Effects of Photobiomodulation Therapy on Patients with Primary Open Angle Glaucoma: A Pilot Study.

OBJECTIVE: The purpose of this work was to study the safety of photobiomodulation therapy in patients with primary open angle glaucoma (POAG). BACKGROUND DATA: Therapeutic options for POAG focus on lowering the intraocular pressure (IOP) but cannot stop disease progression to irreversible damages. METHODS: The study was designed as a controlled, single-blinded, interventional case series (38 patients; 63 eyes). Low-level laser therapy was performed once or twice per week using a continuous wave (CW) diode laser (780 nm; 10 mW; 292 Hz modulation; 3 mm(2) beam spot). The limbus area was circularly irradiated for 30 sec (0.3 W/cm(2); 10 J/cm(2)) at a 1 cm distance. Additional parts of the bulbus were irradiated for 90 sec (30 J/cm(2)) pointing the beam toward retinal areas corresponding to defective visual fields. A control group of 10 patients (20 eyes) received mock treatment. Visual acuity was assessed using Snellen projection optotypes. IOP was determined by applanation tonometry. Visual fields were determined by kinetic Goldmann perimetry. Multifocal visual evoked potential (M-VEP) was recorded in 15 patients (30 eyes). RESULTS: Poor visual acuity (≤ 20/25), initially found in 24 of 63 eyes (38.1%), improved in 17 (70.8%) eyes and did not change in 7 eyes (29.2%). Mean IOP dropped from 24.9 ± 14.9 to 15.0 ± 6.5 mm Hg (-39.7%, p < 0.001). Visual fields were either fully restored, improved by at least 10 degrees, or remained unchanged in 32, 29, and 2 of 63 eyes (51%, 46%, and 3%), respectively. Mean M-VEP latency was reduced by 13.5 msec (-8%, p < 0.001); mean amplitude increased by +677 nV (+14%, p < 0.001). Adverse effects were not observed. No changes were noted in control eyes. CONCLUSIONS: This first small series of cases indicated that photobiomodulation might be a safe approach to lower IOP and to improve visual acuity and fields in eyes with POAG.

Performance of the AQT90 FLEX cTnI point-of-care assay for the rapid diagnosis of acute myocardial infarction in the emergency room.

BACKGROUND: International guidelines stipulate that primarily cardiac troponin (cTn) assays with a coefficient of variation (CV) < or = 10% at the 99th percentile cutoff should be used for diagnosing myocardial infarction. Point-of-care (POC) assays usually do not meet these criteria. Here, we sought to confirm the manufacturer-recommended 99th percentile cutoff and CV of the POC assay AQT90 FLEX cTnI. METHODS: 119 healthy persons without cardiac disorders were examined to determine the 99th percentile cutoff and the corresponding CV. This cutoff was validated in a cohort of 80 patients with unstable angina and 71 patients with non-ST-segment elevation myocardial infarction (NSTEMI), who were admitted to a chest pain unit. cTnI concentrations were measured in serial serum samples obtained from these patients at presentation, 3 and 6 hours after admission. RESULTS: A cTnI concentration of 20 ng/L was found as the 99th percentile cutoff (CV 6.7%). cTnI was > or = 20 ng/L in 51 (75%), 59 (87%), and 60 (88%) of the NSTEMI patients 0, 3 and 6 hours after admission, respectively. At admission, sensitivity was 76% and specificity 95%. Three and six hours later, sensitivity and negative predictive values increased to 88% and 98.8%, and to 92% and 97%, respectively. CONCLUSIONS: We confirmed the manufacturer recommended 99th percentile cutoff of 23 ng/L and established a CV of 6.7% at 20 ng/L. These results demonstrated that the POC assay AQT90 FLEX cTnI must be classified as "guideline acceptable".

Low-level laser therapy improves vision in a patient with retinitis pigmentosa.

