[How I explore: ventricular arrhythmias in athletes]. / Une arythmie ventriculaire chez le sportif.

Documented ventricular tachyarrhythmias or related symptoms need meticulous cardiac investigations. The mechanism of ventricular arrhythmia must be defined. The prognosis is related to underlying cardiac electrical or structural disorders. In the absence of cardiovascular abnormalities, the prognosis is good. No disqualification to competitive activity is required in most cases. Assessment of the risk of sudden death remains a continuing challenge in athletes. This article reviews the diagnostic and therapeutic approaches of ventricular arrhythmias encountered in trained athletes.

Recruitment and growth of two small-bodied resident fish species (Gobiidae and Atherinidae) in oligohaline, seasonally open lagoons.

Spatio-temporal recruitment patterns, growth and survival of the Swan River goby Pseudogobius olorum and western hardyhead Leptatherina wallacei are described from two small, coastal lagoons on the south coast of Western Australia. In these lagoons, estuarine salinity dynamics were relatively stable over much of the autumn-spring period when freshwater inputs from rivers were reduced and there was no oceanic connection. Preflexion and flexion stages of both fish species contributed strongly to population size structure in downstream reaches, whereas upstream reaches were dominated by postflexion larvae and juvenile stages. Spawning of both species was protracted and largely asynchronous, although the episodic presence of stronger preflexion and flexion cohorts suggested some synchronized spawning had occurred. Comparison with estuarine conditions over this period provided evidence that synchronized spawning may be related to temperature and salinity variations from a combination of freshwater inputs and periods of marine exchange. Uninterrupted growth and the progression of cohorts through to juvenile stages were consistent with the generally stable estuarine conditions. Larval and juvenile stages of both species were also tolerant of abrupt changes in salinity and temperature, which occurred due to a non-seasonal oceanic connection. These findings were consistent with the euryhaline nature of adults of both species.

[Molecular and cellular characterization ion of IKAP protein and the Elongator complex. Implications for familial dysautonomia]. / Caractérisation moléculaire et cellulaire des fonctions de la protéine IKAP et du complexe Elongator: implications pour la dysautonomie familiale.

Familial dysautonomia (FD), a severe neuro-developmental and neurodegenerative genetic disorder, is caused by mutations of IKBKAP encoding a subunit of Elongator. FD patients have decreased expression of IKAP in a tissue-specific manner and consequently impaired Elongator function. The biological roles of human IKAP/Elongator remained elusive for a while. However, recent data based on the generation of cellular loss of function models of IKAP through RNA interference strongly suggest a role for this protein in transcriptional elongation. Other data also provide evidence for a role of Elongator in tRNA modifications. Importantly, cells depleted for IKAP have defects in cell motility because of impaired transcriptional elongation of some genes coding for proteins involved in cell migration. Therefore, cell motility deficiency seen in IKAP depleted cells may underlie the neuropathology of FD patients.

[The "footscan" in sport medicine]. / Intérêt du footscan en pathologie sportive.

Clinical examination of the foot in a patient or sportsman requires a detailed analysis of walking (and running). Current technology allows to study temporal fluctuations of plantar pressures and to detect the anomalies responsible for sport specific pathologies or pathologies encountered in sick predisposed people.

[Physiopathology of respiratory muscles]. / Dysfonction des muscles respiratoires.

Different factors can have deleterious effect the inspiratory muscles: increased intrinsic mechanical loading of the inspiratory muscles, functional inspiratory muscle weakness, increased ventilatory demand related to capacity... These muscle changes influence exercise tolerance and contribute to dyspnea.

Biologic effects of recombinant hirudin (CGP 39393) in human volunteers. European Hirudin in Thrombosis Group.

