunol 8:621-629). In contrast, creel-caught samples showed increased levels of both PO and THC (cf. control N. norvegicus), after a 12 h emersion period. Trawling and emersion evoked progressive and significant increases (p < 0.05) in the mean levels of haemolymph L-lactate, glucose and total ammonia. The evidence of overt activity and measured haemolymph parameters suggest that creel fishing yields N. norvegicus that are more likely to survive post-harvest treatments than those that are trawled.


Subject(s)
Fisheries/methods , Immersion , Nephropidae/physiology , Ammonia/metabolism , Animals , Cell Count , Glucose/metabolism , Hemolymph/cytology , Hemolymph/enzymology , Hemolymph/metabolism , Lactic Acid/metabolism , Monophenol Monooxygenase/metabolism , Nephropidae/immunology
11.
Vet Parasitol ; 157(3-4): 321-7, 2008 Nov 07.
Article in English | MEDLINE | ID: mdl-18774229

ABSTRACT

In Europe, Thelazia callipaeda has been reported in Italy and France in the eyes of dogs, cats and foxes and, recently, also in humans. In southern Switzerland (Ticino), the first case of T. callipaeda in a dog was detected in 2000 and because of an increasing number of dog thelaziosis, a survey in veterinary practices was carried out. A total of 106 Thelazia-positive dogs from a retrospective analysis and from ongoing cases between 2005 and 2007 as well as five positive cats were reported. For a cross-sectional study, 529 randomly selected dogs (from six veterinary practices), to which anaesthesia was given for other medical reasons, were additionally checked for the presence of adult specimens of Thelazia in 2006: 28 dogs were found positive indicating an overall prevalence of 5.3%. Thelazia-infection was furthermore diagnosed in 7 of 126 foxes (5.6%) shot in Ticino in winter 2005-2006. Affected foxes, dogs and cats originated from the same regions up to 863m of altitude. The cats and 57.9% (55/95) of the infected dogs had never crossed the Swiss border. Collected nematodes were morphologically identified as T. callipaeda, and this diagnosis was confirmed by the analysis of a part of the sequence of the mitochondrial cytochrome c oxidase subunit 1 gene (cox1), revealing haplotype 1, the only one so far found in Europe. Animals harboured 1-23 eye worms. The most common symptoms were conjunctivitis and epiphora, while keratitis was present only in a low number of animals. Young and small sized dogs were significantly less involved than large animals and over 3 years of age. The results indicate that thelaziosis is endemic in that area.


Subject(s)
Dog Diseases/parasitology , Eye Diseases/veterinary , Spirurida Infections/veterinary , Thelazioidea/isolation & purification , Animals , Cat Diseases/epidemiology , Cat Diseases/parasitology , Cats , Communicable Diseases, Emerging/veterinary , Dog Diseases/epidemiology , Dogs , Eye Diseases/epidemiology , Eye Diseases/parasitology , Foxes/parasitology , Prevalence , Spirurida Infections/epidemiology , Switzerland/epidemiology
12.
Dis Aquat Organ ; 82(2): 135-43, 2008 Nov 20.
Article in English | MEDLINE | ID: mdl-19149376

ABSTRACT

The effects of prolonged emersion (24, 48 and 72 h) and subsequent re-immersion on Nephrops norvegicus (L.) held at 5 degrees C were assessed using an index of physical quality criteria and a suite of haemolymph constituent assays. Collectively, these showed classical hypoxia-induced changes over 48 h of emersion, but, subsequently, between 48 and 72 h emersion, physical activity, haemolymph pH and circulating levels of urate, free amino acids and major ions all returned to normal (control) levels, and L-lactate levels had started to decrease towards control levels. These patterns of changes differed from that of the haemolymph total ammonia levels which continued to increase linearly throughout emersion. N. norvegicus appeared to partially compensate for the post- 48 h emersion increased levels by increasing the production, and hence relative proportions, of other less toxic nitrogenous metabolites. The data replicated that of preliminary trials. Working on the presumption that such events could occur only in the presence of oxygen, possible sources of such oxygen under prolonged hypoxia are discussed. The low holding temperature appears to be the key to prolonged survival of N. norvegicus, and the switch from anaerobic to aerobic respiration itself appears to be a function of a preceding, prolonged period of hypoxia. The ecological and commercial implications for a burrow-dwelling, benthic animal that may experience episodic periods of hypoxia and which forms a highly important proportion of the value of total UK commercial landings are discussed.


