Biomedical subjects

J Lamers

Publications and source records attributed to J Lamers.

14 recordsLinked to original sources

PubMed2006

Highly efficient and specific modulation of cardiac calcium homeostasis by adenovector-derived short hairpin RNA targeting phospholamban.

Impaired function of the phospholamban (PLB)-regulated sarcoplasmic reticulum Ca(2+) pump (SERCA2a) contributes to cardiac dysfunction in heart failure (HF). PLB downregulation may increase SERCA2a activity and improve cardiac function. Small interfering (si)RNAs mediate efficient gene silencing by RNA interference (RNAi). However, their use for in vivo gene therapy is limited by siRNA instability in plasma and tissues, and by low siRNA transfer rates into target cells. To address these problems, we developed an adenoviral vector (AdV) transcribing short hairpin (sh)RNAs against rat PLB and evaluated its potential to silence the PLB gene and to modulate SERCA2a-mediated Ca(2+) sequestration in primary neonatal rat cardiomyocytes (PNCMs). Over a period of 13 days, vector transduction resulted in stable > 99.9% ablation of PLB-mRNA at a multiplicity of infection of 100. PLB protein gradually decreased until day 7 (7+/-2% left), whereas SERCA, Na(+)/Ca(2+) exchanger (NCX1), calsequestrin and troponin I protein remained unchanged. PLB silencing was associated with a marked increase in ATP-dependent oxalate-supported Ca(2+) uptake at 0.34 microM of free Ca(2+), and rapid loss of responsiveness to protein kinase A-dependent stimulation of Ca(2+) uptake was maintained until day 7. In summary, these results indicate that AdV-derived PLB-shRNA mediates highly efficient, specific and stable PLB gene silencing and modulation of active Ca(2+) sequestration in PNCMs. The availability of the new vector now enables employment of RNAi for the treatment of HF in vivo.

Animals↗

PubMed2001

A comparative study of the effects of carbamazepine and the NMDA receptor antagonist remacemide on road tracking and car-following performance in actual traffic.

RATIONALE: Antiepileptic drugs are known to produce side effects which may impair driving performance. Performance effects, however, may differ substantially between individual antiepileptic drugs. OBJECTIVE: To compare the effects of carbamazepine, remacemide, and placebo on actual driving performance during a 12-day incremental dosing regimen. METHODS: Twenty-two healthy volunteers participated in a three-way, double-blind, cross-over driving study. Treatment effects were assessed in two actual driving tests carried out on days 8, 10, and 12 of each treatment period. The Road Tracking Test involved driving an instrumented vehicle at a constant speed and steady lateral position between the delineated lane boundaries. Standard deviation of lateral position (SDLP) was measured to indicate precision of road tracking control. The Car-Following Test involved driving the same vehicle behind a leading car and maintaining that distance while the latter executed a series of deceleration/acceleration maneuvers. Time to speed adaptation (TSA) and brake reaction time were the primary measures. RESULTS: Remacemide did not affect the subjects' driving performance. Carbamazepine increased SDLP throughout treatment and lengthened TSA on day 8. Changes in SDLP relative to placebo were comparable to those previously seen in drivers conducting the same test with blood alcohol concentrations of 0.05 g/dl. CONCLUSION: Remacemide, at the given dose regimen, does not affect driving performance. Carbamazepine, at the given dose regimen, can produce mild but sufficient impairment to put epileptic patients at risk when driving, at least during initiation therapy.

Acetamides↗

PubMed2001

Human coxsackie-adenovirus receptor is colocalized with integrins alpha(v)beta(3) and alpha(v)beta(5) on the cardiomyocyte sarcolemma and upregulated in dilated cardiomyopathy: implications for cardiotropic viral infections.