OBJECTIVES: The purpose of this study was to investigate the biologic efficacy and pharmacokinetics of different doses of recombinant hirudin administered in single or repeated subcutaneous injections in healthy volunteers. BACKGROUND: Hirudin is a highly specific inhibitor of thrombin, the pivotal enzyme in thrombosis. Differences between hirudin and heparin in experimental animals indicate that hirudin may be a superior antithrombotic drug in humans. METHODS: The biologic effect of recombinant desulfato-hirudin (CGP 39393) administered as single or repeated (every 8 h for 3 days or every 12 h for 6 days) subcutaneous injections was studied in 231 healthy human volunteers. RESULTS: Single subcutaneous doses of 0.1, 0.2, 0.3, 0.4, 0.5 and 0.75 mg/kg body weight in 195, 8, 12, 8, 4 and 4 volunteers, respectively, prolonged the activated partial thromboplastin time in a dose-proportional fashion within the 1st 30 min, with a near-maximal effect for 3 to 4 h after the dose. The mean activated partial thromboplastin time increased to 1.48 and 1.93 times baseline values 30 min after single subcutaneous injections of 0.2 and 0.4 mg/kg of CGP 39393, respectively. There was a linear relation over a wide range between the activated partial thromboplastin time prolongation and plasma concentrations of CGP 39393. Plasma clearance was between 1.5 and 1.7 ml/min per kg. The subcutaneous administration of 0.3 and 0.5 mg recombinant hirudin three times a day for 3 days or two times a day for 6 days prolonged the activated partial thromboplastin time by 1.71 to 1.69 and 1.78 to 1.92 times baseline levels, respectively, with the preinjection values maintained in the hypocoagulable range. No prolongation of bleeding time was measured at peak plasma hirudin levels. Because thrombin and prothrombin times are not able to reflect high or low CGP 39393 concentrations, respectively, neither test is suitable for monitoring administration of this drug. CONCLUSIONS: CGP 39393 appears to be well tolerated in volunteers, even after repeated doses. The activated partial thromboplastin time test seems to be well suited to monitor the anticoagulant effect of recombinant hirudin because the dose effect is linear up to 0.5 mg/kg of subcutaneous CGP 39393. The prolongation of activated partial thromboplastin time after subcutaneous injection of CGP 39393 shows a plateau lasting for 3 h. Further studies are now required to determine the dose that will provide the best antithrombotic effect and the lowest bleeding tendency in arterial or venous thrombosis indications.

Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin.

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of desirudin in subjects with various degrees of renal impairment in comparison with subjects with normal renal function. METHODS: Eight subjects with normal renal function (creatinine clearance > 90 ml/min) received 0.5 mg/kg desirudin intravenously over 30 minutes. Four subjects with mild renal failure (creatinine clearance between 61 and 90 ml/min) received 0.5 mg/kg. Five subjects with moderate renal failure (creatinine clearance between 31 and 60 ml/min) received 0.25 mg/kg. Six subjects with severe renal failure (creatinine clearance < 31 ml/min) received 0.125 mg/kg. RESULTS: Specific maximum concentration values (maximum concentrations corrected to a dose of 1 mg/kg) increased slightly with decreasing creatinine clearance. Mean specific area under the plasma concentration-time curve increased by a factor of 1.15, 2.83, and 7.0 for subjects with mild, moderate, and severe renal failure, respectively, compared with healthy subjects. Total urinary excretion of desirudin was about 55% to 60% of the dose in all four groups; elimination was delayed for subjects with moderate and severe renal failure. Total and renal clearance of desirudin were proportional to creatinine clearance. Total plasma clearance of desirudin was proportional to renal clearance of the drug. Prolongation of activated partial thromboplastin time was increased among subjects with moderate and severe renal failure despite a dose reduction. Area under the dynamic activated partial thromboplastin time curve for subjects with moderate renal failure remained the same as that for healthy subjects despite a dose reduction by a factor of two. Area under the dynamic curve increased by a factor of about 1.5 for subjects with severe renal failure despite a dose reduction by a factor of four. CONCLUSION: A dose reduction by a factor of six is recommended for persons with severe renal failure.

A prospective, controlled evaluation of home chemotherapy for children with cancer.

OBJECTIVES: Infusion of chemotherapy at home provides an alternative to hospitalization for children with cancer. Few programs of pediatric home chemotherapy have been described or evaluated. The purpose of this work was to compare prospectively chemotherapy in the hospital to chemotherapy at home with respect to billed medical charges, out-of-pocket expenses, and quality of life. METHODS: Eligibility criteria for home therapy were defined. Parents and nurses were trained. Billed charges, loss of wages, out-of-pocket expenses, medical outcome, and quality of life of 14 patients for one course of chemotherapy in the hospital were compared with those for an identical course at home. RESULTS: Daily charges for chemotherapy were $2329 +/- 627 in the hospital and $1865 +/- 833 at home; out-of-pocket costs, $68 +/- 31 and $11 +/- 6, respectively; and loss of income, $265 +/- 233 and $67 +/- 107, respectively. Patients' independence, well-being, appetite, mood, and school work were significantly better at home, and parental time at work and with the family was greater. CONCLUSION: Administration of selected chemotherapy at home results in lower billed charges, reduced expenses, reduced loss of income for parents, and a more satisfying lifestyle for patients and parents.

