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Biomedical subjects

J Hirsh

Publications and source records attributed to J Hirsh.

At least 163 records · Page 9Linked to original sources
PubMed1995

Low molecular weight heparins (LMWH) in the treatment of patients with acute venous thromboembolism.

We have analysed randomized trials comparing unfractionated heparin and low molecular weight heparin in which symptomatic recurrent venous thromboembolism and major bleeding were objectively confirmed. Studies were classified as level 1 if they were double blind or if there was blinded assessment of outcome measures and level 2 if they did not provide assurance of blinded outcome assessment. In studies classified as level 1, the relative risk (RR) of recurrent venous thromboembolism during the first 15 days and over the entire period of anticoagulant therapy was 0.24 (95% confidence intervals [CI] 0.06-0.08, p = 0.02) and 0.39 (95% CI 0.3-0.4, p = 0.006), respectively, in favour of LMWH treatment. The RR for major bleeding was 0.42 (95% CI 0.2-0.9, p = 0.01), in favour of LMWH. In studies classified as level 2, no significant differences in the rates of recurrent venous thromboembolism and major bleeding were observed. Pooling level 1 and level 2 studies, the RR for overall mortality and mortality in cancer patients was 0.51 (95% CI 0.2-0.9, p = 0.01) and 0.33 (95% CI 0.1-1.8, p = 0.01) respectively, in favour of LMWH.

Anticoagulants↗
PubMed1995

Advances in antithrombotic therapy: novel agents.

Most of the clinical evaluation of the direct thrombin inhibitors has been in coronary artery disease. The recent clinical reports suggest that there is a narrower window of safety with recombinant hirudin than initially thought particularly when it is used in conjunction with thrombolytic agents and aspirin in acute myocardial infarction. The efficacy data, however, indicate that the direct thrombin inhibitors have great potential particularly in the initial management of patients with acute unstable angina and non-Q-wave infarction. There is much to learn regarding the mechanism of action, optimal dose, and optimal concomitant therapy in the use of direct thrombin inhibitors in the management of acute coronary ischaemia; and since hirudin and other direct thrombin inhibitors have so much potential in the management of acute coronary ischaemia, it is critical that dose-finding studies be performed to determine safe regimens of these agents to allow their evaluation in large-scale trials with important clinical outcomes. The direct thrombin inhibitors have also shown to have promise in the prevention of deep vein thrombosis in high-risk surgical patients. There is limited clinical data on the other novel anticoagulants which are currently being developed.

Angina, Unstable↗
PubMed1995

Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis.

The optimal duration of oral anticoagulant therapy for patients with acute proximal deep vein thrombosis (DVT) is uncertain. Based on the hypothesis that a normal impedance plethysmogram (IPG) following DVT defines a group of patients at low risk of recurrent venous thromboembolism (VTE), a trial was conducted to evaluate the efficacy of only four weeks of warfarin. Patients with venographically confirmed acute proximal DVT who had received four weeks of warfarin after initial heparin and whose four week IPG was normal were allocated to either continue warfarin (targeted International Normalized Ratio 2.0 to 3.0) for a further eight weeks or receive placebo. Patients with an abnormal four week IPG received warfarin for a further eight weeks. Based on clinical characteristics at the time of the qualifying thrombosis, all patients were classified as having either continuing or transient risk factors for recurrent VTE. During the eight weeks following randomization, nine (8.6%) of the 105 placebo patients developed recurrent VTE compared to one (0.9%) of the 109 warfarin patients, P = 0.009. Over the entire 11 months of follow-up, 12 placebo patients developed recurrence compared to seven warfarin patients, P = 0.3. Nineteen of the 192 patients with an abnormal four week IPG experienced recurrence during the nine months after discontinuing warfarin. In the 301 patients who received three months of warfarin in the randomized trial or in the cohort study, all 26 recurrent events were in the 212 patients with continuing risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Comparison of the accuracy of impedance plethysmography and compression ultrasonography in outpatients with clinically suspected deep vein thrombosis. A two centre paired-design prospective trial.

