We hypothesized that subcutaneous administration of immunoglobulins (SCIG) in chronic inflammator... more We hypothesized that subcutaneous administration of immunoglobulins (SCIG) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is feasible, safe and superior to treatment with saline for the performance of muscle strength. Thirty patients with motor involvement in maintenance therapy with intravenous immunoglobulin (IVIG) fulfilling the EFNS/PNS criteria for CIDP, aged 18-80 years, were randomized either to SCIG at a dose corresponding to their pre-study IVIG dose or to subcutaneous saline given twice or thrice weekly for 12 weeks at home. At the start and end of the trial as well as 2 weeks before (-2, 0, 10, 12 weeks), isokinetic strength performance of four predetermined and weakened muscle groups was measured. Also, an Overall Disability Sum Score (ODSS), 40-m-walking test (40-MWT), nine-hole-peg test, Neurological Impairment Score (NIS), Medical Research Council (MRC) score, grip strength, standardized electrophysiological recordings from three nerves, and plasma IgG levels were evaluated. SCIG treatment was well tolerated in all 14 patients. Six patients complained of mild side-effects at the injection site. In the SCIG group there was an increase of isokinetic muscle strength of 5.5 ± 9.5% (P < 0.05) as compared with a decline of 14.4 ± 20.3% (P < 0.05) in the placebo group; the difference between the two groups being significant (P < 0.01). ODSS, NIS, MRC, grip strength and 40-MWT improved following SCIG versus saline. SCIG treatment in CIDP is feasible, safe and effective, and seems an attractive alternative to IVIG.
Early stent valve thrombosis after transcatheter aortic valve implantation (TAVI) is a rare compl... more Early stent valve thrombosis after transcatheter aortic valve implantation (TAVI) is a rare complication, which is diagnosed based on the appearance of clinical symptoms of heart failure and echocardiographic findings. After TAVI, transthoracic echocardiography is performed to assess transcatheter heart valve (THV) function. However, preliminary reports indicate the potential additive clinical value of multidetector computed tomography (MDCT) for the diagnosis of THV thrombosis. We sought to determine the value of MDCT for the diagnosis of THV thrombosis and the frequency of this complication after balloon-expandable TAVI. MDCT was performed in 140 patients within 1 to 3 months after TAVI with the Edwards Sapien XT THV to assess the presence of THV thrombosis and THV stent geometry. Post-TAVI MDCT identified THV thrombosis in 5 patients (4%). Of note, 4 of these patients were asymptomatic and had a normal transthoracic echocardiographic examination without signs of thrombus formatio...
To assess the effect and tolerability of zonisamide (ZNS) as adjunctive treatment for difficult-t... more To assess the effect and tolerability of zonisamide (ZNS) as adjunctive treatment for difficult-to-treat epilepsy in adult Scandinavian patients. 151 outpatients (mean age: 42.5 years) from 18 centres in Denmark, Sweden and Norway were recruited to the study. 81.5% had focal epilepsy, and the mean number of previously tried AEDs was 4.5. The patients were given ZNS as add-on treatment, and the ZNS dosing and the visit frequency were governed by the treating physician. The primary efficacy endpoint was the retention rate after 12-month treatment. Assessments included also responder rate, type and frequency of adverse events, healthcare resource utilization (HCRU) and quality of life (QOLIE-31). 90 patients (59.6%) completed the study. Mean daily ZNS dose was 300.8 mg. After 12 months, 81 patients were still on ZNS, that is a retention rate of 53.6%. The mean reduction of seizure frequency at 12 months was 27%. Best effect was seen in those with focal and those with secondary generali...
Neuropathy is an insidious and devastating consequence of diabetes. Early studies provided a stro... more Neuropathy is an insidious and devastating consequence of diabetes. Early studies provided a strong rationale for deficient neurotrophin support in the pathogenesis of diabetic neuropathy in a number of critical tissues and organs. It has now been over a decade since the first failed human neurotrophin supplementation clinical trials, but mounting evidence still implicates these trophic factors in diabetic neuropathy. Since then, tremendous advances have been made in our understanding of the complexities of neurotrophin signaling and processing and how the diabetic milieu might impact this. This in turn changes both our perception of how the altered trophic environment contributes to the etiology of diabetic neuropathy and the design of future neurotrophin therapeutic interventions. This chapter summarizes some of these findings and attempts to integrate neurotrophin actions on the nervous system with an increasing appreciation of their role in the regulation of metabolic processes ...
