Coagulant and fibrinolytic status in tuberculous meningitis.

BACKGROUND: The long-term neurologic sequelae of childhood tuberculous meningitis (TBM) mainly result from ischemia owing to cerebral vasculitis. Deep vein thrombosis occurs in adults with pulmonary tuberculosis owing to hypercoaguability. The present study aimed to investigate coagulation status during acute childhood TBM. METHODS: Coagulation status, including the natural anticoagulants, antithrombin, protein C and protein S; procoagulant FVIII; fibrinolytic factors, tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) as well as anticardiolipin antibodies (ACA), was determined in 16 children with TBM before and during treatment. RESULTS: A prothrombotic profile was found as expressed by a decrease of anticoagulant (protein S) and increase of the procoagulant (factor VIII) activity. Raised PAI-1 and normal tissue plasminogen activator values indicated deficient fibrinolysis. This hypercoagulable state was more pronounced in stage 3 patients than in stage 2 patients. The bleeding time on admission ranged from 1.2 to 10 minutes [mean 4.2 minutes]. The mean platelet count on admission was 577.9 +/- 188.6 x 10/L and increased further during the course of the treatment. CONCLUSIONS: The hypercoagulable state in childhood TBM is comparable to that described in adults with pulmonary tuberculosis and may further increase the risk for infarction. Therapeutic measures that reduce the risk for thrombosis could therefore be potentially beneficial in childhood TBM.

Fine needle aspiration biopsy and flow cytometry in the diagnosis of lymphoma.

UNLABELLED: Fine needle aspiration biopsy (FNAB) is emerging as a technique of potential value in the diagnosis of benign and malignant lesions in areas such as the breast and thyroid gland. Its place in distinguishing reactive from neoplastic lymphoid proliferations, when compared to the established practice of excision biopsy and histopathology, continues to undergo evaluation. Morphology alone discriminates poorly between atypical or lymphoproliferative disorders as seen in the presence of Epstein-Barr or human immunodeficiency virus. Furthermore the polymorphic populations of follicular lymphoma may mimic reactive changes. In addition previous classifications of these tumours using working formulation or Kiel classification relied heavily on architecture, which is a feature not reflected in cytology smears. The World Health Organisation approach includes clinical features, immunophenotyping and cytogenetic profiles to define neoplasms of immunohaematopoietic tissues. Flow cytometry on fine needle aspiration biopsy offers additional advantages in being rapid and objective in quantitatively as well as qualitatively documenting cell surface characteristics. All patients referred for this procedure to Tygerberg Academic Hospital with suspected nodal or extranodal lymphoma between January 2002 and December 2004 were analysed. In each case flow cytometry and cytomorphology were correlated with histopathology on tissue biopsy, bone marrow examination and clinical follow-up for confirmation of diagnosis. Results of the 124 cases were tabulated and statistically processed. Eighty-one met the inclusion criteria, thirteen (16.1%) were not malignant, two (2.5%) were falsely negative, two (2.5%) were equivocal needing histology and in the remaining sixty-four (79%) diagnosis was achieved. SUMMARY: Fine needle aspiration coupled with flow cytometry can reliably distinguish between nodal and extranodal neoplastic B-cell population. It is concluded that appropriate use, in a collaborative multidisciplinary setting, may eliminate the need for surgical procedures in many cases. CONCLUSION: These advances are not widely recognised and this is particularly true in South Africa. Accordingly, such an approach has been prospectively evaluated in the Western Cape showing that the combination of ready availability and diagnostic accuracy, after an initial learning curve, allow accurate characterisation of haematologic malignancies so that excision biopsy may be reserved for specific further studies to provide data not available from this less invasive procedure.

The cardioprotective effect of wine on human blood chemistry.

We investigated the in vivo effects of regular consumption of red and white wine on the serum lipid profile, plasma plasminogen activator-1, homocysteine levels, and total antioxidant status. This study confirmed that moderate consumption of wine, red more than white, exerts cardioprotective effects through beneficial changes in lipid profiles and plasma total antioxidant status.

The in vivo antithrombotic effect of wine consumption on human blood platelets and hemostatic factors.

We compared the in vivo effect of red vs. white wine consumption on platelet aggregation, responsiveness and membrane viscosity, plasma total antioxidant status, thromboxane B(2) levels, and fibrinolysis. Diet and red wine had a synergistic effect in decreasing platelet aggregation. Red wine did not have a significantly more favorable effect on the fibrinolytic factors than white wine. The reduction in platelet membrane viscosity after red wine, which could contribute to the protective antithrombotic role of red wine, needs further explanation.

