Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group.

PURPOSE: To compare the risk of recurrent venous thromboembolism in patients with and without antiphospholipid antibodies. PATIENTS AND METHODS: Anticardiolipin antibodies were tested 6 months after a first or second episode of venous thromboembolism. Of the patients with a first episode of venous thromboembolism only the 412 who received 6 months of anticoagulation were studied. Two hundred and eleven patients with a second episode received oral anticoagulation for 6 months or indefinitely. The therapy was targeted at an international normalized ratio (INR) of 2.0 to 2.85. All patients were followed up for 4 years after enrollment. RESULTS: Among the 412 patients with a first episode of venous thromboembolism the risk of recurrence was 29% in patients with anticardiolipin antibodies and 14% in those without antibodies (P = 0.0013). In those with antibodies, there was an increased risk during the first 6 months after cessation of anticoagulation. The risk of recurrence increased with the titer of the antibodies. Four-year mortality rate was 15% in those with antibodies and 6% in those without (P = 0.01). Among 34 patients with a second event of venous thromboembolism and anticardiolipin antibodies, there were no recurrences during anticoagulant therapy versus 20% in those who received only 6 months of treatment (P = 0.08). CONCLUSIONS: The presence of elevated titers of anticardiolipin antibodies 6 months after an episode of venous thromboembolism is a predictor for an increased risk of recurrence and of death. Patients with anticardiolipin antibodies and venous thromboembolism seem to benefit from prolonged oral anticoagulation.

Ten years' experience of bone marrow transplantation for Gaucher disease.

Six patients underwent allogeneic bone marrow transplantation (BMT) because of severe Gaucher disease. Their ages was from 2 to 9 years at the time of transplantation. The donors were 4 HLA-identical siblings, a father with one incompatible HLA antigen and an HLA-A, -B, and -DR-identical unrelated donor. Among the donors, three were heterozygous for glucocerebrosidase and three were healthy homozygotes. Four patients underwent total splenectomy and two patients partial splenectomy prior to transplantation. In the former group one patient developed pneumococcal meningitis. In the latter group transfusion requirements were increased. The parental graft was rejected, but 4 of 5 other patients have donor enzyme levels from 2 up to 11 years after BMT. Two patients became mixed chimeras with around 40% of donor erythrocyte markers for one and 80% for the other. One of these had low enzyme activity in his lymphocytes, but the clinical outcome is excellent. This case gives good hope for future trials with gene therapy in Gaucher disease. Glucosylceramide in plasma was within the normal range in all other patients with engraftment, but glucosylceramide in erythrocytes were in the upper normal range in the two chimeric patients with heterozygous donors. Glucosylceramide levels in the liver decreased markedly in the two patients where it was studied. Gaucher cells disappeared in the bone marrow and liver size normalized or decreased within two to three years after BMT. All patients with engraftment had a growth spurt. Skeletal kyphosis was unaffected by BMT in three patients and became apparent in one patient 8 years after BMT. The patients had a favorable psychological development after BMT, with an excellent IQ between 112 and 120 ten years after BMT in the longest survivor. The data suggest that in advanced Gaucher disease BMT still may be a treatment of choice if an HLA-identical related or unrelated donor is available.

Long-term follow-up of the first successful bone marrow transplantation in Gaucher disease.

A 9-year-old girl with juvenile Gaucher disease underwent splenectomy and allogeneic bone marrow transplantation. Her HLA-identical brother with normal cerebroside-beta-glucosidase activity served as donor. One month after transplantation, cerebroside-beta-glucosidase activity in the lymphocytes were normal. Plasma glucosylceramide normalized already after splenectomy and further decreased after marrow transplantation. Glucosylceramide in the erythrocytes was normal around a year after transplantation. The enlarged liver normalized in size by 2 years. Gaucher cells were still present in the bone marrow 1 year after transplantation but had completely disappeared at 3 years. The patient has grown 29 cm during the 5 years that have passed after transplantation compared to 1 cm/year during 3 years before. The patient has a slight obstructive ventilatory impairment, and chest deformities have appeared. Wechsler intelligence scale performance has slowly decreased after transplantation. This may be caused by continued neuronal storage of glucosylceramide. Otherwise, this patient is active and healthy 5 years after bone marrow transplantation.

