Biomedical subjects
Publications and source records attributed to J Ingerslev.
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In the healthy population P-homocysteine increases with age and the level is higher in men aged 30-60 years as compared to women of the same age group. Most often, elevated P-homocysteine is caused by genetic defects, vitamin deficiency (folic acid, B6- and B12-vitamin) or renal failure. Based on retrospective as well as prospective studies, it can be concluded that elevated P-homocysteine is a risk factor for arterial as well as venous thrombosis. Severely elevated P-homocysteine is capable of causing premature arteriosclerosis, whereas slightly elevated levels may also be involved. A slightly positive correlation has been found between P-homocysteine on one hand, and smoking, blood pressure and cholesterol on the other, whereas physical activity is slightly negatively correlated to P-homocysteine. Altered function of endothelial cells and coagulation has been demonstrated in relation to elevated P-homocysteine, but the pathogenetic mechanisms have not been fully elucidated. Usually, an elevated P-homocysteine is normalised by folic acid supplementation, although additional treatment with vitamin B6 may be required. Presumably, the risk of thrombosis is thereby reduced, but future controlled studies may reveal whether this holds true.
We elucidated the intron-exon boundaries of the 15 coding exons of the human cystathionine beta-synthase (CBS) gene in order to establish an improved method based on PCR and direct sequencing for detection of CBS mutations. Using this method we identified the pathogenic mutations in two Danish siblings with CBS deficiency. Patients were compound heterozygotes: we detected the 833T-->C mutation and a novel 22 bp deletion of exon 4 (493-514del) that introduces a frameshift and a stop codon immediately after the deletion. The deletion resulted in no detectable mRNA from this allele, as assessed by sequencing of cDNA. The established method represents an improvement of the existing method based on sequencing of cDNA because it permits the detection of mutations within the entire coding region of the CBS gene from a peripheral blood sample, including splice mutations and mutations resulting in the lack or a reduced amount of transcript.
The aim of this study was to study how the slimming drug, Letigen, containing ephedrine (E) 20 mg and caffeine (C) 200 mg (E + C) affects blood pressure in normotensive and hypertensive patients treated with adrenergic beta-receptor blocking drugs and/or other antihypertensive agents, during a period of six weeks. We followed 136 patients in a double blind, randomised, placebo controlled study of five parallel groups of overweight patients from general practices. The systolic blood pressure was reduced significantly (5.5 mmHg) in the patients treated with antihypertensive agents other than betablockers, plus E + C. In normotensive patients treated with E + C the systolic and diastolic blood pressure declined significantly (4.4/3.9 mmHg). A mean loss of weight of 4 kg over six weeks was significant for all groups. This study does not support the assumption that E + C should cause rises in blood pressure in either normotensive or hypertensive obese patients. The antihypertensive effect of the betablockers was not reversed by E + C.
We have treated two groups of infertile men with growth hormone (GH), namely nine oligozoospermic (< 5 x 10(6) sperm/mL) males and nine asthenozoospermic (percentage mobile sperm < 30 and > 15 x 10(6) sperm/mL) males. The patient groups had a significantly lower GH response to an arginine GH stimulation test as compared to a control group. Each patient was treated with GH for 12 weeks and followed for a total of 36 weeks with sampling of blood and semen. Sperm motility increased significantly during GH treatment in both patient groups. There was no difference in sperm count during the treatment. There were three pregnancies in the nine couples from the asthenozoospermic group and no pregnancies in the oligozoospermic group. Furthermore, we found that seminal plasma IGF-I increased simultaneously with the increase in sperm motility. These data suggest that GH stimulates IGF-I production from Sertoli and/or Leydig cells, which in a paracrine/autocrine manner stimulates maturation of spermatozoa with subsequent increased sperm motility.
Haemostasis is initiated by the complex formed by TF and FVIIa present in the blood (1% of the FVII protein). Recombinant FVIIa, which is active only after having formed complex with TF exposed following tissue damage, has been demonstrated to induce haemostasis in haemophilia patients with life- and limb-threatening bleedings with an efficacy rate of 76-84% in patients having failed on other treatment. Several had proven septicaemia but only one patient developed consumption coagulaopathy during extensive surgical manipulation and removal of myonecrotic tissue. No antibody formation against FVII has been seen in haemophilia patients. In 13 major surgical episodes complete intra- and post-operative haemostasis was achieved. rFVIIa has been used successfully in FVII-deficient patients and has been found to normalise the PT in patients with liver disease and in warfarin treated individuals. Single patients with platelet defects and with vWillebrand's disease type 3 achieved haemostasis with rFVIIa.