Direct thrombin inhibition with Rec-hirudin CGP 39393 as prophylaxis of thromboembolic complications after total hip replacement.

Hirudin is an anticoagulant originally extracted from the leech Hirudo medicinalis. Using recombinant DNA technology a new compound, recombinant desulphato hirudin CGP 39393 has now been produced. The aim of this study was to determine the maximum tolerated dose in patients undergoing elective hip replacement. This open safety trial represents, to our knowledge, the first experience of recombinant hirudin in orthopedic patients. In this study 48 patients undergoing primary total hip replacement were included and the safety of subcutaneous injections of 10, 15, 20 and 40 mg CGP 39393 twice daily, was evaluated. Prophylaxis was started immediately pre-operatively and continued for 8-10 days. A mandatory bilateral phlebography was performed at the end of the prophylactic treatment period and a clinical follow-up was done 6 weeks after surgery. A major bleeding event occurred in the first 3 patients receiving 40 mg CGP 39393 b.i.d. and the prophylaxis regimen at this dosage level was therefore discontinued. Median values of total blood loss and requirements of blood transfusion in the patients receiving 10-20 mg CGP 39393 were similar to those reported in previous studies on total hip replacement performed at the same centre, using other prophylactic drugs. Deep vein thrombosis (DVT) was confirmed by phlebography in 5 out of 12 patients in the 10 mg group (41.7%, 95% confidence limits [CL]: 15.2-72.3%), 1 out of 11 patients in the 15 mg group (9.1%, CL: 0.23-41.3%) and 2 out of 20 patients in the 20 mg group (10.0%, CL: 1.2-31.7%) during the prophylaxis period. CGP 39393 was safe and well tolerated, when administered as subcutaneous injections of 10-20 mg twice daily. The dose level of 40 mg CGP 39393 twice daily resulted in serious disturbance of the hemostasis in patients after hip prosthesis surgery.

Percentage of inadequate phlebograms and observer agreement in thromboprophylactic multicenter trials using standardized methodology and central assessment.

This study examines inadequacy rates for phlebography in two multicenter trials for the prevention of post-operative DVT and determines inter-and intra-observer variability in evaluating phlebograms. A total of 991 (I) and 385 (II) patients underwent bilateral phlebography in two studies of thromboprophylaxis. Phlebography was performed using a standard method designed to visualize and assess all deep veins. Each vein was scored as normal, DVT or inadequate by both local and central assessment. The study showed low inadequacy rates for phlebograms of 12.2% (121/991) and 6.5% (25/385). Inter-observer agreement (local vs. central assessment) was moderate in both studies (I: 74.8%, Kappa-value 0.41; II: 82.6%, Kappa-value 0.51). Good intra-observer agreement (within the central assessment group) was observed (I:88.8%, Kappa-value 0.75). This study demonstrates low inadequacy rates for phlebograms using a standardized methodology and superior intra-observer agreement compared to inter-observer agreement and supports the importance of central assessment of phlebograms in thromboprophylactic multicenter trials to reduce observer variability.

Effect of a 15-minute infusion of DDAVP on the pharmacokinetics and pharmacodynamics of REVASC during a four-hour intravenous infusion in healthy male volunteers.

Plasma pharmacokinetics, effect on coagulation parameters, and safety and tolerability of an intravenous infusion of REVASC before, during and after a DDAVP infusion were investigated. Twelve healthy volunteers were given an intravenous bolus dose followed by a constant rate four-hour infusion of REVASC. Fifteen-minute infusions of 0.9% saline and DDAVP were started two and three hours respectively after the start of the REVASC infusion. Plasma REVASC concentrations were not affected by either the saline or DDAVP infusion. REVASC infusion produced an increase in APTT which plateaued between 0.5 and 3 hours. After the DDAVP infusion there was a tendency towards a new lower plateau whilst the REVASC infusion continued. There were no serious adverse events or bleeding episodes throughout the study. In conclusion, the co-administration of intravenous DDAVP has no effect on the plasma pharmacokinetics of REVASC and partially reverses the REVASC-induced increase in APTT. This may represent a role for DDAVP in the partial reversal of anticoagulation induced by REVASC.