Red wines good, white wines bad?

A review of the literature on the 'antioxidant' action of white wines on the cardiovascular system is given. The conclusion is that ingestion only of white wines very low, or lacking, in polyphenolics leads to a reduction in the antioxidant action of blood serum, and to an increase in the low density lipoprotein to high density lipoprotein ratio.

Amyloidosis: a changing clinical perspective.

Primary amyloidosis is a plasma cell dyscrasia characterised by excess production of abnormal immunoglobulin light chains with their subsequent accumulation in kidneys, heart, liver as well as gastrointestinal tract and bone marrow 1-21, 2. These tissue deposits take the form of a fibrillar protein which damages the involved organ in proportion to the extent of the infiltration and roughly parallels the duration of the disease. Most cases have evidence of the underlying lymphoplasmacytoid neoplasm recognisable in two ways. Firstly, the monoclone appears in the serum [2]. Secondly is a morphologically and immunohistochemically distinctive cellular infiltrate in the bone marrow [3] that has a specific microscopic and ultrastructural pattern 4-54, 5. Interestingly occasional patients, who survive long enough, may progress to multiple myeloma [6] but the correlation is variable [7].

Lack of clinical manifestation of hereditary haemochromatosis in South African patients with multiple sclerosis.

Caucasian South African patients with multiple sclerosis (MS) were screened for the most common hereditary haemochromatosis (HH) mutations, H63D and C282Y, in order to determine the impact of iron overload on clinical outcome of MS. DNA screening for mutations H63D and C282Y in 118 apparently unrelated MS patients did not reveal significant differences in allele frequencies in comparison with a control group from the same population. Of 17 MS patients heterozygous for C282Y, 3 had below normal and none had above normal transferrin saturation levels. One of the index MS patients, and subsequently also her sister who also has MS, tested positive for two copies of mutation C282Y. Determination of iron status revealed high serum ferritin and transferrin saturation levels in both patients. However, the index patient, being unaware of her C282Y status, had received treatment for iron deficiency in the past and her MS symptoms were less severe than those of her sister who has been wheelchair bound for the past 12 years and who did not take iron supplements. Lack of clinical manifestation of HH without any signs of organ damage in the C282Y homozygous MS patients is in accordance with a role of iron dysregulation in the aetiology of MS.

The 2000 Burkitt lymphoma trial in Malawi.

BACKGROUND: We previously reported 57% 12-month event free survival (EFS) in Malawian children with stage I to III Burkitt lymphoma (BL) with an intermediate dose chemotherapy protocol lasting 77 days. This protocol was shortened to 42 days and evaluated in children with stage I to IV disease for EFS and toxicity. METHODS: All Malawian children admitted to Queen Elizabeth Central Hospital, from 03/08/2000 to 12/03/2002 with confirmed BL were eligible. A fine needle aspirate, bone marrow aspirate, cerebrospinal fluid cytology, haemoglobin (Hb), white cell count (WCC), malaria smear, ELISA for HIV, and abdominal ultrasound were performed routinely. Murphy staging was used. The first dose of chemotherapy (COP1) consisted of 300 mg cyclophosphamide (CPM), 1 mg vincristine, and 60 mg prednisone given on day 1 and followed by COP2 on day 8 (only for patients with larger tumour volumes, stage III or IV disease). The vincristine dose in COP2 was 2 mg. COMP1 and 2 given on days 22 and 36 consisted of 500 mg CPM, 2 mg vincristine, 60 mg prednisone, and 2 g methotrexate. All doses were calculated per body surface area. Intrathecal methotrexate and hydrocortisone were given with COP1 and 2. RESULTS: Forty-two patients, 30 boys and 12 girls median ages 6 and 7.5 years, respectively, had Murphy stage I(n5), II(n8), III(n21), and IV(n8) disease. The face was involved in 74%, abdomen in 55%, bone marrow in 14%, kidneys in 24%, and 12% had paraplegia. Fourteen children died during or shortly after completion of chemotherapy. Three of these were disease related. Twelve patients suffered a local relapse after 57-328 days, and one a CNS relapse at 76 days. The projected EFS at 12 months is 50% in stage I, 50% in stage II, 24% in stage III, 25% in stage IV, and 33% for all patients. The cumulative mean dose of CPM was 62 mg/kg in survivors and 64 mg/kg in children who relapsed. One third of patients experienced significant marrow suppression, and infections after COMP1. CONCLUSIONS: Thirty-three percent of children are in first remission at 12 months. The morbidity and mortality of treatment was high. The high relapse rate in all stages may be due to the low cumulative dose of CPM.