BACKGROUND: The coxsackievirus and adenovirus receptor (CAR) was identified as a common cellular receptor for both viruses, but its biological and pathogenic relevance is uncertain. Knowledge of CAR localization in the human cardiovascular system is limited but important with respect to CAR-dependent viral infections and gene transfer using CAR-dependent viral vectors. METHODS AND RESULTS: Explanted failing hearts from 13 patients (8 with dilated cardiomyopathy [DCM] and 5 with other heart diseases [non-DCM]) and normal donor hearts (n=7) were investigated for the expression levels and subcellular localization of CAR and the adenovirus coreceptors alpha(v)beta(3) and alpha(v)beta(5) integrins. CAR immunoreactivity was very low in normal and non-DCM hearts, whereas strong CAR signals occurred at the intercalated discs and sarcolemma in 5 of the 8 DCM hearts (62.5%); these strong signals colocalized with both integrins. In all hearts, CAR was detectable in subendothelial layers of the vessel wall, but not on the luminal endothelial surface, and on interstitial cells. Human CAR (hCAR) expressed in rat cardiomyocytes was targeted to cell-cell contacts, which resembled CAR localization in DCM hearts and resulted in 15-fold increased adenovirus uptake. CONCLUSIONS: Low hCAR abundance may render normal human myocardium resistant to CAR-dependent viruses, whereas re-expression of hCAR, such as that observed in DCM, may be a key determinant of cardiac susceptibility to viral infections. Asymmetric expression of hCAR in the vessel wall may be an important determinant of adenovirus tropism in humans. hCAR subcellular localization in human myocardium and hCAR targeting to cell-cell contacts in cardiomyocyte cultures suggest that hCAR may play a role in cell-cell contact formation.

Adenoviridae↗

PubMed1999

Expression of coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers.

Recombinant adenoviral vectors are broadly applied in gene therapy protocols. However, adenovector-mediated gene transfer has limitations in vivo. One of these is the low gene transfer rate into organs other than the liver after systemic intravenous vector injection. Local direct injection into the target organ has been used as one possible solution, but increases necessary equipment and methodology and is traumatic to the target. Wild-type adenovirus infection as well as adenovector-mediated gene transfer depends on virus interaction with the Coxsackie adenovirus receptor (CAR) mediating virus attachment to the cell surface, and on interaction with alphavbeta3 and alphavbeta5 integrins mediating virus entry into the cell. In order to assess the receptor-associated potential of different tissues to act as adenovector targets, we have therefore determined CAR and alphav-integrin expression in multiple organs from different species. In addition, we have newly determined several human, rat, pig and dog CAR-mRNA sequences. Sequence comparison and structural analyses of known and of newly determined sequences suggests a potential adenovirus binding site between amino acids 29 and 128 of the CAR. With respect to the virus receptor expression patterns we found that CAR-mRNA expression was extremely variable between different tissues, with the highest levels in the liver, whereas alphav-integrin expression was far more homogenous among different organs. Both CAR and alphav-integrin showed similar expression patterns among different species. There was no correlation, however, between the adenovector expression patterns after intravenous, intracardiac and aortic root injection, respectively, and the virus receptor patterns. In summary, many organs carry both receptors required to make them potential adenovector targets. In sharp contrast, their actual targeting clearly indicates that adenovirus receptor expression is necessary but not sufficient for vector transfer after systemic injection. The apparently very important role of anatomical barriers, in particular the endothelium, requires close attention when developing non-traumatic, organ-specific gene therapy protocols.

Adenoviridae↗

PubMed1986

Chordoma of the thorax.

Chordomata are malignant tumours which arise from foetal notochordal rests. They occur alongside the vertebral column, mostly at the cranial or caudal extremities, but they are seldom found in the thorax. A description is given of a thoracic chordoma in a 70-year-old male patient who presented with difficulty in swallowing and breathing. Emphasis is placed on the role of computer-assisted tomography in reaching the diagnosis.

Aged↗

PubMed1983

A supernumerary bronchus of the right upper lobe.

A patient with a bronchogenic carcinoma in the right lower lobe was found during bronchography to have an accessory right superior cardiac bronchus. Inspection of the right lung at operation and a control bronchogram, made 6 months after right lower lobectomy, confirmed that the congenital anomaly was a supernumerary bronchus and not a cardiac bronchus which had migrated proximally.

Bronchi↗

PubMed1980