We describe a Danish family with an, until recently, unknown X-linked disease with muscular dystr... more We describe a Danish family with an, until recently, unknown X-linked disease with muscular dystrophy (MD), facial dysmorphology and pulmonary artery hypoplasia. One patient died suddenly before age 20 and another was resurrected from cardiac arrest at the age of 28. Linkage analysis pointed to a region of 25 Mb from 123.6 Mb to 148.4 Mb on chromosome X containing over 100 genes. Exome sequencing identified a single nucleotide splice site mutation c.502-2A > T, which is located 5' to exon 6 in the gene encoding four and a half LIM domain 1 (FHL1) protein. FHL1 expresses three main splice variants, known as FHL1A, FHL1B and FHL1C. In healthy individuals, FHL1A is the predominant splice variant and is mainly found in skeletal and cardiac muscle. The FHL1 transcript profiles from two affected individuals were investigated in skin fibroblasts with quantitative real-time PCR. This demonstrated loss of isoform A and B, and an almost 200-fold overexpression of isoform C confirming that lack of FHL1A and overexpression of FLH1C results in an extended phenotype of EDMD as recently shown by Tiffin et al. [2013].
Bleeding following cardiac surgery involving cardiopulmonary bypass (CPB) remains a major concern... more Bleeding following cardiac surgery involving cardiopulmonary bypass (CPB) remains a major concern. Coagulation factor XIII (FXIII) functions as a clot-stabilising factor by cross-linking fibrin. Low post-operative levels of FXIII correlate with increased post-operative blood loss. To evaluate preliminary safety and pharmacokinetics of recombinant FXIII (rFXIII-A(2)) in cardiac surgery, patients scheduled for coronary artery bypass grafting were randomised to receive a single dose of either rFXIII-A(2) (11.9, 25, 35 or 50 IU/kg) or placebo in a 4:1 ratio. Study drug was given post-CPB within 10 to 20 minutes after first protamine dose. Patients were evaluated until day 7 or discharge, with a follow-up visit at weeks 5-7. The primary end-point was incidence and severity of adverse events. Thirty-five patients were randomised to rFXIII-A(2) and eight to placebo. Eighteen serious adverse events were reported. These were all complications well recognised during cardiac surgery. Although one patient required an implantable defibrillator, all recovered without sequelae. One myocardial infarction in a patient receiving 35 IU/kg rFXIII-A(2) was identified by the Data Monitoring Committee after reviewing ECGs and cardiac enzymes. No other thromboembolic events were seen. Dosing with 25-50 IU/kg rFXIII-A(2) restored levels of FXIII to pre-operative levels, with a tendency towards an overshoot in receiving 50 IU/kg. rFXIII-A(2), in doses from 11.9 IU/kg up to 50 IU/kg, was well tolerated. For post-operative FXIII replenishment, 35 IU/kg of rFXIII-A(2) may be the most appropriate dose.
To calculate the incidence and analyse and outcome after coronary artery bypass grafting (CABG) w... more To calculate the incidence and analyse and outcome after coronary artery bypass grafting (CABG) within the first year after randomisation of 1,572 patients with acute myocardial infarctions with ST-segment elevation (STEMI) to either percutaneous coronary intervention (PCI) or fibrinolysis. The study includes 131 patients: 108 male and 23 female with a mean age 62 years. The total 30-day mortality after CABG was 4.6% (7.5% in the PCI group and 2.6% in the fibrinolysis group). The 30-day mortality was 9.8% after CABG within the first 30-days and 1.3% after CABG within 31-365 days. The patients who were operated early had a reduced EF to 43% as compared to 50% in patients who were not operated or patients having CABG after 30-days (p=0.002). CABG was performed within the first year after STEMI in 10% of patients randomised to fibrinolysis and in 6.7% of patients randomised to PCI. Patients having CABG within the first 30-days after treatment of STEMI had an increased mortality of 9.8%.