Following a survey among all Danish haemophiliac patients 49 HIV-negative patients with chronic hepatitis C were offered enrollment in a randomized controlled open label study comparing two different maintenance regimens following standard interferon-alpha-2b treatment. Dose modifications and treatment discontinuation were based upon changes in transaminase levels. Forty-seven patients enrolled received 3 MU of alpha interferon thrice weekly (TIW) for 3 months. Twenty-six nonresponders had their dose increased to 6 MU TIW for an additional 3 months, while 21 responding patients continued on 3 MU TIW. At 6 months, 25 patients with a complete or a partial biochemical response were randomly allocated to either a fixed dose regimen (13 patients) (3 or 6 MU thrice weekly) or an individualized dose regimen (12 patients) tapering interferon dose from 3 or 6 MU by one-third every 2 months if transaminases were persistently normal. The remaining 22 biochemical nonresponders were followed for an additional 6 months without further treatment. After 12 months of treatment, 18 patients (38%) had a virological response, irrespective of regimen, and seven patients (16%) had a sustained virological and biochemical response after 6 months of follow up. Overall, the individualized treatment regimen did not seem to offer any advantage over the fixed dose regimen. The response to alpha interferon treatment in Danish haemophiliac patients with chronic hepatitis C immediately after treatment is comparable to that obtained in previous studies among nonhaemophiliacs. However, a sustained virological and biochemical response was seen in only 16% of treatment patients.
Factor VII is a trace protein required for normal haemostasis. Deficiency of factor VII comprises a highly heterogeneous disease group. Factor VII deficiency can cause bleeding, in particular if factor VII is extremely low, but a few cases lacking factor VII function entirely or subtotally may not present with a history of bleeding. Bleeding problems are not often reported in patients having a factor VII:C level at 10-15% of normal or more. Bleeding is frequently of mucocutaneous type, but the whole array of haemophilic bleeding may also occur. To control bleeding, during surgery in particular, substitution is required in the severe case of factor VII deficiency, but clinical studies documenting which correctional levels of factor VII:C to aim are lacking. It appears that a critical low level (trough) value at 10-15% may be anticipated, but clear documentation does not exist. Substitution programmes may include plasma or plasma derived factor IX concentrates of lower degrees of purity, so-called prothrombin complex concentrates that also are relatively impure, and pure factor VII concentrates. An alternative is a recombinant factor VIIa molecule. However, this concentrate has not received license in a number of countries. Thrombotic manifestations appear to occur more often than expected in the factor VII deficient patients, some have been linked to the use of impure concentrates, others to preexisting thrombophilic risk factors, but some are unexplained and may bear a relationship to the deficiency state of factor VII itself. Controlled clinical trials are highly warranted in this rare bleeding condition.
Recombinant factor VIIa (rFVIIa) represents a major therapeutic advance in the treatment of haemophilia patients with inhibitors. The efficacy and safety of rFVIIa has been extensively studied in over 1900 surgical and non-surgical bleeding episodes in over 400 patients with haemophilia A or B (with or without inhibitors) or acquired haemophilia. Of 103 evaluable surgical bleeding episodes, the response to treatment with rFVIIa was considered to be either excellent or effective in 81%, 86% and 92% of major, minor and dental bleeding episodes, respectively. Treatment has been evaluated in 518 serious bleeding episodes and the response was considered either excellent or effective in 62% of muscle, 80% of ear, nose and throat, 88% of central nervous system, 76% of joint, and 75% of internal or retroperitoneal bleeding episodes. An excellent safety profile has also been demonstrated: of 1957 treatments with rFVIIa, only 16 serious adverse events have been reported that were considered to be possibly, but not necessarily, related to treatment.