Impedance plethysmography (IPG) and compression ultrasonography (CUS) have been reported to be highly accurate for the diagnosis of deep vein thrombosis (DVT) in symptomatic patients. In many centres CUS has become the method of choice. However, direct comparisons of the accuracy of IPG to CUS have not been performed. To determine the test of choice we performed a two centre prospective comparison of IPG and CUS, with venography, and determined how the size and distribution of thrombi influenced the accuracy of each test. 495 symptomatic outpatients with suspected DVT had evaluable venograms. The prevalence of DVT was 27% (130/495), 84% (109) of which were proximal. The sensitivity of IPG and CUS for proximal vein thrombosis was 77% and 90% respectively (p = .002). The specificity of IPG was 93% whereas the specificity of CUS was 98% (p = 0.04). There were significant differences in accuracy between the two centres as a consequence of differences in the size and location of thrombi The majority of proximal thrombi not detected by IPG and CUS involved less than 5 cm of the distal half of the popliteal vein and most of these thrombi occurred in one centre. Exclusion of these thrombi from the analysis increases the sensitivity of CUS to 99% (86/87) and IPG to 91% (72/79), for proximal thrombi (P = .019). The positive predictive value of CUS was strongly influenced by the number of abnormal venous segments (three sites were examined); 100% (80/80) if two or three sites were abnormal, but only 68% if a single site was involved. We conclude that: 1) CUS is more accurate than the IPG for the diagnosis of DVT in symptomatic outpatients, and this relationship holds true regardless of the size or location of the DVT, 2) the sensitivities of IPG and CUS are much lower for small proximal DVT, and 3) confirmatory venography is warranted if the abnormality with CUS is limited to one venous segment.

Ambulatory Care↗
PubMed1994

Interactions of warfarin with drugs and food.

PURPOSE: To evaluate the quality of studies about drugs and food interactions with warfarin and their clinical relevance. DATA SOURCES: MEDLINE and TOXLINE databases from 1966 to October 1993 using the Medical Subject Headings warfarin, drug interactions, and English only. STUDY SELECTION: All articles reporting original data on drug and food interactions with warfarin. DATA EXTRACTION: Each report, rated independently by at least two investigators (using causality assessment), received a summary score indicating the level of assurance (level 1 = highly probable, level 2 = probable, level 3 = possible, and level 4 = doubtful) that a clinically important interaction had or had not occurred. Inter-rater agreement was assessed using a weighted kappa statistic. RESULTS: Of 793 retrieved citations, 120 contained original reports on 186 interactions. The weighted kappa statistic was 0.67, representing substantial agreement. Of 86 different drugs and foods appraised, 43 had level 1 evidence. Of these, 26 drugs and foods did interact with warfarin. Warfarin's anticoagulant effect was potentiated by 6 antibiotics (cotrimoxazole, erythromycin, fluconazole, isoniazid, metronidazole, and miconazole); 5 cardiac drugs (amiodarone, clofibrate, propafenone, propranolol, and sulfinpyrazone); phenylbutazone; piroxicam; alcohol (only with concomitant liver disease); cimetidine; and omeprazole. Three patients had a hemorrhage at the time of a potentiating interaction (caused by alcohol, isoniazid, and phenylbutazone). Warfarin's anticoagulant effect was inhibited by 3 antibiotics (griseofulvin, rifampin, and nafcillin); 3 drugs active on the central nervous system (barbiturates, carbamazepine, and chlordiazepoxide); cholestyramine; sucralfate; foods high in vitamin K; and large amounts of avocado. CONCLUSIONS: Many drugs and foods interact with warfarin, including antibiotics, drugs affecting the central nervous system, and cardiac medications. Many of these drug interactions increase warfarin's anticoagulant effect.

Animals↗
PubMed1994

A novel and major isoform of tyrosine hydroxylase in Drosophila is generated by alternative RNA processing.

We report that two isoforms of Drosophila tyrosine hydroxylase protein are encoded via alternatively spliced exons. The major isoform (Type II) contains a novel acidic extension of 71 amino acids in the amino-terminal regulatory domain, which is likely to alter the regulatory properties of the tyrosine hydroxylase protein. The minor isoform (Type I) corresponds to the cDNA sequence reported previously. We also report the structure of the Drosophila tyrosine hydroxylase (DTH) gene and the diversity and tissue localization of its transcripts. At least three types of DTH mRNA are generated from a single primary transcript through alternative splicing and polyadenylation. Type II mRNA is the most abundant tyrosine hydroxylase transcript in Drosophila and is found predominantly in the hypoderm throughout all stages of development. Type I mRNA is present only in the CNS, where it is the primary form. The DTH transcripts detected in the CNS contain a longer 3'-untranslated region than the transcript expressed in the hypoderm, due to differential polyadenylation. In contrast, the same start site is used for DTH gene transcription in both tissues. These results show unexpected diversity in the DTH transcripts and point out possible mechanisms for differential regulation of tyrosine hydroxylase activity in the CNS and in the hypoderm.

Alternative Splicing↗
PubMed1994

Diagnostic tests for deep vein thrombosis. Clinical usefulness depends on probability of disease.