OBJECTIVE: This case report describes the effects of low-level laser therapy (LLLT) in a single patient with retinitis pigmentosa (RP). BACKGROUND DATA: RP is a heritable disorder of the retina, which eventually leads to blindness. No therapy is currently available. METHODS: LLLT was applied using a continuous wave laser diode (780 nm, 10 mW average output at 292 Hz, 50% pulse modulation). The complete retina of eyes was irradiated through the conjunctiva for 40 sec (0.4 J, 0.333 W/cm2) two times per week for 2 weeks (1.6 J). A 55-year-old male patient with advanced RP was treated and followed for 7 years. RESULTS: The patient had complained of nyctalopia and decreasing vision. At first presentation, best visual acuity was 20/50 in each eye. Visual fields were reduced to a central residual of 5 degrees. Tritan-dyschromatopsy was found. Retinal potential was absent in electroretinography. Biomicroscopy showed optic nerve atrophy, and narrow retinal vessels with a typical pattern of retinal pigmentation. After four initial treatments of LLLT, visual acuity increased to 20/20 in each eye. Visual fields normalized except for a mid-peripheral absolute concentric scotoma. Five years after discontinuation of LLLT, a relapse was observed. LLLT was repeated (another four treatments) and restored the initial success. During the next 2 years, 17 additional treatments were performed on an "as needed" basis, to maintain the result. CONCLUSIONS: LLLT was shown to improve and maintain vision in a patient with RP, and may thereby have contributed to slowing down blindness.

Whole-genome analysis of gene expression associates the ubiquitin-proteasome system with the cardiomyopathy phenotype in disease-sensitized congenic mouse strains.

AIMS: Penetrance and phenotypic expressivity of cardiomyopathies are modulated by modifier genes both in model systems and patients. We aimed to dissect the disease-modifying mechanisms by examining genome-wide gene expression in a new set of mouse (Mus musculus) congenic strains. METHODS AND RESULTS: Mutant alleles of the genes calsarcin-1 (Myoz2), sarcoglycan-delta (Sgcd), and muscle LIM protein (Csrp2) were each transferred onto inbred strain backgrounds C57BL/6, C3H/He, 129S1/Sv, and FVB/N, respectively. At 9-10 weeks of age, left ventricular pump function (fractional shortening, FS) was determined by echocardiography in non-sedated congenic animals. Gene expression was then analysed in myocardial tissue using the Affymetrix Mouse 430.2 microarray platform. Variance stabilization, linear mixed-effects modelling, correlations, gene functional classification, and pathway analysis were conducted using the standard software. Strain background FVB/N appeared to protect against the consequences of gene inactivation. Sgcd-deficient congenics showed normal FS, which was consistent with their hypertrophic cardiomyopathy phenotype. Animals with other allele/background combinations developed an impaired ventricular pump function (FS <65%). Gender did not influence FS significantly, yet it determined the sets of genes that were differentially expressed in mice with low FS. In particular, genes encoding the elements of the ubiquitin-proteasome system (UPS) were strongly correlated with the cardiac impairment (absolute Spearman r ≥ 0.7) in both males and females. CONCLUSION: Gene expression profiling in a novel set of congenic strains revealed an association between the UPS and myocardial contractile function, indicating that the UPS may be an important modifier of phenotypic variability in cardiomyopathies.

Low-level laser therapy improves visual acuity in adolescent and adult patients with amblyopia.

OBJECTIVE: The purpose of this study was to examine the effects of low-level laser therapy (LLLT) on visual acuity in adolescent and adult patients with amblyopia. BACKGROUND DATA: Currently, amblyopia can be treated successfully only in children. METHODS: In this single-blinded, placebo-controlled study, 178 patients (mean age 46.8 years) with amblyopia caused by ametropia (110 eyes) or strabismus (121 eyes) were included. For LLLT, the area of the macula was irradiated through the conjunctiva from 1 cm distance for 30 sec with laser light (780 nm, 292 Hz, 1:1 duty cycle; average power 7.5 mW; spot area 3 mm(2)). The treatment was repeated on average 3.5 times, resulting in a mean total dose of 0.77 J/cm(2). No occlusion was applied, and no additional medication was administered. Best corrected distant visual acuity was determined using Snellen projection optotypes. In 12 patients (12 eyes), the multifocal visual evoked potential (M-VEP) was recorded. A control group of 20 patients (20 eyes) received mock treatment. RESULTS: Visual acuity improved in ∼90% of the eyes treated with LLLT (p<0.001), increasing by three or more lines in 56.2% and 53.6% of the eyes with amblyopia caused by ametropia and strabismus, respectively. The treatment effect was maintained for at least 6 months. The mean M-VEP amplitude increased by 1207 nV (p<0.001) and mean latency was reduced by 7 msec (p=0.14). No changes were noted in the control group. CONCLUSIONS: LLLT led to a significant improvement in visual acuity in adolescent and adult patients with amblyopia caused by ametropia or strabismus.