A comparison between low molecular weight heparin (KABI 2165) and standard heparin in the intravenous treatment of deep venous thrombosis.

In order to study whether a low molecular weight heparin (LMWH) of mw 4000 D is effective in the treatment of deep venous thrombosis (DVT), patients with DVT verified by phlebography were randomized to treatment by continuous intravenous infusion of either unfractionated heparin (UFH) or LMWH. The initial dose was 240 U (anti F Xa)/kg/12 h. This study (study I) was stopped because of major bleeding in 2 newly operated patients in the LMWH group after 27 patients had been treated. The heparin activity measured as F Xa inhibition assayed in retrospect, was found to be much higher in the LMWH group (mean 1.6-2.0 anti F Xa U/ml) than in the UFH group (mean 0.5-0.8 anti F Xa U/ml). A second study was therefore initiated in which the DVT patients were randomly given UFH (240 U/kg/12 h) or LMWH only 120 U (anti F Xa)/kg/12 h, as initial doses (study II). In this study 27 patients could be evaluated, the mean heparin activity still being higher in the LMWH group (0.9-1.2 anti F Xa U/ml) than in the UFH group (0.5-0.7 anti F Xa U/ml). A second phlebographic investigation showed progression of thrombus size in 3 (11%) of the UFH patients of studies I and II (n = 29) and improvement in 14 (48%). There was no progression in any LMWH patient, 6 (50%) had improved in study I and 10 (77%) in study II. The mean decrease of thrombus size score (according to Marder) during treatment did not differ between the 3 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis.

Two hundred and four consecutive patients with venographically confirmed deep vein thrombosis (DVT) were randomised either to a low molecular weight heparin, Fragmin, administered subcutaneously (s.c.) once daily as a fixed dose of 200 IU anti-factor Xa/kg or to continuous intravenous infusion of unfractionated heparin (UFH). The UFH dose was adjusted to maintain the activated partial thromboplastin time between 1.5 and 3.0 times the upper limit of the reference value at each centre. Fragmin or UFH was given for a minimum of 5 days until anticoagulation with warfarin, given from day 1, was established (i.e. an Internation Normalised Ratio, of 2.0-3.0). A second venogram was obtained after Fragmin or UFH treatment. There were no significant differences in the change in mean Marder score before and after treatment between the two treatment groups, irrespective of thrombus localisation. No major bleeding events, symptomatic pulmonary embolism, symptomatic thrombosis progression or death occurred during hospitalisation. Eight documented venous thromboembolic events occurred before the follow-up visit 6 months after randomisation: 5 in patients treated with Fragmin and 3 in those treated with UFH. Six of these events occurred after cessation of warfarin treatment. In conclusion Fragmin given s.c. once daily in a fixed dose adjusted for body weight, is no less effective or safe than a continuous infusion of UFH in the initial treatment of acute DVT.

A 6-month venographic follow-up in 164 patients with acute deep vein thrombosis.

UNLABELLED: A total of 164 patients were recruited from a randomized trial comparing a low molecular weight heparin, dalteparin, given subcutaneously once daily with a continuous intravenous infusion of unfractionated heparin in the initial treatment of acute deep vein thrombosis. The primary objective of this follow-up study was to investigate whether there were any differences between the two treatment groups with respect to Marder score changes 6 months after the initial diagnosis using repeated venography. The secondary objectives were to analyse whether certain haemostatic and acute phase parameters or patient characteristics influenced the venographic outcome. RESULTS: Complete lysis of the thrombus was observed in 38.4% of the patients and a partial lysis in another 54.3% assessed by venography 6 months after the acute event. Extension of the thrombus was seen in 7.3% of the patients. There were no significant differences in the change in mean Marder score before treatment and at the 6 month follow-up between the two treatment groups, irrespective of thrombus localisation. In a regression model, male gender, low levels of orosomucoid and increased levels of d-dimer in plasma on day 5 were independently associated (p <0.05) with an enhanced absolute resolution of the thrombus at 6 months. No differences in symptoms and signs in the thrombotic leg at follow-up, comparing the treatment given, or thrombus extension at diagnosis and 6 months later, were demonstrated. CONCLUSION: Dalteparin given once daily subcutaneously was as effective as continuous intravenous infusion of unfractionated heparin in the initial treatment of deep vein thrombosis assessed by Marder score evaluation 6 months after the acute event.