We review the general principles that govern the clinical utility of diagnostic tests, particularly with respect to the diagnosis of deep vein thrombosis (DVT). We stress the importance of clinical probability of disease, which strongly influences the positive predictive value (true-positive rate) and negative predictive value (true-negative rate) of all diagnostic tests. In selecting a diagnostic procedure for DVT, the physician must first consider the clinical probability of disease and then the local accuracy of the test employed and its cost-effectiveness. In 75% to 80% of patients suspected to have DVT, clinical management can be based on the results of noninvasive tests, such as ultrasonography or impedance plethysmography (IPG), rather than venography. Ultrasonography has clear advantages over venography with respect to cost and patient comfort, and it defines the anatomic extent of the thrombus. It should be considered the new diagnostic standard for symptomatic DVT. Despite recent reports of lower sensitivity than previously reported, IPG remains an acceptable alternative to ultrasonography for symptomatic DVT in selected patients. Even if the recently reported lower sensitivity proves to be accurate, the probability of adverse clinical outcomes as a result of overlooked disease is still extremely low in patients with a low probability of DVT. The negative predictive value of IPG under these circumstances approaches 99%. Impedance plethysmography is also useful in patients with a high probability of DVT, in whom the positive predictive value may be as high as 97%. When the findings of IPG (or ultrasonography) are at variance with a strong clinical impression, venography should be considered, especially when there is a high clinical probability of disease and a negative noninvasive test result.

Bias↗
PubMed1994

Reevaluation of the sensitivity of impedance plethysmography for the detection of proximal deep vein thrombosis.

BACKGROUND: To reevaluate the sensitivity of impedance plethysmography (IPG) for proximal deep vein thrombosis (DVT) and to establish a relationship between the location and size of thrombi and the results of IPG. DESIGN: Prospective cohort study. METHODS: One hundred thirty-two consecutive patients with clinically suspected DVT underwent IPG testing and most (n = 118) underwent contrast-enhanced venography; in 14 patients, venous ultrasonography was performed and demonstrated definitive proximal DVT in which the size and extent of the thrombus could be delineated. All patients with dubious or normal ultrasound results underwent contrast-enhanced venography. All tests were performed and test results were interpreted without knowledge of the results of the other tests. Patients were considered to have proximal DVT if this was demonstrated on venography or ultrasound, calf DVT if this was demonstrated on venography, or no DVT if venography yielded normal findings. The sensitivity and specificity of IPG for DVT were calculated. RESULTS: Of the 132 patients, 40 (30%) had proximal DVT, seven (5%) had calf DVT, and 85 (64%) had no DVT. The sensitivity of IPG for proximal DVT was 65% and the specificity was 93%. Of the proximal vein thrombi, IPG detected three (23%) of 13 that involved the popliteal vein but not the superficial femoral vein and 23 (85%) of 27 proximal vein thrombi that involved the superficial femoral vein. CONCLUSIONS: Our study demonstrated that the sensitivity of IPG for proximal DVT at our center is only 65%, a figure that is much lower than those reported in earlier studies from our institution. We hypothesize that because of a change in referral practice, an increased proportion of patients with less severe symptoms are now referred to our center than in the past. These patients have thrombi that are smaller, less likely to be occlusive, and therefore less likely to yield abnormal IPG findings.

Adult↗
PubMed1994

Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer.

Patients receiving chemotherapy for metastatic breast cancer are at high risk of thromboembolic disease. Long-term oral anticoagulant therapy is needed but increases the risk of haemorrhagic complications. We have assessed the safety and efficacy of warfarin in very low doses as prophylaxis. Women receiving chemotherapy for metastatic breast cancer were randomly assigned either very-low-dose warfarin (152 patients) or placebo (159). The warfarin dose was 1 mg daily for 6 weeks and was then adjusted to maintain the prothrombin time at an international normalised ratio (INR) of 1.3 to 1.9. Study treatment continued until 1 week after the end of chemotherapy. The average daily dose from initiation of titration was 2.6 (SD 1.2) mg for the warfarin group and the mean INR was 1.52. The mean time at risk of thrombosis was 199 (126) days for warfarin-treated patients and 188 (137) days for placebo recipients (p = 0.45). There were 7 thromboembolic events (6 deep-vein thrombosis, 1 pulmonary embolism) in the placebo group and 1 (pulmonary embolism) in the warfarin group, a relative risk reduction of about 85% (p = 0.031). Major bleeding occurred in 2 placebo recipients and 1 warfarin-treated patient. There was no detectable difference in survival between the treatment groups. Very-low-dose warfarin is a safe and effective method for prevention of thromboembolism in patients with metastatic breast cancer who are receiving chemotherapy.