High-sensitivity troponin T improves the prognostic value of N-terminal pro-B-type natriuretic peptide in patients with stable coronary artery disease: results from the LURIC Study.

BACKGROUND: Cardiac troponin T is an established prognostic marker in patients with acute coronary syndromes, but not in stable coronary artery disease (CAD) like N-terminal pro-B-type natriuretic peptide (NT-proBNP). We examined the additive prognostic value of a high-sensitivity troponin T (hsTnT) assay to predict adverse clinical outcomes in stable CAD. METHODS: A retrospective nested case-control analysis of 256 patients with stable CAD who participated in the LURIC study: 128 cases who died from cardiovascular causes during a median follow-up of 7.5 years and 128 survivors (controls) matched for age and gender, were included. hsTnT and NT-proBNP were determined in baseline samples using immunoassays (Roche Diagnostics, Germany). RESULTS: Sixty-two percent of the 256 subjects exhibited concentrations of hsTnT≥14 ng/L, the manufacturer recommended cut-off to diagnose myocardial infarction in patients with acute chest pain. hsTnT, NT-proBNP, diabetes mellitus and fasting glucose were associated with cardiovascular mortality in univariate analysis. Logistic regression identified hsTnT and NT-proBNP as independent risk markers. Receiver operator characteristic (ROC) curves analysis identified optimal cut-offs at 15 ng/L and 352 µg/L for hsTnT (AUC 0.728, p<0.05) and NT-proBNP (AUC 0.751, p=0.07), respectively. Patients with one or two positive markers exhibited 5-year cardiovascular mortalities of 40% and 60%, respectively, compared to 10% in patients with negative markers. The addition of hsTnT to NT-proBNP significantly increased c-statistics of proportional hazards calculated from survival times as well as net reclassification indexes. CONCLUSIONS: Many patients with stable CAD exhibited increased concentrations of hsTnT. The combined determination of NT-proBNP and hsTnT was superior for risk stratification compared to determining either marker alone.

Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation.

AIMS: Left ventricular non-compaction (LVNC) is caused by mutations in multiple genes. It is still unclear whether LVNC is the primary determinant of cardiomyopathy or rather a secondary phenomenon with intrinsic cardiomyocyte dysfunction being the actual cause of the disease. Here, we describe a family with LVNC due to a novel missense mutation, pE96K, in the cardiac troponin T gene (TNNT2). METHODS AND RESULTS: The novel mutation was identified in the index patient and all affected relatives, but not in 430 healthy control individuals. Mutations in known LVNC-associated genes were excluded. To investigate the pathophysiological implications of the mutation, we generated transgenic mice expressing human wild-type cTNT (hcTNT) or a human troponin T harbouring the pE96K mutation (mut cTNT). Animals were characterized by echocardiography, histology, and gene expression analysis. Mut cTNT mice displayed an impaired left ventricular function and induction of marker genes of heart failure. Remarkably, left ventricular non-compaction was not observed. CONCLUSION: Familial co-segregation and the cardiomyopathy phenotype of mut cTNT mice strongly support a causal relationship of the pE96K mutation and disease in our index patient. In addition, our data suggest that a non-compaction phenotype is not required for the development of cardiomyopathy in this specific TNNT2 mutation leading to LVNC.

Prediction of coronary artery disease by a systemic atherosclerosis score index derived from whole-body MR angiography.