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Significant advances have been achieved in prevention of haemophilic disability through prophylactic administration of concentrates and early administration of coagulation factors to control new bleeding episodes, but there is only limited experience with home treatment in haemophilia patients with inhibitors. A home treatment programme using recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) in early intervention against minor bleeds in patients with high responding inhibitors was initiated in Denmark in June 1994. Following careful education and instruction, 2-3 doses each giving 90-100 micrograms/kg bodyweight of rFVIIa were stored in each patient's home. At the onset of a new bleeding episode patients were instructed to inject 1 dose of rFVIIa, and to call the Haemophilia Centre to discuss further management of the episode. If the drug was not completely effective after 1-2 h, a second dose was injected after 3 h. Patients were further instructed to contact us the following day for final efficacy reporting. In total, 7 patients have been enrolled into the study, and to date 114 bleeding episodes have been managed at home with a mean of 2.1 doses per bleed. On 4 occasions, recurrence of bleeding was noted within 24 h. Hospital admission was required in 9 cases, because of a serious injury, insufficient compliance or, in 2 cases, because bleeding required prolonged treatment. Management of these bleeding episodes required a mean of 18 doses. We propose and discuss key criteria for selection of patients for a home treatment programme. The results of this study demonstrate that early intervention in the home setting with rFVIIa is safe and effective in the management of minor bleeding episodes in haemophilia patients with inhibitors.
A commercially available kit, Amplicor, was compared with a locally developed nested reverse-transcriptase (RT) PCR for qualitative detection of HCV-RNA. Sixty-one serum samples from sixty-one patients with liver disease, and 60 samples from 60 hemophiliacs without symptoms, but known to have been heavily exposed to hepatitis C virus, were investigated. There was a high degree of concordance between the two diagnostic tests (97%), the Amplicor kit being slightly more sensitive than the in-house PCR, when evaluated using serial dilutions of samples showing discrepant results. The relationship between viremia and abnormal ALT levels was studied in the two groups of patients. Among those with chronic liver disease, 8.3% of patients with viremia had normal ALT levels, whereas transaminases were normal in 20% of hemophiliacs with viremia. This points to ALT as being a poor marker of ongoing viral replication.
Haemophilia patients developing an inhibitor against factor VIII (FVIII) or FIX require alternative treatment for the management of their bleeding, rather than standard procedures. In patients with low titre inhibitors, increased doses of FVIII or FIX may improve haemostasis. If a higher titre is present, a porcine FVIII concentrate may be efficacious in selected cases. 'Bypassing' agents, such as low purity FIX concentrates, or activated or unactivated concentrates of prothrombin complex may also be useful in inhibitor patients. An activated factor VII molecule (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark), has been produced by recombinant DNA cell technology. In June 1994, we established a home treatment programme with rFVIIa for five inhibitor patients to study its efficacy in the early intervention of bleeding episodes; our results from the first 3 years are presented. Self-treatment in the home took place in 50 instances of acute minor bleeding. A mean of 2.02 doses of rFVIIa (each dose of about 90 microg/kg bodyweight) was required to arrest bleeding (range 1-4 doses). Four bleeding episodes required in-hospital management either because the acute condition was caused by severe trauma, or because treatment had not been instituted in the early phase of bleeding. Here, the range of rFVIIa doses was 4-37. For comparison, we also report 36 minor bleeding episodes managed in-hospital in three of these five patients who participated in the Compassionate Use Study where home treatment was not permitted. These bleeding episodes required considerably more administrations of rFVIIa with a mean consumption of 8 doses in joint bleeds and 9.5 doses in muscle and soft tissue bleeds. In conclusion, we feel that our home treatment results strongly suggest that early intervention by home treatment with rFVIIa in acute minor bleeding is efficacious and cost effective.