Antineoplastic Agents↗
PubMed1994

The international normalized ratio. A guide to understanding and correcting its problems.

With the increasing use of the international normalized ratio (INR) to monitor warfarin therapy, a number of problems with prothrombin time (PT) testing have been identified that have led some laboratory physicians to question the reliability of the INR. This is ironic, because it was the introduction of the INR system that brought to light some of the long-standing problems with the technique of PT monitoring. However, these problems are not insurmountable if a compromise can be reached between the expectations of laboratory physicians and of clinicians. Thus, the laboratory physician seeks a perfect assay system, which in the case of the INR is unattainable at present, because of differences in PT reagents and methods. In contrast, the clinician is satisfied with a system of monitoring that provides safe and effective warfarin dosing. This goal can be achieved provided that certain details of PT testing are observed. In this communication, which is directed to practicing clinicians, the potential problems with the INR system are discussed, their clinical relevance is critically reviewed, and solutions are offered.

Anticoagulants↗
PubMed1994

A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin.

BACKGROUND: The management of heparin therapy in patients who have a subtherapeutic activated partial thromboplastin time (APTT) despite high doses of heparin is problematic because the risk of heparin-associated bleeding increases with dose. Results of experimental studies in animals indicate that when the APTT response to heparin is blunted by infusion of procoagulants, dose escalation can be avoided without compromising efficacy, by monitoring treatment with a heparin assay. METHODS: A randomized, controlled trial was conducted in which patients with acute deep vein thrombosis, pulmonary embolism, or axillary vein thrombosis who required 35,000 U or more of intravenous heparin by continuous infusion during the previous 24 hours were allocated to have their heparin therapy monitored either by anti-factor Xa levels (targeted range, 0.35 to 0.67 U/mL) or by the APTT (targeted range, 60 to 85 seconds). Both ranges were equivalent to a heparin level of 0.2 to 0.4 U/mL by protamine titration. RESULTS: Three (4.6%) of 65 patients in the anti-factor Xa group experienced recurrent venous thromboembolism compared with four (6.1%) of 66 patients in the APTT group (difference, 1.5%; confidence interval, -6.7% to 8.4%) (P = .7). There were four bleeding events (6.1%) in the APTT group compared with one (1.5%) in the anti-factor Xa group (difference, 4.6%; confidence interval, -3.3% to 7.5%) (P = .4). During the period of heparin therapy before warfarin treatment was begun, the patients in the APTT group required a statistically significantly greater amount of heparin compared with the patients in the anti-factor Xa group. The daily mean APTT was subtherapeutic in patients in the anti-factor Xa group, and it was within the therapeutic range in the APTT group. The daily mean anti-factor Xa levels for both groups were within the therapeutic range. CONCLUSION: The heparin assay is a safe and effective method for monitoring heparin treatment in patients with acute venous thromboembolism whose APTT remains subtherapeutic despite large daily doses of heparin. In such patients, dosage escalation can be avoided if the heparin level is therapeutic.

Acute Disease↗
PubMed1994

Graduated compression stockings in the prevention of postoperative venous thromboembolism. A meta-analysis.

BACKGROUND: The effectiveness of graduated compression stockings in prophylaxis of postoperative venous thromboembolism is unclear to many physicians. Surveys show there is considerable variability in their use and their perceived effectiveness. We undertook to establish, by a systematic overview of the literature, the effectiveness of graduated compression stockings in the prophylactic setting of postoperative venous thromboembolism. METHODS: Studies published between 1966 and June 1992 were identified through the MEDLINE database, with a search in all languages, through reviews of Current Contents, and including references cited in identified articles. Articles were selected for initial analysis if they assessed the use of graduated compression stockings for the prophylaxis of venous thromboembolism, and if the stocking group was compared with an untreated or unconfounded control group. Criteria were established a priori, to select only studies with sound methods. On the basis of these criteria, 12 studies were identified for the combined analysis. Each eligible study was independently analyzed for the risk of development of deep venous thrombosis in the control and stocking groups, and this was expressed as an odds ratio. Odds ratios were combined across studies by means of the Mantel-Haenszel chi 2 procedure. The data were analyzed separately for orthopedic surgery because of its high risk for venous thromboembolism. RESULTS: Eleven of the 12 studies were in moderate-risk surgery (abdominal, gynecologic, and neurosurgery); the summary odds ratio was 0.28, which translates into a risk reduction of 68% (95% confidence interval, 53% to 73%), which is statistically significant (P < .0001). In the one study in orthopedic surgery that was eligible for inclusion, the odds ratio was 0.50 (95% confidence interval, 0.19 to 1.29; P = .17). CONCLUSIONS: The use of graduated compression stockings for prophylaxis of venous thromboembolism after moderate-risk surgery results in a significant risk reduction. It is unknown whether the use of graduated compression stockings in combination with other forms of prophylaxis results in further risk reduction. The efficacy of graduated compression stockings in orthopedic surgery has been assessed by only one study that used sound methods, hence no definitive conclusions can be made in these high-risk patients.