BACKGROUND: Whole-body magnetic resonance angiography (WB-MRA) has shown its potential for the non-invasive assessment of nearly the entire arterial vasculature within one examination. Since the presence of extra-cardiac atherosclerosis is associated with an increased risk of coronary events, our goal was to establish the relationship between WB-MRA findings, including a systemic atherosclerosis score index, and the presence of significant coronary artery disease (CAD). METHODS: WB-MRA was performed on a 1.5T scanner in 50 patients scheduled to undergo elective cardiac catheterization for suspected CAD. In each patient, 40 extra-cardiac vessel segments were evaluated and assigned scores according to their luminal narrowing. The atherosclerosis score index (ASI) was generated as the ratio of summed scores to analyzable segments. RESULTS: ASI was higher in patients with significant (> 50% stenosis) CAD (n = 27) vs. patients without CAD (n = 22; 1.56 vs. 1.28, p = 0.004). ASI correlated with PROCAM (R = 0.57, p < 0.001) and Framingham (R = 0.36, p = 0.01) risk scores as estimates of the 10-year risk of coronary events. A ROC derived ASI of > 1.54 predicted significant CAD with a sensitivity of 59%, specificity of 86% and a positive predictive value of 84%. Logistic regression revealed ASI > 1.54 as the strongest independent predictor for CAD with a 11-fold increase in likelihood to suffer from significant coronary disease. On the contrary, while 15/27 (55%) of patients with CAD exhibited at least one extra-cardiac stenosis > 50%, only 3/22 (14%) of those patients without CAD did (p = 0.003). The likelihood for an extra-cardiac stenosis when CAD is present differed between vascular territories and ranged from 15% for a carotid stenosis to 44% for a stenosis in the lower extremities. CONCLUSION: This study provides important new evidence for the close association of extra-cardiac and coronary atherosclerosis. The novel findings that a WB-MRA derived systemic atherosclerosis score index is not only associated with established cardiovascular risk scores but is also predictive of significant CAD suggest its potential prognostic implications and underline the importance to screen for coronary disease in patients with extra-cardiac manifestations of atherosclerosis.

Early diagnosis of ocular hypertension using a low-intensity laser irradiation test.

OBJECTIVE: We investigated the potential use of low-intensity laser irradiation (LILI) as a diagnostic tool for identifying hypertensive eyes at risk of glaucoma. BACKGROUND DATA: The diagnosis of early-stage ocular hypertension is particularly difficult to establish. METHODS: This study of a case series included 123 healthy subjects with normal vision. The intraocular pressure (IOP) was determined before (baseline) and 30 min after a 30-sec irradiation of the limbus area with laser light (780 nm; 7.5 mW; 292 Hz modulation). RESULTS: Baseline IOP was >21 mm Hg in 44 of 211 eyes (20.9%), consistent with ocular hypertension. LILI decreased the mean IOP by 6.2 mm Hg (-25.7%; p < 0.001; paired t test) in these eyes. The remaining 167 eyes (79.1%) exhibited a normotensive IOP

Dll1 haploinsufficiency in adult mice leads to a complex phenotype affecting metabolic and immunological processes.

BACKGROUND: The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1) is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1(C413Y)). Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized. CONCLUSIONS/SIGNIFICANCE: In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes.

Dual antiplatelet drug resistance is a risk factor for cardiovascular events after percutaneous coronary intervention.