Subject(s)
Hemolymph/chemistry , Nephropidae/physiology , Oxygen/metabolism , Amino Acids/analysis , Amino Acids/metabolism , Ammonia/metabolism , Animals , Electrolytes/metabolism , Hemocyanins/metabolism , Hemolymph/physiology , Hydrogen-Ion Concentration , Immersion , Lactic Acid/metabolism , Uric Acid/metabolism , Water
13.
Am J Transplant ; 8(1): 50-7, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17973969

ABSTRACT

Renal transplantation faces challenges: the organ shortage resulting in extended waiting times and an aging population resulting in death with a functioning graft. The Eurotransplant Senior Program (ESP) allocates kidneys within a narrow geographic area from donors aged >/=65 years to recipients >/=65 years regardless of HLA. This analysis investigates the impact of the ESP on waiting time, graft and patient survival. The ESP group (n = 1406, old to old) was compared to two groups allocated via the Eurotransplant Kidney Allocation System (ETKAS) with either similar donor age (old to any [O/A], donor age >/=65, n = 446) or recipient age (any to old, [A/O], recipient age 60-64, n = 1687). All patients were transplanted between 1999 and 2004. Since initiation of the ESP (1999), availability of elderly donors doubled and waiting time for ESP patients decreased. Local allocation led to shorter cold ischemia time (11.9 vs. >17.0 h, p < 0.001) and less delayed graft function (DGF, ESP 29.7% vs. O/A 36.2%, p = 0.047) but 5-10% higher rejection rates. Graft and patient survival were not negatively affected by the ESP allocation when compared to the standard allocation. The ESP age matching of elderly donors and recipients is an effective allocation system for organs from elderly donors.


Subject(s)
Kidney Transplantation , Tissue Donors , Tissue and Organ Procurement , Age Factors , Aged , Europe , Female , Follow-Up Studies , Graft Survival , Histocompatibility Testing/statistics & numerical data , Humans , Kidney Transplantation/statistics & numerical data , Male , Middle Aged , Retrospective Studies , Risk Factors , Tissue and Organ Procurement/statistics & numerical data , Waiting Lists
14.
Water Sci Technol ; 54(3): 141-5, 2006.
Article in English | MEDLINE | ID: mdl-17037145

ABSTRACT

The European Drinking Water Directive defines reference methods for the enumeration of microbiological parameters in drinking water. The method to be used for Escherichia coli and coliforms is the membrane filtration technique on Lactose TTC agar with Tergitol 7. Many technical drawbacks of the procedure, as well as its limitations regarding the recent taxonomy of coliforms, make it necessary to evaluate alternative methods. Two alternative assays, a chromogenic media (m-ColiBlu24) and a defined substrate technology-DST test (Colilert 18/Quanty Tray) were compared with the ISO standard with attention to the phenotypic characteristic of the isolates. Results showed that the ISO method failed to detect an important percentage of coliforms and E. coli while m-ColiBlu24 and Colilert 18 provided results in a shorter time allowing the simultaneous detection of E. coli and coliforms with no further confirmation steps.


Subject(s)
Enterobacteriaceae/isolation & purification , Escherichia coli/isolation & purification , Water Microbiology , Culture Media , Enterobacteriaceae/classification , Species Specificity
15.
Leukemia ; 19(8): 1424-31, 2005 Aug.
Article in English | MEDLINE | ID: mdl-15920496

ABSTRACT

The impact of clinical parameters, International Prognostic Scoring System (IPSS) scores/cytogenetic categories, and some single cytogenetic defects on overall survival (OS) and time to myelodysplastic syndromes (MDS)/AML progression (progression-free interval (PFI)) was evaluated in 331 MDS patients. Statistical analysis demonstrated that OS and PFI were significantly affected by all these parameters. Since single 7q- showed a better survival than the poor IPSS cytogenetic category (P=0.009), it was considered as a new prognostic entity ('modified IPSS categories'). In multivariate analysis OS was significantly influenced by age, marrow blast cell percentage, number of cytopenias and either modified or standard IPSS cytogenetic categories; hazard ratios for MDS/AML progression were influenced by all the former, except for age and cytopenias. Multivariate analysis of del(7)(q31q35) confirmed the results of univariate analysis, but the Akaike Information Criterion showed no difference in evaluating OS and PFI between the modified and standard IPSS cytogenetic grouping. In conclusion, (i) chromosome defects as grouped by IPSS and blast cell percentage are the most relevant parameters for predicting OS and PFI; (ii) the prognostic power of the IPSS cytogenetic grouping is not ameliorated by the introduction of del(7)(q31q35) as a new entity; (iii) complex karyotypes have a prognostic value independent of blast cell percentage.