Bandages↗
PubMed1994

Temporal and spatial development of serotonin and dopamine neurons in the Drosophila CNS.

We present a high-resolution profile of the temporal and spatial immunoreactivity for dopamine and serotonin in the Drosophila embryonic CNS and the expression pattern of two enzymes important in their biosynthesis, DOPA decarboxylase (DDC) and tyrosine hydroxylase (TH). DDC performs the final catalytic step in the synthesis of both biogenic amines and TH is the rate-limiting enzymatic step in the synthesis of dopamine. We show that the DDC-expressing neurons synthesize either serotonin or dopamine, but not both, and that the two neuronal subtypes follow similar axonal pathways. In addition, we describe two DDC-expressing cell types that do not synthesize detectable levels of serotonin or dopamine. We also describe a novel set of TH-expressing neurons that are detected only during embryogenesis. The initial appearance of both enzymes and their metabolites during embryogenesis shows unexpected diversity. The onset of Ddc expression is heterogeneous, such that certain classes of cells express high levels of DDC several hours before others. High levels of TH immunoreactivity are observed at a time when DDC immunoreactivity is barely detectable. Despite low levels of DDC, both dopamine and serotonin are first detected at the earliest stages of DDC expression. We discuss the implications of these observations in the differentiation of dopamine and serotonin neurons.

Animals↗
PubMed1994

Low molecular weight heparins.

Low molecular weight heparins are derived from unfractionated heparin by chemical or enzymatic depolymerization; as a result, the mean molecular weight of unfractionated heparin is reduced by about one third and its biochemical and pharmacologic properties are improved. Demonstrated advantages of low molecular weight heparins over unfractionated heparin are the greater bioavailability at low doses, the longer half-life, and the more predictable dose response, which allows for fixed doses to be administered without laboratory monitoring; a potential advantage is the reduced hemorrhagic-to-thrombotic ratio observed in experimental animals. Clinical studies in the prevention of venous thromboembolism have shown that whereas the advantages offered by low molecular weight heparin over unfractionated heparin are modest in general surgery, they are substantial when compared with these and other agents in orthopedic surgery. In addition, low molecular weight heparins are at at least as safe and effective as unfractionated heparin in the treatment of established deep vein thrombosis, but have the advantage that they can be administered once or twice daily without laboratory monitoring and can be used to treat uncomplicated deep venous thrombosis on outpatient basis.

Animals↗
PubMed1994

cis-regulatory sequences responsible for alternative splicing of the Drosophila dopa decarboxylase gene.

The Drosophila dopa decarboxylase gene, Ddc, is expressed in the hypoderm and in specific sets of cells in the central nervous system (CNS). The unique Ddc primary transcript is alternatively spliced in these two tissues. The Ddc CNS mRNA contains all four exons (A through D), whereas the hypodermal mRNA contains only three exons (A, C, and D). To localize cis-regulatory sequences responsible for Ddc alternative splicing, a Ddc minigene and several fusion genes containing various amounts of Ddc sequences fused to fushi tarazu (ftz) exon 1 were constructed and introduced into flies by P-element-mediated germ line transformation. We find that Ddc intron ab and exon B are sufficient to regulate Ddc alternative splicing, since transcripts of a minimal fusion gene containing most of Ddc intron ab and exon B are spliced to exon B in the CNS but not in the hypoderm. These results indicate that Ddc alternative splicing is regulated by either a negative mechanism preventing splicing to exon B in the hypoderm or a positive mechanism activating splicing to exon B in the CNS. Our previous data suggest that Ddc hypodermal splicing is the actively regulated splicing pathway (J. Shen, C. J. Beall, and J. Hirsh, Mol. Cell. Biol. 13:4549-4555, 1993). Here we show that deletion of Ddc intron ab sequences selectively disrupts hypodermal splicing specificity. These results support a model in which Ddc alternative splicing is negatively regulated by a blockage mechanism preventing splicing to exon B in the hypoderm.

Alternative Splicing↗