BACKGROUND: Nonresponsiveness to clopidogrel and acetylsalicylic acid (ASA), a frequent result of platelet aggregometry studies, has unclear clinical and prognostic significance. METHODS: We performed impedance aggregometry in 182 patients 12-24 h after percutaneous coronary intervention (PCI) and a 600-mg loading dose of clopidogrel, adding 5 micromol/L ADP and 1 mg/L collagen to diluted whole blood to determine platelet inhibition by clopidogrel and ASA, respectively. Samples from nonresponders were incubated in vitro with methyl-S-adenosine monophosphate or ASA to distinguish between pharmacodynamic and pharmacokinetic types of resistance. We assessed a combined primary endpoint of myocardial infarction, target vessel revascularization, late stent thrombosis, or cardiac death. RESULTS: Nineteen patients (10.4%) were dual nonresponders (nonresponsive to both ASA and clopidogrel), and 163 patients (89.6%) were designated responders. The latter group also included 15 and 14 single nonresponders (responsive to either clopidogrel or ASA, respectively), who exhibited endpoint frequencies comparable to those of full responders (n = 134). Pharmacokinetic resistance was most prevalent. Primary endpoints occurred more frequently in dual nonresponders (n = 6, 31.6%) than in responders (n = 20, 12.3%) (relative risk 2.57; 95% CI 1.18-5.61; log-rank P = 0.03). Multivariate analysis confirmed dual nonresponsiveness (hazard ratio 2.9; 95% CI 1.17-7.2; P = 0.02) as an independent risk factor. CONCLUSIONS: Dual nonresponders carry a high cardiovascular risk after PCI and should obtain intensified antiplatelet therapy and follow-up.

Minor troponin T elevation in patients 6 months after acute myocardial infarction: an observational study.

BACKGROUND: Troponin elevation in patients with stable coronary heart disease is associated with adverse outcome and prognosis. However, the mechanism is not yet clearly understood. Our objectives were to examine the prevalence and range of cardiac troponin T (cTnT) in stable patients, 6 months after acute myocardial infarction (AMI) using a new high sensitive cTnT assay and to investigate the association of minor cTnT elevation in these patients to clinical variables, NT-proBNP and cardiac MRI-findings. STUDY DESIGN AND METHODS: cTnT was measured in 98 patients 6 months after AMI with a precommercial assay by electrochemiluminescence methods (Roche Diagnostics, Mannheim, Germany). cTnT values were correlated with clinical and angiographic variables, NT-proBNP concentrations and with cardiac MRI-findings. RESULTS: Minor cTnT concentrations were detectable in 90% of the entire cohort, of whom 16% had cTnT values above the 99th percentile (>12 ng/L). These patients were also significantly older, suffered more frequently from hypertension, had a higher New York Heart Association class and received more often diuretics at follow up. Patients with cTnT elevation had a more impaired left ventricular ejection fraction (P = 0.02) but did not have an increased infarct size (P = 0.73). CONCLUSIONS: Elevated minor cTnT levels are frequently detectable in patients 6 months after AMI. Increased cTnT level were associated with clinical parameter for heart failure, impaired ejection fraction and higher NT-proBNP levels suggesting that myocardial dysfunction is a main cause for cTnT elevation in these patient group.

Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y12-ADP receptor gene.

BACKGROUND: Platelet hyperreactivity was reported in clopidogrel-naiotave carriers of the H2 haplotype of the P2Y(12) platelet ADP receptor. Here, we studied the influence of this genetic variant on clopidogrel responsiveness. METHODS: ADP-mediated (5 micromol/L) platelet aggregation was determined by impedance (Omega) aggregometry in 43 clopidogrel-naïve blood donors and 557 patients treated with aspirin and clopidogrel after percutaneous coronary stent implantation. A cut-off of 5 Omega was used to classify the aggregation response. Haplotype tagging single nucleotide polymorphism G52T was genotyped using a TaqMan assay. RESULTS: The number of H2 alleles correlated with aggregation in clopidogrel-naïve subjects in healthy subjects (p=0.041): impedance results were 8.4+/-3.6, 10.5+/-1.6 and 12.5+/-2.1 Omega in carriers of the H1/H1 (n=30), H1/H2 (n=11) and H2/H2 (n=2) haplotypes, respectively. 87.1% (n=485) and 12.9% (n=72) of clopidogrel treated patients were responders and nonresponders, respectively. Women were more likely to be nonresponders (O.R. 3.90 [95% CI 2.34-6.50]). Carriers of a H2/H2 haplotype (n=14) exhibited stronger aggregation than patients with at least one H1 allele (6.3+/-7.5 vs. 1.8+/-3.3 Omega, p=0.0212) and were more frequently nonresponders (p=0.004). Consequently, the H2/H2 haplotype was associated with clopidogrel resistance (O.R. 5.42 [95% CI 1.82-16.11]). This risk factor was independent of the gender effect. CONCLUSIONS: This is the first large study in clopidogrel treated patients suggesting that a homozygote H2 genotype contributes to clopidogrel resistance. The clinical significance of this finding remains to be demonstrated.

Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene.

BACKGROUND: Mutations in MYBPC3 encoding myosin binding protein C belong to the most frequent causes of hypertrophic cardiomyopathy (HCM) and may also lead to dilated cardiomyopathy (DCM). MYBPC3 mutations initially were considered to cause a benign form of HCM. The aim of this study was to examine the clinical outcome of patients and their relatives with 18 different MYBPC3 mutations. METHODS: 87 patients with HCM and 71 patients with DCM were screened for MYBPC3 mutations by denaturing gradient gel electrophoresis and sequencing. Close relatives of mutation carriers were genotyped for the respective mutation. Relatives with mutation were then evaluated by echocardiography and magnetic resonance imaging. A detailed family history regarding adverse clinical events was recorded. RESULTS: In 16 HCM (18.4%) and two DCM (2.8%) index patients a mutation was detected. Seven mutations were novel. Mutation carriers exhibited no additional mutations in genes MYH7, TNNT2, TNNI3, ACTC and TPM1. Including relatives of twelve families, a total number of 42 mutation carriers was identified of which eleven (26.2%) had at least one adverse event. Considering the twelve families and six single patients with mutations, 45 individuals with cardiomyopathy and nine with borderline phenotype were identified. Among the 45 patients, 23 (51.1%) suffered from an adverse event. In eleven patients of seven families an unexplained sudden death was reported at the age between 13 and 67 years. Stroke or a transient ischemic attack occurred in six patients of five families. At least one adverse event occurred in eleven of twelve families. CONCLUSION: MYBPC3 mutations can be associated with cardiac events such as progressive heart failure, stroke and sudden death even at younger age. Therefore, patients with MYBPC3 mutations require thorough clinical risk assessment.

Tirofiban optimizes platelet inhibition for immediate percutaneous coronary intervention in high-risk acute coronary syndromes.

It was the aim of this study to compare the efficacy of early platelet inhibition by 600 mg clopidogrel and acetylsalicylic acid (ASA) to a triple therapy including a glycoprotein IIb-IIIa receptor blocker. Immediate percutaneous coronary intervention (PCI) is recommended for high-risk acute coronary syndromes. In this setting the efficacy of platelet inhibition is unknown. One hundred patients were randomized to receive ASA and 600 mg clopidogrel, or additional open-label tirofiban (bolus of 10 microg/kg body weight followed by continued infusion of 0.15 microg/kg body weight per minute) as soon as non-ST-segment elevation myocardial infarction was diagnosed. The primary endpoint was the reduction of infarct size determined by post-interventional increases of cardiac troponin T (cTnT). Secondary endpoints included platelet function measured by optical and impedance aggregometry using ADP (5 and 20 microM) and collagen (1 microg/ml) as platelet agonists. Tirofiban maximized platelet inhibition (p < 0.0001) immediately and was associated with significantly lower post-interventional cTnT concentrations (p = 0.0352). In the dual platelet inhibition arm, clopidogrel was not effective in 69% of patients at the time of coronary intervention, and still in 47%, if pre-treatment time was >120 minutes. The frequency of cardiovascular (death, myocardial infarction, revascularization) and bleeding events was comparable. Platelet aggregation is not adequately inhibited in cTnT-positive patients in the setting of immediate PCI with very short pre-treatment times. Only tirofiban provided consistent and effective inhibition of platelet aggregation at the time of immediate or very early invasive therapy.

[Anticoagulation and platelet inhibition - dosing recommendations at the beginning and the end of treatment]. / Antikoagulation und Thrombozytenaggregationshemmung - Arzneimittel-Dosierung am Anfang und Ende einer Therapie.