Subject(s)
Chromosome Aberrations , Myelodysplastic Syndromes/genetics , Aged , Blast Crisis , Chromosome Deletion , Chromosomes, Human, Pair 7 , Classification , Disease-Free Survival , Female , Gene Rearrangement , Humans , Incidence , Male , Middle Aged , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/pathology , Prognosis , Risk Factors , Survival Rate
16.
Br J Cancer ; 90(5): 1059-68, 2004 Mar 08.
Article in English | MEDLINE | ID: mdl-14997208

ABSTRACT

The expression and function in growth and apoptosis of the renin-angiotensin system (RAS) was evaluated in human glioblastoma. Renin and angiotensinogen (AGT) mRNAs and proteins were found by in situ hybridisation and immunohistochemistry in glioblastoma cells. Angiotensinogen was present in glioblastoma cystic fluids. Thus, human glioblastoma cells produce renin and AGT and secrete AGT. Human glioblastoma and glioblastoma cells expressed renin, AGT, renin receptor, AT(2) and/or AT(1) mRNAs and proteins determined by RT-PCR and/or Western blotting, respectively. The function of the RAS in glioblastoma was studied using human glioblastoma cells in culture. Angiotensinogen, des(Ang I)AGT, tetradecapaptide renin substrate (AGT1-14), Ang I, Ang II or Ang III, added to glioblastoma cells in culture, did not modulate their proliferation, survival or death. Angiotensin-converting enzyme inhibitors did not diminish glioblastoma cell proliferation. However, the addition of selective synthetic renin inhibitors to glioblastoma cells decreased DNA synthesis and viable tumour cell number, and induced apoptosis. This effect was not counterbalanced by concomitant addition of Ang II. In conclusion, the complete RAS is expressed by human glioblastomas and glioblastoma cells in culture. Inhibition of renin in glioblastoma cells may be a potential approach to control glioblastoma cell proliferation and survival, and glioblastoma progression in combination therapy.


Subject(s)
Angiotensinogen/metabolism , Apoptosis , Brain Neoplasms/metabolism , Glioblastoma/metabolism , Renin/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensinogen/genetics , Animals , Brain Neoplasms/pathology , Brain Neoplasms/surgery , CHO Cells , Cell Division/drug effects , Cricetinae , Glioblastoma/pathology , Glioblastoma/surgery , Humans , Immunoenzyme Techniques , In Situ Hybridization , Protease Inhibitors/pharmacology , RNA, Messenger/metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/genetics , Receptor, Angiotensin, Type 2/metabolism , Renin/genetics , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Serine Proteinase Inhibitors/genetics , Serine Proteinase Inhibitors/metabolism , Tumor Cells, Cultured
17.
Leukemia ; 17(11): 2107-12, 2003 Nov.
Article in English | MEDLINE | ID: mdl-12931223

ABSTRACT

Conventional cytogenetics (CC) at clinical diagnosis shows a normal karyotype in 40-60% of de novo myelodysplastic syndromes (MDSs). Fluorescence in situ hybridization (FISH) might detect occult aberrations in these patients. Therefore, we have used FISH to check 57 MDS patients who were karyo-typically normal on CC. At clinical diagnosis, FISH revealed a clonal abnormality in 18-28% interphase cells from nine patients, five of whom also presented the same defect on metaphase FISH. In five out of nine patients, the occult defect effected a change in the international prognostic scoring system (IPSS). An abnormal FISH pattern was significantly correlated with marrow blast cell percentage (P<10(-3)) and IPSS (P<10(-3)). Patients with an occult abnormality showed an overall survival and event-free survival significantly inferior in comparison to those of patients with normal FISH (P<10(-3), P<10(-3)). Death and AML progression were 15- and eight-fold more frequent in FISH abnormal patients. In conclusion, occult defects (1) are revealed in about 15% of CC normal MDS patients, (2) are overlooked by CC either because of the poor quality of metaphases or their submicroscopic nature, (3) are clinically relevant as they may cause a change in the IPSS category and may identify a fraction of CC normal patients with an unfavorable clinical outcome.