Duplication and loss of chromosome 21 in two children with Down syndrome and acute leukemia.

Acute leukemia in Down syndrome (DS) is often associated with additional changes in the number or structure of chromosome 21. We present two DS patients whose leukemic karyotypes were associated with changes in chromosome 21 ploidy. Patient 1 developed acute lymphocytic leukemia (type L1); disomy for chromosome 21 was evident in all blast cells examined. Loss of the paternal chromosome in the leukemic clone produced maternal uniparental disomy with isodisomy over a 25-cM interval. The second patient had acute monoblastic leukemia (type M5) with tetrasomy 21 in all leukemic cells. DNA polymorphism analysis showed duplicate paternal chromosomes in the constitutional genotype. The maternal chromosome was subsequently duplicated in the leukemic clone. The distinct inheritance patterns of chromosome 21 in the blast cells of these patients would appear to indicate that leukemogenesis occurred by different genetic mechanisms in each individual.

SCL/Tal-1 expression in T-acute lymphoblastic leukemia: an immunohistochemical and genotypic study.

A comparative study of the immunohistochemical (Stem cell leukemia/T-cell acute leukemia [SCL/TAL-1] protein expression) and genotypic (deletions in the SCL/tal-1 gene) findings in T-acute lymphoblastic leukemia (T-ALL) is presented. Formalin-fixed tissue from 50 cases of T-ALL were stained with a novel monoclonal antibody, 2TL 242, which recognizes SCL/TAL-1 protein. Twenty-four cases showed nuclear immunolabeling of leukemic cells. Nuclear positivity was not evident in any other type of leukemia or lymphoma tested with the antibody. Genotypic analysis of 25 cases of T-ALL showed a deletion involving the SCL/tal-1 gene in nine cases. These results suggest that protein expression is not dependent on derangement of the SCL/tal-1 gene, because immunohistochemical detection of the protein was noted in the presence and absence of a tal-d1 deletion.

Anaplastic large-cell Ki-1 lymphoma. Pulmonary presentation mimicking miliary tuberculosis.

An unusual presentation of anaplastic large-cell (ALC) Ki-1 lymphoma is described, in which pulmonary involvement mimicked miliary tuberculosis. Lung involvement is uncommon in this type of lymphoma, and it is not clear from previous reports whether this was a presenting feature. Bone marrow involvement, rare in Ki-1 lymphoma, also was present in this case. Despite therapy skin involvement subsequently developed, and the patient died 3 months after presentation. Postmortem examination revealed lymphomatous involvement of the heart, liver, kidneys, stomach, and lymph nodes. This case highlights the need for awareness of ALC Ki-1 lymphoma particularly when it presents at uncommon extranodal sites.

Improved prognosis of Epstein-Barr virus associated childhood Hodgkin's lymphoma: study of 47 South African cases.

AIM: To study the distribution of Hodgkin's lymphoma in South African children and report the incidence of Epstein-Barr virus (EBV) as regards age, race, sex, and histological subtype; to investigate whether EBV is relevant to survival. METHODS: Immunohistochemistry (IHC) and in situ hybridisation (ISH) to detect EBV were performed on 47 South African children with classical Hodgkin's lymphoma, ranging in age from 3 to 14 years and coming from different ethnic backgrounds. The correlation between the presence of the virus and clinical outcome was assessed. RESULTS: The nodular sclerosing subtype predominated, comprising 89% of cases; the remaining 11% were of the mixed cellularity subtype. EBV was present in 68%. Full clinical data were available for 36 cases; EBV positive patients presented with less aggressive symptoms at diagnosis and had a significantly longer median survival than EBV negative patients. CONCLUSIONS: The distribution of EBV in South African childhood Hodgkin's lymphoma follows a pattern intermediate to that of industrialised and non-industrialized countries. Furthermore, our data suggest that there is an association between poor prognosis and the non-detection of EBV products in South African childhood Hodgkin's lymphoma.

Massive thymic hyperplasia.