Two daily subcutaneous injections of fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis (DVT).

In a prospective, randomized, open study 119 consecutive patients with phlebographically verified deep venous thrombosis (DVT) of the leg (36% distal and 64% proximal) were treated either with a low molecular weight heparin (Fragmin, Kabi-Vitrum) subcutaneously (120 anti-FXa U/kg) twice daily or standard heparin (SH) as continuous intravenous infusion (480 IU kg-1 day-1). The Fragmin doses were adjusted to achieve an anti-FXa activity of 0.2-0.4 U/ml before injection and not greater than 1.5 U/ml 4 h after the morning injection. The SH dose was modified to prolong the APTT 2-3 times. Repeat phlebography after 5-7 days showed improvement in 34/45 patients (76%) in the Fragmin group and in 30/49 patients (61%) in the SH group and progress in 2/45 (4%) and 3/49 (6%), respectively. The mean Marder scores decreased from 18.7 +/- 12.1 to 15.7 +/- 12.7 in the Fragmin group and from 16.9 +/- 12.0 to 14.4 +/- 11.8 in the SH group (ns). Two patients in the SH group and none in the Fragmin group had major bleedings. After 22 +/- 7 months follow up 6 rethromboses had occurred in the SH group and 4 in the Fragmin group. Postthrombotic signs and symptoms were similar in both groups. We conclude that two daily sc Fragmin doses seem as effective and safe as continuous SH in the treatment of DVT of the leg.

A comparative randomized trial of low-dose versus high-dose streptokinase in deep vein thrombosis of the thigh.

Fibrinolytic treatment of acute deep vein thrombosis (DVT) of the leg with high-dose streptokinase (SK) (100,000 U/h) in 39 cases, or low-dose SK (approx 10,000 U/h) in combination with low-dose heparin in 41 cases, was studied in a prospective randomized trial. The degree of thrombolysis was similar in both groups and did not correlate with age or size of the thrombus or with fibrinogen level. The degree of late recanalization was also similar in both groups. There were however significantly more patients with postthrombotic changes in the low-dose group than in the high-dose group after a mean follow-up time of 31 and 38 months respectively. In the low-dose group 2 intracranial hemorrhages occurred (one was fatal) and one patient died of pulmonary embolism, but there were significantly less allergic side effects to SK. There were no cases of such serious side effects in the highdose group. Although low-dose SK has equal thrombolytic effect it seems inferior to high-dose SK, since it probably causes more severe hemorrhagic side-effects.

Once-daily subcutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis.

The aim of the study was to compare the efficacy and safety of once-daily subcutaneous injection of dalteparin, a low molecular weight heparin, with that of intravenous unfractionated heparin in the treatment of deep venous thrombosis (DVT). Patients were included if they had deep venous thrombosis distal to inguinal ligament and were randomised either before, if it was considered necessary, or after phlebographic verification of the diagnosis. There was no pre-inclusion treatment with unfractionated heparin. One hundred and twenty patients received dalteparin, administered subcutaneously once-daily at a fixed dose of 200 IU anti-factor Xa/kg, and 133 patients received a continuous intravenous infusion of unfractionated heparin (UFH). Oral anticoagulation was started on the first or second day, and initial treatment with dalteparin or UFH discontinued when the prothrombin time was in the therapeutic range (2 < INR < 3) on two consecutive days. Control phlebograms were taken within 4 days, thereafter. There were no significant differences between the two initial treatment groups in improvements in Marder score. Two major bleeding events occurred in the UFH group versus none in the dalteparin group. One patient in each group experienced clinically significant pulmonary embolism. During a mean follow-up period of 6.9 +/- 1.5 months, recurrent DVT occurred in four patients in the dalteparin group and in two of the UFH group. These results confirm those of a previous study on dalteparin in the initial treatment of DVT, and suggest that dalteparin administered once-daily at a fixed dose of 200 UI/kg is as effective and well-tolerated as UFH in patients with DVT below the inguinal ligament. The present study also demonstrates that dalteparin can be started as soon as the diagnosis of DVT is suspected and without pre-treatment with UFH. Given that the administration of once-daily subcutaneous injections needs not require a patient to be hospitalised, studies to investigate the possibility of using dalteparin for the initial treatment of DVT in the outpatient setting are warranted.