Anticoagulants and anti-platelet drugs are essential and widely used therapeutic tools in modern cardiovascular medicine. However, the initiation of anti-thrombotic therapies, their termination, or transient discontinuation (e.g. for surgical procedures) are critical steps which have to be managed appropriately. In the near future, several novel irreversibly or reversibly acting anti-thrombotic drugs with direct and indirect mechanisms of action, will be approved. Their prescription will require a deep understanding of their pharmacodynamics and -kinetics. In addition, pharmacogenomic issues will become increasingly important for the optimization of individual therapeutic strategies. This review summarizes clinically relevant principles and discusses them in the light of the assessment of the individual thrombotic and bleeding risks.

Low-level laser therapy improves vision in patients with age-related macular degeneration.

OBJECTIVE: The objective of this study of a case series was to examine the effects of low-level laser therapy (LLLT) in patients with age-related macular degeneration (AMD). BACKGROUND DATA: AMD affects a large proportion of the elderly population; current therapeutic options for AMD are limited, however. PATIENTS AND METHODS: In total, 203 patients (90 men and 113 women; mean age 63.4 +/- 5.3 y) with beginning ("dry") or advanced ("wet") forms of AMD (n = 348 eyes) were included in the study. One hundred ninety-three patients (mean age 64.6 +/- 4.3 y; n = 328 eyes) with cataracts (n = 182 eyes) or without cataracts (n = 146 eyes) were treated using LLLT four times (twice per week). A semiconductor laser diode (780 nm, 7.5 mW, 292 Hz, continuous emission) was used for transconjunctival irradiation of the macula for 40 sec (0.3 J/cm2) resulting in a total dose of 1.2 J/cm2. Ten patients (n = 20 eyes) with AMD received mock treatment and served as controls. Visual acuity was measured at each visit. Data were analyzed retrospectively using a t-test. RESULTS: LLLT significantly improved visual acuity (p < 0.00001 versus baseline) in 162/182 (95%) of eyes with cataracts and 142/146 (97%) of eyes without cataracts. The prevalence of metamorphopsia, scotoma, and dyschromatopsia was reduced. In patients with wet AMD, edema and bleeding improved. The improved vision was maintained for 3-36 mo after treatment. Visual acuity in the control group remained unchanged. No adverse effects were observed in those undergoing therapy. CONCLUSION: In patients with AMD, LLLT significantly improved visual acuity without adverse side effects and may thus help to prevent loss of vision.

Incomplete nonsense-mediated decay of mutant lamin A/C mRNA provokes dilated cardiomyopathy and ventricular tachycardia.

We have identified a family in which several members died of sudden cardiac death or suffer from dilated cardiomyopathy (DCM) and rhythm disturbances. Mutation screening revealed co-segregation of a novel nonsense mutation (pR321X) in the lamin A gene, LMNA, with the disease. Lamin A, and its smaller splice form lamin C are nuclear intermediate filament proteins forming a major part of the lamina, which is underlying the inner nuclear membrane. They are involved in the organization of heterochromatin and both in DNA replication and transcription. Recently, an increasing number of missense mutations in LMNA have been discovered to cause various types of rare diseases. Here, we investigated the causal role of the new nonsense mutation for the disease. Quantification of wild type and mutant lamin A mRNA from explanted myocardial tissue and cultured fibroblasts revealed an up to 30-fold reduction in the relative amount of the mutant transcript indicating that its synthesis was massively down-regulated by nonsense-mediated mRNA decay (NMD). Correspondingly, we did not detect the mutant truncated lamin A by Western blot analysis in extracts of patient fibroblasts and cardiac muscle tissue. Both wild type lamin A and C were present, however, in normal quantities. The immunohistochemical analyses of patient tissues revealed a normal distribution of lamin A/C and of major inner nuclear membrane proteins such as emerin and the lamin B receptor. Moreover, both chromatin distribution and nuclear shape were normal. However, over-expression of truncated lamin A in HeLa cells by transient transfection caused major disturbances of lamin A organization within both the nucleoplasm and the cytoplasm. In addition, after treatment of patient fibroblasts with the proteasome inhibitor epoxomicin, mutant truncated lamin A was detected in relatively high levels by Western blotting demonstrating that it is synthesized in these cells. Therefore, we conclude that NMD is not sufficient to completely prevent the expression of truncated lamin A and that even trace amounts of it may negatively interfere with structural and/or regulatory functions of lamin A/C eventually leading to the development of DCM and rhythm disturbances.

