What you need to know about migraine in Hughes syndrome patients.

BACKGROUND: Headache, often migrainous, is common in patients with antiphospholipid antibodies, whether or not they meet Sydney criteria for a definite diagnosis of Hughes syndrome. Migraine may be a harbinger of stroke in this patient population and even refractory migraine may be highly responsive to antithrombotic therapy in this clinical context. PURPOSE: To summarize what is known to date about managing this important manifestation of the immune-mediated hypercoagulable Hughes syndrome. RESULTS: We provide a suggested management algorithm for refractory headache in this unique patient population. CONCLUSION: Most neurologists don't see or recognize many aPL-positive patients in their practice, so hematologists and rheumatologists who see these patients should recognize that refractory headache may be a manifestation of their immune-mediated hypercoagulable disorder and understand that the potential risks of not addressing this issue may be high.

Dosing considerations in the use of the direct oral anticoagulants in the antiphospholipid syndrome.

WHAT IS KNOWN AND OBJECTIVES: At least four prospective trials have been initiated investigating the direct oral anticoagulants in the antiphospholipid syndrome. Preliminary reports have supported their use in patients with a history of venous thrombosis and a target INR of 2-3, but there have also been reports of failure of these agents in the antiphospholipid syndrome. The objective is to present a case report that illustrates there may be important dosing issues when considering the use of these agents in patients with the antiphospholipid syndrome. CASE SUMMARY: A 50-year-old woman with the antiphospholipid syndrome, manifesting clinically with recurrent pyoderma gangrenosum-like leg ulcers, was treated with apixaban, resulting in improved ulcer healing. For insurance purposes, she was switched to rivaroxaban with worsening of the ulcers which again improved when apixaban was resumed. WHAT IS NEW AND CONCLUSION: Despite a similar half-life, pharmacokinetics and pharmacodynamics, the manufacturer-recommended maintenance dosing of apixaban is twice daily and rivaroxaban once daily. We believe this difference in recommended dose accounts for the differential clinical response noted in the present case report and that twice daily dosing and a larger daily dose of these agents may be more efficacious in potent hypercoagulable disorders, such as the antiphospholipid syndrome.

Postural tachycardia syndrome (POTS) and other autonomic disorders in antiphospholipid (Hughes) syndrome (APS).

BACKGROUND: Antiphospholipid syndrome (APS) is an autoimmune hypercoagulable disorder that has been shown to cause a large number of cardiac and neurological manifestations. Two recent studies have demonstrated abnormalities in cardiovascular autonomic function testing in APS patients without other cardiovascular or autoimmune disease. However, an association between autonomic disorders such as postural tachycardia syndrome and APS has not previously been described. METHODS AND RESULTS: Data were obtained by retrospective chart review. We identified 15 patients who have been diagnosed with APS and an autonomic disorder. The median age of the patients at the time of data analysis was 39 years. The autonomic disorders seen in these patients included postural tachycardia syndrome, neurocardiogenic syncope and orthostatic hypotension. The majority of patients (14/15) were female and the majority (14/15) had non-thrombotic neurological manifestations of APS, most commonly migraine, memory loss and balance disorder. Many also had livedo reticularis (11/15) and Raynaud's phenomenon (nine of 15). In some patients, the autonomic manifestations improved with anticoagulation and/or anti-platelet therapy; in others they did not. Two patients with postural tachycardia syndrome who failed to improve with the usual treatment of APS have been treated with intravenous immunoglobulin with significant improvement in their autonomic symptoms. CONCLUSION: We believe that autonomic disorders in APS may represent an important clinical association with significant implications for treatment.

A new myeloproliferative syndrome.

We report here two cases of a previously undescribed myeloproliferative disorder. Both were young adult males who presented with generalized lymphadenopathy, splenomegaly, leukocytosis, polycythemia, and persistent thrombocytopenia. The leukocyte alkaline phosphatase (LAP) score was low in both cases, and the bone marrow was hypercellular without dysplasia or fibrosis, but lacked the Philadelphia chromosome, BCR gene rearrangement, or other karyotypic abnormalities. The clinical course was indolent in each case. One patient died from an unusual "blast crisis" after 12 years, while the second patient remains in a complete hematologic remission on hydroxyurea and alpha interferon 4 years from diagnosis. Interestingly, changes in therapy in this patient have consistently resulted in precise and concerted fluctuations in his blood counts, with the red and white cells cycling together and the platelets and mean corpuscular volume (MCV) changing concomitantly but in the opposite direction. This unique myeloproliferative disorder is distinguishable from all previously described forms of chronic myeloid leukemia and other myeloproliferative syndromes.

Low doses of interferon-alpha are as effective as higher doses in inducing remissions and prolonging survival in chronic myeloid leukemia.

OBJECTIVE: To determine the toxicity and efficacy of low-dose interferon-alpha therapy in inducing remissions and prolonging survival in patients with chronic myeloid leukemia. DESIGN: Phase II evaluation and comparison with historical control patients and other series in which the investigators used higher interferon-alpha doses. SETTING: Tertiary care leukemia research clinic. PATIENTS: 41 patients with newly diagnosed or previously treated chronic-phase, Philadelphia chromosome-positive chronic myeloid leukemia received interferon-alpha at a dose of 2 x 10(6) U/m2 body surface area daily for 28 days and then three times weekly. MEASUREMENTS: Complete blood counts and physical examinations were done monthly to determine hematologic remission and toxicity. To determine karyotypic response, bone marrow cytogenetic analyses were done at 6 monthly intervals in patients who achieved a complete hematologic remission. In addition, Kaplan-Meier survival curves and median survival values were generated from diagnosis and the start of therapy with interferon-alpha. RESULTS: 70% of patients treated with low-dose interferon-alpha within 1 year of diagnosis achieved a complete hematologic remission, and 22% of these patients had a major or complete karyotypic response. Investigators who used higher interferon-alpha doses in similar patient populations have reported complete hematologic remission rates of 59% to 70% and major and complete cytogenetic response rates of 16% to 29%. The Kaplan-Meier estimated 5-year survival rate of minimally pretreated patients in our study is 73% (95% CI, 51% to 95%), which compares favorably with survivals reported by investigators who used higher doses. The estimated yearly cost of the interferon-alpha used in our study is $5953 compared with a median of $24,375 for the higher doses used by other investigators. Less toxicity was also observed. CONCLUSION: Low-dose interferon-alpha is as effective as higher-dose interferon-alpha in inducing remissions and prolonging survival in patients with chronic myeloid leukemia but is considerably less expensive and toxic.