Thrombolysis and fibrinolytic parameters during heparin treatment of deep vein thrombosis.

Thirty-nine patients with symptomatic, venographically verified deep vein thrombosis (DVT) were studied during treatment with heparin in order to investigate the correlation between the venographic changes and parameters of heparin therapy or fibrinolytic components. Venograms were scored with a 40-grade scale, and after one week a significant improvement with an average reduction of the thrombi of 17% was observed. No statistically significant correlation was found between reduction of thrombus size and duration of heparin treatment, total amount of heparin administered, mean levels of APTT, plasmin-alpha 2-antiplasmin complex (PAP), tissue plasminogen activator (t-PA) antigen or t-PA-inhibitor. Only a short history of the thrombus was significantly correlated to thrombolysis. The concentrations of PAP and t-PA-inhibitor were not influenced, while that of t-PA antigen showed a significant increase during heparin infusion. Even if statistically significant correlations were not obtained, the patients with pronounced thrombolytic effect had high PAP-levels. Furthermore, patients with high t-PA-inhibitor levels had no lysis. The results suggest, that also other factors than plasminogen dependent fibrinolysis are of importance for the thrombolytic effect.

A pilot study; desmopressin (DDAVP) in the treatment of deep venous thrombosis.

In a pilot study on 9 patients with acute deep venous thrombosis of the leg the fibrinolytic response and the possible thrombolytic effect of desmopressin (DDAVP), when given supplementary to standard heparin treatment, was examined. Six injections of 0.3-0.4 microgram DDAVP/kg b.w. at 12 hours intervals were given. No serious side effects were observed. The fibrinolytic variables that followed showed that plasma levels of t-PA increased significantly and most pronounced after the first injection. Rephlebography 4-7 days after hospitalization showed partial thrombolysis in 7 out of 9 patients. The phlebographic score according to Marder was reduced from 22.7 +/- 12.1 to 18.4 +/- 10.1 (p = 0.018), corresponding to a thrombus size reduction of 19%. No correlation between the level of the fibrinolytic variables measured and the degree of thrombolysis in the individual patients, could be demonstrated in this small number of patients.

Crohn's disease of the appendix: remission obtained by total parenteral nutrition.

A woman, aged 37 years, who had been suffering from advanced Crohn's disease for many years, was treated with long-term total parenteral nutrition (TPN), given in two 2-month periods at an interval of 6 months. Prior to the introduction of TPN there was inflammation of the appendix, the terminal ileum, and the entire colon. During the first period of TPN there was a temporary clinical and radiological improvement in the state of the intestinal tract, including the appendix. Two months after the first period of TPN abdominal pain recurred, and colonoscopy disclosed renewed severe inflammation of the mucosa from the cecum to the rectum. At operation, on day 45 of the second period of TPN, due to remaining stenosis of the terminal ileum, there was no longer any inflammation of the appendix, confirmed by histological examination.

Botulinum toxin injections for essential voice tremor.

Fifteen patients, 13 women and 2 men, with a mean age of 72.7 years (56 to 86 years) and a clinical diagnosis of essential voice tremor, were treated with botulinum injections to the thyroarytenoid muscles, and in some cases, to the cricothyroid or thyrohyoid muscles. Evaluations were based on subjective judgments by the patients, and on perceptual and acoustic analysis of voice recordings. Subjective evaluations indicated that the treatment had a beneficial effect in 67% of the patients. Perceptual evaluations showed a significant decrease in voice tremor during connected speech (p < .05). Acoustic analysis showed a nearly significant decrease in the fundamental frequency variations (p = .06) and a significant decrease in fundamental frequency during sustained vowel phonation (p < .01 ). The results of perceptual evaluation coincided most closely with the subjective judgments. It was concluded that the treatment was successful in 50% to 65% of the patients, depending on the method of evaluation.

Voice source characteristics in Mongolian "throat singing" studied with high-speed imaging technique, acoustic spectra, and inverse filtering.