Increased plasma concentrations of soluble CD40 ligand in acute coronary syndrome depend on in vitro platelet activation.

BACKGROUND: Soluble CD40 ligand (sCD40L) was suggested as a novel biomarker of cardiovascular risk. We examined the effect of preanalytical variation on the measurement of sCD40L concentration. METHODS: From healthy control individuals (n = 20) and patients with acute coronary syndrome (ACS) (n = 20) or sepsis (n = 20), we obtained blood drawn into 5 tubes containing citrate or a mixture of citrate, theophylline, adenosine, and dipyridamole (CTAD). The tubes were incubated for 30 min at room temperature or 0 degrees C before a single or double centrifugation (15 min, 2500 g) at room temperature or 4 degrees C, respectively. sCD40L, beta-thromboglobulin (betaTG), and platelet factor 4 (PF4) concentrations were measured using immunoassays. RESULTS: Concentrations of sCD40L were very low in all CTAD and citrated samples maintained at 0 degrees C (median < or = 0.076 microg/L). Although increased betaTG and PF4 confirmed disease-related in vivo platelet activation, sCD40L was not higher in patients than in controls. In contrast, if the samples were processed at room temperature, sCD40L was significantly higher in ACS patients than in controls (P <0.02 in CTAD and citrated plasma at room temperature). Moreover, the betaTG:PF4 ratio decreased in patient but not control CTAD samples, suggesting a greater susceptibility of patient platelets to in vitro activation. CONCLUSIONS: Increased sCD40L concentrations resulted from in vitro platelet activation during sample preparation. Disease-related in vivo activation did not contribute to sCD40L concentrations in plasma. Therefore, published studies of sCD40L demand cautious interpretation, because their preanalytical conditions were not standardized.

Determination of aspirin responsiveness by use of whole blood platelet aggregometry.

BACKGROUND: Insufficient platelet inhibition is associated with an increased cardiovascular risk in up to 30% of patients taking regular doses of aspirin. We describe an assay to study aspirin responsiveness. METHODS: We performed impedance aggregometry on diluted whole blood with 1 mg/L collagen and 0.5 mmol/L arachidonic acid (AA). We measured thromboxane B(2) (TXB(2)) by RIA. We examined 66 healthy control individuals, 144 aspirin users with stable coronary artery disease (CAD), and 245 CAD patients treated with aspirin and clopidogrel. Nonresponsive samples were incubated with excess DL-lysinmonoacetylsalicylic acid. RESULTS: Assay imprecision (CV) was 9.8% and 8.2% at mean (SD) 6-min impedance of 13.7 (2.8) Omega and 13.6 (2.3) Omega for collagen and AA, respectively. Collagen induced stronger aggregation (P = 0.0199) in women [n = 28, 14.6 (2.4) Omega] than in men [n = 38, 13.1 (2.9) Omega], even after sample incubation with 0.1 mmol/L acetylsalicylic acid (ASA) or 1 micromol/L terbogrel, a combined inhibitor of thromboxane synthase and receptors. The sex association persisted in aspirin users, but not if clopidogrel was also taken. A 6-min impedance >8 Omega with collagen (mean - 2 SD of the controls) was taken as evidence of nonresponsiveness, particularly if incubation with ASA did not inhibit aggregation further (>2 Omega). Compared with AA, collagen identified more nonresponsive samples among aspirin users (15%) and CAD patients who also received clopidogrel (10%). Incubation with ASA improved inhibition of aggregation in 70% of samples and consistently reduced TXB(2) formation during aggregation. CONCLUSIONS: Impedance aggregometry may prove useful to study aspirin responsiveness, and incubation with ASA may help to identify nonresponders and classify resistance.