Chondrons from articular cartilage. (IV). Immunolocalization of proteoglycan epitopes in isolated canine tibial chondrons.

Chondrons have recently been extracted from adult articular cartilages and techniques developed to study their structure and composition in isolation. This study introduces methods to immobilize isolated canine chondrons in thin layers of agarose gel for immunohistochemistry and future in vitro studies. An antibody to Type VI collagen which stained the chondron in suspension was used to successfully validate the system and its feasibility for immunoelectron microscopy. Monoclonal and polyclonal antibodies to a variety of epitopes on the proteoglycan molecule were tested on fresh and fixed plugs cored from chondron-agarose gels. Plugs were immunolabeled with peroxidase-diaminobenzidine before or after digestion with testicular hyaluronidase or chondroitinase ABC. Trypsin/chymotrypsin were used to challenge epitopes of the core protein. The results indicate that epitopes to keratan sulfate, chondroitin sulfate, hyaluronate binding region, and core protein are localized in the chondron. Consistent staining was found in the tail and interconnecting segments between chondrons, whereas staining of the pericellular matrix and capsule adjacent to the chondrocyte varied according to the enzyme pre-treatment employed. We conclude that isolated chondrons are rich in proteoglycan monomer, which is particularly concentrated in the tail and interconnecting segments of the chondron where it could function to protect and stabilize the chondrocyte.

Chondrons from articular cartilage. III. Morphologic changes in the cellular microenvironment of chondrons isolated from osteoarthritic cartilage.

Chondrons were isolated from human and canine osteoarthritic cartilage using low-speed homogenization techniques. Changes in chondron morphology were evaluated using differential interference-contrast microscopy, phase-contrast microscopy, and histochemical and ultrastructural methods. Chondrocyte viability was assessed using fluorescein diacetate staining, and chondron metabolism was investigated using autoradiography. The results suggest that initial changes in the collagen and proteoglycan distribution within the chondron are followed by chondrocyte proliferation to form clusters. These techniques offer the potential to study cell matrix interactions in degenerative osteoarthritis.

Chondrons from articular cartilage (II): Analysis of the glycosaminoglycans in the cellular microenvironment of isolated canine chondrons.

A chondron rich preparation was isolated from mature canine tibial cartilage using low-speed homogenization techniques. Proteoglycans were extracted from this preparation by exhaustive treatment with 4M guanidine-HCl. A significant proportion of the total proteoglycan, measured as uronic acid, was resistant to extraction and represented 27.9% in intact cartilage chips and 18.6% in the chondron fraction. Histochemical examination of chondrons confirmed that extraction resistant proteoglycans remained within the capsule of the chondron after 4M guanidine-HCl treatment. Electrophoretic analysis of the glycosaminoglycans extracted from intact cartilage chips and the chondron fraction showed approximately equivalent amounts of chondroitin sulphate (79.3%), keratan sulphate (16.3%) and hyaluronic acid (4.3%) present. In contrast, the extraction resistant residue in the chondron fraction was significantly enriched for hyaluronic acid (10.5%, p less than 0.05) but was depleted of chondroitin sulphate (70.9%, p less than 0.05). The major chondroitin sulphate isomer in the resistant fraction was chondroitin 6-sulphate while in the soluble fraction, the quantities of the two isomers were approximately equivalent. Comparison with previously published data suggests a role for minor collagens in the retention of proteoglycans in the cellular microenvironment.

Chondrons from articular cartilage: I. Immunolocalization of type VI collagen in the pericellular capsule of isolated canine tibial chondrons.

A heterogenous population of intact chondrons extracted from low-speed homogenates of canine tibial cartilage were stained by indirect immunofluorescence methods with a polyclonal antibody to type VI collagen. In each of the four chondron groups examined, anti-(type VI collagen) anti-serum was concentrated in the capsule immediately adjacent to the chondrocyte complex. A constant but weaker fluorescent reaction persists in 'tail-like' extensions common to single and double chondrons and in the medial connections between adjacent chondrons in linear columns and aggregated clusters. Frayed collagen bundles typical of chondron preparations did not react with the antibody. Similarly, chondrons reacted with normal rabbit serum, or treated by type VI collagen extraction procedures, showed no staining reaction. The differential localization of type VI collagen in the pericellular capsule is discussed in relation to the maintenance of the chondron's integrity and to the protection of the chondrocyte during dynamic compressive loading.

Study of required clerkships in internal medicine in U.S. and Canadian medical schools.

The authors studied teaching of clinical skills and the supervision of clinical education of undergraduate medical students by reviewing students' patient-related experiences in required internal medicine clerkships in the United States and Canada during the 1979-1982 accreditation cycle of the Liaison Committee on Medical Education. The reported patient-related experiences of 180 medical students from 42 medical schools who took histories and performed physical examinations on 2,891 patients formed the basis of this paper. Variability in clerkship length, time worked, supervision, and patient mix suggests that additional quantitative data should be sought on medical students' experiences during the clerkship.