Massive thymic hyperplasia is an extremely rare form of true thymic hyperplasia most often described in infants and children. Hyperplasia of this order is not known to occur in any other organ, and its etiology and prognostic significance remain unknown. As there is no accurate way of preoperatively differentiating massive thymic hyperplasia from other tumors of the thymus and anterior mediastinum, we advise excision in all cases for histological analysis and relief of mediastinal compression. This description of 4 cases updates the 30 previously reported cases, and includes a literature review.

Detection of the T(14;18) translocation in follicle centre cell lymphomas in South African ethnic groups using PCR.

PCR was used to detect the t(14;18) translocation in 64 South African cases with follicle centre cell lymphoma. DNA was purified from paraffin-embedded tissue collected from different ethnic groups namely white, black and "mixed" race patients, and primers used to detect both mbr and mcr. The overall incidence of the translocation was 45%, which is similar to that of Caucasian and Chinese patients. The ratio of rearrangements occurring at the mbr and mcr was 7:1 which may be an overestimation. The ratio was three times higher for the "mixed" race group compared to whites, and this suggests that there may be ethnic variation in breakpoints in South African patients.

Abortive mitoses and nuclear DNA fragmentation in CD30+ large cells of Hodgkin's disease.

This study was undertaken to better comprehend the reasons for the scarcity of Hodgkin and Reed-Sternberg (H-RS) cells in Hodgkin's disease (HD) despite their expression of "proliferation-associated antigens". To this end, we assessed the relative frequency of mitotic phases and nuclear damage (detected by in situ end-labeling of DNA strand breaks) in CD30+ large cells of nodular sclerosis and mixed cellularity HD. Our results show that a) most CD30+ cells in HD exhibit abortive mitoses, with a highly significant arrest at the metaphase-ana/telophase transition, and b) many of these elements, i.e. mainly H-RS cells, show fragmentation of nuclear DNA, suggesting imminent or actual death. Percentages of CD30+ cells that entered mitosis and those with DNA strand breaks were of a similar order of magnitude and correlated significantly in a linear fashion. These findings are consistent with the concept that cell deletion is the major cause of the paucity of H-RS cells in HD.

Mitotic activity and nuclear DNA damage of large cells in Hodgkin's disease: comparison with the expression of p53 and bcl-2 proteins and the presence of Epstein-Barr virus.

The roles of the bcl-2 and p53 proteins in Hodgkin's disease (HD) are poorly understood. We therefore compared their detected presence in Hodgkin and Reed-Sternberg/large atypical (H-RS/LA) cells immunohistochemically with the percentages of these cells double-labeled for CD30 and DNA strand breaks (DNA fragmentation index, DFI); mitotic indices (MI); and the EBV infection status. We found a highly significant inverse correlation between the fractions per case of H-RS/LA cells expressing bcl-2/p53 proteins and the DFI of CD30+ elements. No marked effect of these two oncoproteins on MI was noticed, although these parameters and DFI of CD30+ cells were linearly related. EBV infection of H-RS/LA cells exerted only a limited effect on the parameters tested. The results of this study suggest that overexpressed bcl-2 and, to some extent, p53 proteins in H-RS/LA cells of HD primarily counteract deletion of these cells.

Preliminary studies on toxic effects of cyclopiazonic acid alone and in combination with aflatoxin B1 in non-human primates.

Results of experimental studies on toxicity of cyclopiazonic acid (CPA), a mycotoxin isolated from Aspergillus flavus, and toxicity of this toxin in combination with aflatoxin B1 (AFB1) are reported. Experiments were conducted in 16 vervet monkeys of both sexes. One male monkey was given 1 mg/kg per day of CPA intragastrically and the dose was doubled every third day to eventually achieve 60 mg/kg per day. Two males and 3 female monkeys were fed 20 mg/kg per day of CPA and terminated after 60 and 120 days, respectively. Two monkeys received AFB1 0.1 mg/kg per day, 2 received the same dose of AFB1 and 20 mg/kg per day of CPA. Four monkeys of both sexes served as controls. Results of experiments showed low toxicity of CPA in non-human primates with mild pathological changes in hepatocyte rough endoplasmic reticulum, small vessels and myocardium. Combined treatment with CPA and AFB1 indicated lack of a synergistic cumulative effect of both toxins. Animals treated with AFB1 only developed more advanced liver lesions and died earlier than those which also received high doses of CPA.