Malignancy: 2'-Chlorodeoxyadenosine Effectively Induces Complete Remission in Hairy Cell Leukaemia.

Hairy cell leukaemia, previously known as leukaemic reticuloendotheliosis, is an indolent lymphoproliferative disorder of unknown etiology. It typically affects males, causes marked splenomegaly and moderate enlargement of the liver, whilst lymphadenopathy is inconspicuous. Pancytopenia is characteristic with unusually profound monocytopenia, variable reduction in platelets, and the presence in the peripheral blood and marrow of abnormal small lymphocytes having irregular cytoplasmic margins. Ultrastructure, combined with cytochemistry and flow cytometry, have refined diagnosis. A variant exists between this classical entity and B prolymphocytic leukaemia, where blastic transformation or massive lymph node enlargement are found, and this is of ominous significance. In all these patients with this entity conventional chemotherapy is ineffective and shortens survival. Our previous experience with splenectomy results in excellent clinical control for long periods of time, but without disease eradication. There followed a vogue for the use of interferon but this is limited by high cost and dose-dependent side-effects. Contemporary management centres on the purine analogues, where durable responses are possible with fludarabine and deoxycoformycin, but best with 2'chlorodeoxyadenosine (2-CDA). To document the efficacy of the latter agent, we analysed the outcome in seventeen consecutive patients treated over the last five years. Four were ineligible for analysis, although two had 2-CDA. The other thirteen, managed on a standard seven-day course of 0.1 mg/kg 2-CDA given as a continuous intravenous infusion, all responded promptly. Apart from transient leucopenia complications have been minimal, and oral co-trimoxazole prophylaxis for pneumocystis carinii was maintained during the first one year. In all thirteen there was a rapid return to normal of peripheral blood count and marrow on aspiration and trephine biopsy. Even in the longest follow-up clinical and haematologic remission has been maintained and no patients have required retreatment. One individual has relapsed in the marrow at two years. Despite the relative expense of the agent the excellent treatment outcome and patient acceptability, coupled with its safety, leads to the recommendation that in South Africa - as elsewhere in the world - this be regarded as the first line of treatment.

Malawi pilot study of Burkitt lymphoma treatment.

BACKGROUND: Burkitt lymphoma (BL) accounts for 50% of childhood cancer in Malawi. Lack of resources precludes the use of new successful treatment approaches such as the LMB 89 group B protocol, which cures >80% of children with stage III BL with high dose chemotherapy and matching supportive care. Our objective was to achieve a good cure rate in Murphy stage I-III BL with manageable toxicity in Malawi at a drug cost of <1000 US dollars per patient. PROCEDURE: The intensity and toxicity of the LMB 89 group B protocol was reduced and adapted to Malawi realities. All stages received the same treatment. Children with suspected BL in the period July 1997-November 1999 were subjected to abdominal ultrasound, a tumor biopsy and/or fine needle aspirate (FNA) and bone marrow (BM), cerebrospinal fluid (CSF), and peripheral blood examination. HIV seropositive children were excluded. Endpoints are projected event free survival (EFS) at minimum 1 year, blood and gastro-intestinal tract toxicity, and risk for and severity of infections. RESULTS: Forty-four children were eligible for treatment and analysis. Their median age was 7.2 years, M:F ratio 1.4:1 with 10 stage I, 5 stage II, and 29 stage III patients. Projected Kaplan-Meier EFS for all was 57% (CI 41-73) at 1 year with 90% EFS in stage I and 52% EFS in stage III. The survival curve remained stable at 500 days. Toxicity and delays in appropriate supportive care contributed to ten deaths during treatment. Local recurrent tumor caused five and CNS recurrence one death. Two children died from progressive disease. The incidence of severe (grade 3 and/or 4) hematologic toxicity varied from 13% to 36%, gastro-intestinal toxicity (GIT) from 2% to 17%, and infections from 7% to 41% per chemotherapy module. CONCLUSIONS: It is possible to administer less intense and less costly multiagent chemotherapy to children with BL in a developing society with acceptable EFS rates. Adequate supportive care of the at-times associated severe toxicity must be made available to better the results.