We hypothesized that subcutaneous administration of immunoglobulins (SCIG) in chronic inflammator... more We hypothesized that subcutaneous administration of immunoglobulins (SCIG) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is feasible, safe and superior to treatment with saline for the performance of muscle strength. Thirty patients with motor involvement in maintenance therapy with intravenous immunoglobulin (IVIG) fulfilling the EFNS/PNS criteria for CIDP, aged 18-80 years, were randomized either to SCIG at a dose corresponding to their pre-study IVIG dose or to subcutaneous saline given twice or thrice weekly for 12 weeks at home. At the start and end of the trial as well as 2 weeks before (-2, 0, 10, 12 weeks), isokinetic strength performance of four predetermined and weakened muscle groups was measured. Also, an Overall Disability Sum Score (ODSS), 40-m-walking test (40-MWT), nine-hole-peg test, Neurological Impairment Score (NIS), Medical Research Council (MRC) score, grip strength, standardized electrophysiological recordings from three nerves, and plasma IgG levels were evaluated. SCIG treatment was well tolerated in all 14 patients. Six patients complained of mild side-effects at the injection site. In the SCIG group there was an increase of isokinetic muscle strength of 5.5 ± 9.5% (P < 0.05) as compared with a decline of 14.4 ± 20.3% (P < 0.05) in the placebo group; the difference between the two groups being significant (P < 0.01). ODSS, NIS, MRC, grip strength and 40-MWT improved following SCIG versus saline. SCIG treatment in CIDP is feasible, safe and effective, and seems an attractive alternative to IVIG.
Early stent valve thrombosis after transcatheter aortic valve implantation (TAVI) is a rare compl... more Early stent valve thrombosis after transcatheter aortic valve implantation (TAVI) is a rare complication, which is diagnosed based on the appearance of clinical symptoms of heart failure and echocardiographic findings. After TAVI, transthoracic echocardiography is performed to assess transcatheter heart valve (THV) function. However, preliminary reports indicate the potential additive clinical value of multidetector computed tomography (MDCT) for the diagnosis of THV thrombosis. We sought to determine the value of MDCT for the diagnosis of THV thrombosis and the frequency of this complication after balloon-expandable TAVI. MDCT was performed in 140 patients within 1 to 3 months after TAVI with the Edwards Sapien XT THV to assess the presence of THV thrombosis and THV stent geometry. Post-TAVI MDCT identified THV thrombosis in 5 patients (4%). Of note, 4 of these patients were asymptomatic and had a normal transthoracic echocardiographic examination without signs of thrombus formatio...
To assess the effect and tolerability of zonisamide (ZNS) as adjunctive treatment for difficult-t... more To assess the effect and tolerability of zonisamide (ZNS) as adjunctive treatment for difficult-to-treat epilepsy in adult Scandinavian patients. 151 outpatients (mean age: 42.5 years) from 18 centres in Denmark, Sweden and Norway were recruited to the study. 81.5% had focal epilepsy, and the mean number of previously tried AEDs was 4.5. The patients were given ZNS as add-on treatment, and the ZNS dosing and the visit frequency were governed by the treating physician. The primary efficacy endpoint was the retention rate after 12-month treatment. Assessments included also responder rate, type and frequency of adverse events, healthcare resource utilization (HCRU) and quality of life (QOLIE-31). 90 patients (59.6%) completed the study. Mean daily ZNS dose was 300.8 mg. After 12 months, 81 patients were still on ZNS, that is a retention rate of 53.6%. The mean reduction of seizure frequency at 12 months was 27%. Best effect was seen in those with focal and those with secondary generali...
Neuropathy is an insidious and devastating consequence of diabetes. Early studies provided a stro... more Neuropathy is an insidious and devastating consequence of diabetes. Early studies provided a strong rationale for deficient neurotrophin support in the pathogenesis of diabetic neuropathy in a number of critical tissues and organs. It has now been over a decade since the first failed human neurotrophin supplementation clinical trials, but mounting evidence still implicates these trophic factors in diabetic neuropathy. Since then, tremendous advances have been made in our understanding of the complexities of neurotrophin signaling and processing and how the diabetic milieu might impact this. This in turn changes both our perception of how the altered trophic environment contributes to the etiology of diabetic neuropathy and the design of future neurotrophin therapeutic interventions. This chapter summarizes some of these findings and attempts to integrate neurotrophin actions on the nervous system with an increasing appreciation of their role in the regulation of metabolic processes ...