Mongolian "throat singing" can be performed in different modes. In Mongolia, the bass-type is called Kargyraa. The voice source in bass-type throat singing was studied in one male singer. The subject alternated between modal voice and the throat singing mode. Vocal fold vibrations were observed with high-speed photography, using a computerized recording system. The spectral characteristics of the sound signal were analyzed. Kymographic image data were compared to the sound signal and flow inverse filtering data from the same singer were obtained on a separate occasion. It was found that the vocal folds vibrated at the same frequency throughout both modes of singing. During throat singing the ventricular folds vibrated with complete but short closures at half the frequency of the true vocal folds, covering every second vocal fold closure. Kymographic data confirmed the findings. The spectrum contained added subharmonics compared to modal voice. In the inverse filtered signal the amplitude of every second airflow pulse was considerably lowered. The ventricular folds appeared to modulate the sound by reducing the glottal flow of every other vocal fold vibratory cycle.

[Endoscopic ultrasound in the investigation of gastric tumors]. / Endoskopiskt ultraljud vid utredning av magsäckstumörer.

Preoperative staging has been considered to be of importance in gastric cancer. Recently, 133 patients were examined preoperatively using endoscopic ultrasound, and 77 of these had gastric cancer. Preoperative staging (T + M) using endoscopic ultrasound coincided with findings at surgery in 84% of the cases. The depth of penetration was accurate in 92% of the cases. It is concluded that endoscopic ultrasound is more reliable for preoperative staging than conventional ultrasound, computer tomography or magnetic resonance imaging for gastric cancer. Whether or not improved preoperative staging has a bearing on the treatment of patients with gastric cancer, depends largely on whether or not cytostatic therapy is used. We believe that centralizing diagnosis and treatment of gastric cancer is beneficial.

Distribution of polyps in the large bowel in relation to age. A colonoscopic study.

In a colonoscopic study of the anatomical distribution of 600 adenomas, polyps of all sizes in patients up to 55 years old were predominantly located distally. With advancing age of the patients a successively greater proportion of at first small and then also larger polyps was found in the intermediate and proximal parts of the colon. These findings support the assumption that polyps of the gut as a rule originate in the distal part of the large bowel, only later to appear proximally. This concept is important, since it might serve to explain conflicting experience with regard to the site of colorectal tumours.

Postoperative follow-up of patients with colorectal carcinoma by colonoscopy.

OBJECTIVE: To find out if colonoscopy is of use in the follow-up of patients who have been operated on for colorectal carcinoma. DESIGN: Retrospective study. SETTING: Department of diagnostic radiology, university hospital. SUBJECTS: 390 consecutive patients operated on for colorectal carcinoma during the 10-year period 1981 to 1990. MAIN OUTCOME MEASURES: Number of recurrences, synchronous of metachronous tumours, and number and size of adenomas found on colonoscopy. RESULTS: Neoplastic lesions were found in 175 (45%) of the 390 patients studied. There were 14 anastomotic recurrences and 12 new primary carcinomas. At operation for recurrent tumours Dukes' A or B lesions were found in half of the 14 patients who had no symptoms, and a quarter of the 12 who had had symptoms. Those with recurrent carcinoma were younger than those without. Adenomas 1 cm in diameter or more were found in 44 patients and 104 had adenomas less than 1 cm. In addition one carcinoid was found. CONCLUSION: Colonoscopy gave a high yield of neoplastic lesions when used to follow-up patients after resection of colorectal carcinoma, particularly at six months, and resulted in half the recurrent carcinomas being diagnosed before the patients had symptoms. We recommend its use for follow-up of high risk patients, but further studies are needed to establish the optimum time intervals.

A new technique for insertion of the colonoscope through the ileocaecal valve.

At colonoscopy it is important to examine the distal part of ileum in inflammatory diseases particularly. Different techniques for insertion of the colonoscope into the ileum have been described. In our experience these methods require considerable skill and practice. We have therefore worked out a technique for easier access to the ileum with a colonoscope. A closed biopsy forceps is used for identification of the ileocaecal valve by dislodging the upper lip. The forceps is manoeuvred through the ostium and then the colonoscope can be inserted into the ileum with the forceps as a guide.