Subject(s)
Chromosome Aberrations , Chromosome Mapping , In Situ Hybridization, Fluorescence , Myelodysplastic Syndromes/genetics , Adult , Aged , Aged, 80 and over , Disease Progression , Female , Humans , Karyotyping , Male , Middle Aged , Myelodysplastic Syndromes/therapy , Prognosis , Proportional Hazards Models , Reference Values , Treatment Outcome
18.
Scand J Immunol ; 56(5): 448-55, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12410794

ABSTRACT

The protective activity of a DNA plasmid encoding the immunodominant capsid protein VP1 of coxsackievirus B4 (CBV-4) was studied in BALB/c mice. The plasmid pCI-B4-1-c - which gave the highest expression level of VP1 in cultured monkey and human cells - was chosen for immunization. Two injections of pCI-B4-1-c (1 month apart) into the regenerating mouse muscle tissue induced a specific antibody response to CBV-4, as shown by immunoenzyme and neutralization assays. Upon challenge with live CBV-4, the mortality rate of mice vaccinated with the recombinant plasmid was significantly reduced (21% versus >58%) as compared with that of mice that had been either nontreated or injected with a control plasmid devoid of the insert. The VP1-based vaccine, however, did not provide complete protection as - after virus challenge - moderate viraemia occurred together with modest plasma elevations of pathogenesis-related enzymes (amylase and creatine kinase). Yet, immunofluorescence of the small intestine and heart did confirm the protective effect of the VP1-encoding vaccine. In order to obtain a more complete protection against CBV-4, it may be beneficial to immunize mice with combinations of separate DNA plasmids encoding not only VP1 but also the VP2 and VP3 capsid proteins.


Subject(s)
Capsid Proteins/immunology , Enterovirus B, Human/immunology , Vaccines, DNA/pharmacology , Viral Vaccines/pharmacology , Animals , Antibodies, Viral/blood , Antigens, Viral/genetics , COS Cells , Capsid Proteins/genetics , Cell Line , Enterovirus B, Human/genetics , Enterovirus B, Human/pathogenicity , Enterovirus B, Human/physiology , Enterovirus Infections/immunology , Enterovirus Infections/prevention & control , Humans , Kinetics , Male , Mice , Mice, Inbred BALB C , Plasmids/genetics , Vaccines, DNA/genetics , Viral Vaccines/genetics , Virus Replication
19.
Leukemia ; 16(10): 2078-83, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12357360

ABSTRACT

ET is a chronic myeloproliferative disorder rarely evolving into AML, sometimes preceded by a myelodysplastic syndrome (MDS). Such transformations mostly occur in patients treated with radiophosphorous ((32)P) or alkylating agents, especially busulfan. Recently, concern has also arisen about the long-term safety of hydroxyurea (HU). Pipobroman (PI), a well tolerated and simple to use drug, constitutes a valid alternative to those cytoreductive treatments. The present study reports on 155 ET patients treated at our institution from 1985 to 1995, and monitored until December 2000. A good control of thrombocytosis was achieved with PI as the only treatment in 106 patients and with HU in 23 patients. Twenty-six patients received no treatment. After a median follow-up of 104 months, seven patients (four treated with HU, and three with PI) developed AML whereas one patient treated with PI developed MDS. A significant difference in progression-free survival was observed between HU- and PI-treated patients (P = 0.004). A short-arm deletion of chromosome 17 was most frequently detected in HU-treated patients, while a long-arm trisomy of chromosome 1 and a monosomy 7q were seen in PI-treated patients. No TP53 mutation was discovered in the six patients studied (two HU-treated and four PI-treated). We conclude that these cytogenetic abnormalities are not linked to the natural history of the disease, but rather that they might be induced by the cytoreductive treatment.


Subject(s)
Chromosome Aberrations , Hydroxyurea/therapeutic use , Leukemia, Myeloid/etiology , Pipobroman/therapeutic use , Thrombocythemia, Essential/complications , Acute Disease , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , Thrombocythemia, Essential/drug therapy
20.
J Am Chem Soc ; 123(48): 11890-8, 2001 Dec 05.
Article in English | MEDLINE | ID: mdl-11724595

ABSTRACT

The pK(a) values of a cationic selenyl- (5H(+)) and a benzothienylcarbene complex (6H(+)) and rate constants for the reversible deprotonation of these complexes by water, carboxylate ions, primary aliphatic amines, secondary alicyclic amines (5H(+) only), and OH(-) (5H(+) only) were determined in 50% MeCN-50% water (v/v) at 25 degrees C. In comparison with neutral Fischer-type carbene complexes such as 1H, the cationic complexes 5H(+) and 6H(+) are much more acidic, and the intrinsic barriers to proton transfer are substantially higher. This paper discusses a variety of factors that contribute to these differences, with the most important ones being that 5H(+) and 6H(+) are cationic, which makes the C(5)H(5)(NO)(PPh(3))Re moiety a stronger pi-acceptor than the (CO)(5)M moieties, coupled with the fact that the deprotonated forms of 5H(+) and 6H(+ )are aromatic molecules.

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