We describe a Danish family with an, until recently, unknown X-linked disease with muscular dystr... more We describe a Danish family with an, until recently, unknown X-linked disease with muscular dystrophy (MD), facial dysmorphology and pulmonary artery hypoplasia. One patient died suddenly before age 20 and another was resurrected from cardiac arrest at the age of 28. Linkage analysis pointed to a region of 25 Mb from 123.6 Mb to 148.4 Mb on chromosome X containing over 100 genes. Exome sequencing identified a single nucleotide splice site mutation c.502-2A > T, which is located 5' to exon 6 in the gene encoding four and a half LIM domain 1 (FHL1) protein. FHL1 expresses three main splice variants, known as FHL1A, FHL1B and FHL1C. In healthy individuals, FHL1A is the predominant splice variant and is mainly found in skeletal and cardiac muscle. The FHL1 transcript profiles from two affected individuals were investigated in skin fibroblasts with quantitative real-time PCR. This demonstrated loss of isoform A and B, and an almost 200-fold overexpression of isoform C confirming that lack of FHL1A and overexpression of FLH1C results in an extended phenotype of EDMD as recently shown by Tiffin et al. [2013].
Bleeding following cardiac surgery involving cardiopulmonary bypass (CPB) remains a major concern... more Bleeding following cardiac surgery involving cardiopulmonary bypass (CPB) remains a major concern. Coagulation factor XIII (FXIII) functions as a clot-stabilising factor by cross-linking fibrin. Low post-operative levels of FXIII correlate with increased post-operative blood loss. To evaluate preliminary safety and pharmacokinetics of recombinant FXIII (rFXIII-A(2)) in cardiac surgery, patients scheduled for coronary artery bypass grafting were randomised to receive a single dose of either rFXIII-A(2) (11.9, 25, 35 or 50 IU/kg) or placebo in a 4:1 ratio. Study drug was given post-CPB within 10 to 20 minutes after first protamine dose. Patients were evaluated until day 7 or discharge, with a follow-up visit at weeks 5-7. The primary end-point was incidence and severity of adverse events. Thirty-five patients were randomised to rFXIII-A(2) and eight to placebo. Eighteen serious adverse events were reported. These were all complications well recognised during cardiac surgery. Although one patient required an implantable defibrillator, all recovered without sequelae. One myocardial infarction in a patient receiving 35 IU/kg rFXIII-A(2) was identified by the Data Monitoring Committee after reviewing ECGs and cardiac enzymes. No other thromboembolic events were seen. Dosing with 25-50 IU/kg rFXIII-A(2) restored levels of FXIII to pre-operative levels, with a tendency towards an overshoot in receiving 50 IU/kg. rFXIII-A(2), in doses from 11.9 IU/kg up to 50 IU/kg, was well tolerated. For post-operative FXIII replenishment, 35 IU/kg of rFXIII-A(2) may be the most appropriate dose.
To calculate the incidence and analyse and outcome after coronary artery bypass grafting (CABG) w... more To calculate the incidence and analyse and outcome after coronary artery bypass grafting (CABG) within the first year after randomisation of 1,572 patients with acute myocardial infarctions with ST-segment elevation (STEMI) to either percutaneous coronary intervention (PCI) or fibrinolysis. The study includes 131 patients: 108 male and 23 female with a mean age 62 years. The total 30-day mortality after CABG was 4.6% (7.5% in the PCI group and 2.6% in the fibrinolysis group). The 30-day mortality was 9.8% after CABG within the first 30-days and 1.3% after CABG within 31-365 days. The patients who were operated early had a reduced EF to 43% as compared to 50% in patients who were not operated or patients having CABG after 30-days (p=0.002). CABG was performed within the first year after STEMI in 10% of patients randomised to fibrinolysis and in 6.7% of patients randomised to PCI. Patients having CABG within the first 30-days after treatment of STEMI had an increased mortality of 9.8%.
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