Numerous recent publications point to significant improvements in haemostasis in the bleeding patient suffering from haemophilia with inhibitors when a recombinant activated factor VII (rFVIIa) molecule is administered in high doses. In theory, activated factor VII (FVIIa) is believed to initiate haemostasis through its physiological interaction with tissue factor at sites of cellular injury, whereby factor X (FX) activation and, in consequence, thrombin formation is amplified. There has been speculation, however, whether high circulating FVII procoagulant (FVII:C) levels may induce systemic coagulation activation. The present retrospective investigation was undertaken to study, ex vivo, the influence of treatment with rFVIIa as assessed by the sensitive marker of prothrombin conversion, prothrombin fragment F1+2, in plasma samples. Study subjects consisted of: seven people suffering from thrombocytopenia participating in a study of the influence of rFVIIa on the bleeding time, in whom serial plasma samples had been collected before and subsequently at 10, 60 and 180 min after infusion of rFVIIa; four haemophilia A patients with inhibitors to FVIII undergoing surgery; two haemophilia A patients with inhibitors treated with rFVIIa for minor bleedings on 16 occasions in whom plasma samples had been collected before and 10-15 min after rFVIIa infusion; and two FVII-deficient patients undergoing treatment with rFVIIa. A group of seven haemophilia A patients with no signs of inhibitors subjected to a pharmacokinetic study of a plasma-derived FVIII concentrate served as controls. In the group of thrombocytopenic patients our results showed a mean increase in F1+2 following doses of 50 microg/kg body weight and 100 microg/kg body weight of rFVIIa of 1.1 and 1.4 nmol/l, respectively, with a gradual increase over time, but there was no significant correlation between FVII:C and the corresponding values of F1+2. During and after haemophilic inhibitor surgery, a mean increase in F1+2 of 1.44 nmol/l (range 0.6-3.2 nmol/l) was found, whereas 16 matched samples collected during treatment for minor bleedings showed a mean increase in F1+2 of 0.10 nmol/l (range -0.12 to 0.20 nmol/l). In FVII-deficient individuals, the mean rise in F1+2 was <0.10 nmol/l. In the control group, the mean elevation of F1+2 was 0.13 nmol/l (range -0.5 to 0.7 nmol/l). Hence, our results show that only discrete changes in F1+2 follow administration of rFVIIa.
We designed a prospective unicentre study to evaluate the safety and efficacy of continuous infusion of different factor VIII (FVIII) and FIX concentrates in haemophilia A (n = 9) and haemophilia B (n = 4) patients undergoing surgical procedures. This study was designed to assess the potential risk of developing thromboembolic complications during different types of surgery and to provide some comparative data with respect to continuous infusion of clotting factor concentrates. Heparin prophylaxis was not used in most cases. As pointed out by others, we did not find any significant changes in prothrombin fragment F1+2 and D-dimers during a pharmacokinetic study using a bolus dose of 50 U/kg of a very high purity clotting factor concentrate. Moreover, prothrombin F1+2 and D-dimer serial assays were also carried out postoperatively, and compared with levels in control non-haemophilic patients who had undergone similar surgery with heparin prophylaxis. In haemophilia patients, despite (in most cases) an absence of heparin prophylaxis, no thrombotic complications occurred, and neither the coagulation cascade nor the fibrinolytic system were significantly over-activated, compared with the control group. From a clinical standpoint, all patients achieved excellent haemostasis without clinical evidence of thrombosis. This study emphasizes the convenient and safe administration of highly-purified FVIII and FIX concentrates in haemophiliacs undergoing surgical procedures, and constitutes a small comparative database for the evaluation of new products.
Elevated plasma von Willebrand factor (vWf) levels are found in diabetes and other vasculopathies, and predict cardiovascular mortality. vWf is stored and released from endothelial cell secretory granules, along with equimolar amounts of its propeptide (vWf:AgII). In the present study, we examined plasma propeptide levels as a marker of endothelial secretion in vivo, using an ELISA based on monoclonal antibodies. vWf but not propeptide levels are influenced by blood groups, explaining in part the smaller variation in plasma propeptide levels among normal individuals. In both controls and insulin-dependent diabetic patients, we found a close correlation between propeptide and immunoreactive vWf levels (r2=0.54, p <0.0001). vWf and propeptide were elevated in patient subgroups with microalbuminuria or overt diabetic nephropathy, whereas only the propeptide was significantly elevated in the normoalbuminuric subgroup. This observation suggests that in conjunction with vWf, propeptide measurements may improve the identification of endothelial activation, which occurs frequently even without increased urinary albumin excretion. In 12 NIDDM patients, a 3-week diet enriched in monounsaturated fat (MUFA) resulted in parallel decreases in vWf (-22%, p <0.05) and propeptide (-17%, p <0.05) levels, indicating that the experimental diet affected endothelial secretion rather than vWf catabolism. A carbohydrate-enriched control diet did not significantly influence either marker. Our results suggest that concomitant determinations of plasma vWf and propeptide are useful tools to assess endothelial activation in vivo, and reinforce our previous conclusion that a diet rich in MUFA can improve endothelial function in NIDDM.
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