Cardiogenic shock due to thrombotic thrombocytopenic purpura.

We report the case of a 49-year-old man with thrombotic thrombocytopenic purpura (TTP) leading to cardiogenic shock. Laboratory data were typical for TTP with thrombocytopenia and microangiopathic hemolytic anemia. The electrocardiogram recorded significant ST-segment elevations in the anterior and inferior leads. In addition' coronary angiography showed normal epicardial coronary arteries with slow flow. The patient died due to electromechanical dissociation six hours after admission. During autopsy typical features of thrombotic thrombocytopenic purpura were found. Histological preparation of the heart showed a diffuse myocardial necrosis due to microvascular thrombosis. Cardiac involvement is common in TTP but extended myocardial necrosis has been reported in only a few cases.

[Interventional therapy after failed fibrinolysis in acute myocardial infarct. Acute and long-term outcome of referral for rescue balloon angioplasty]. / Interventionelle Therapie nach fehlgeschlagener Fibrinolyse beim akuten Myokardinfarkt. Akut- und Langzeitergebnisse nach Verlegung zur "Rescue"-Ballonangioplastie.

BACKGROUND: The results from studies of coronary angioplasty after failed thrombolysis (rescue-PTCA) in acute myocardial infarction are contradictory. Long-term results were not presented till now. Therefore we analyzed the data from our registry of those patients whose acute and long-term results were available. PATIENTS AND METHODS: Data of 49 patients were analyzed who had been admitted for rescue-PTCA from other hospitals. Thrombolysis had to be started < 6 hours (mean 2.7 hours) from onset of symptoms. Rescue-PTCA had to be completed within < 24 hours (mean 10.5 hours). 37 patients received streptokinase, seven rt-PA, three urokinase and two prourokinase. Electrocardiographic and clinical criteria were used to define failure of thrombolysis. The data of the acute results were from a prospective registry and the long-term results came from clinical follow-up visits and a questionnaire sent to the patients. RESULTS: Mean age of the patients was 48.5 years (38-78 years), 45 male, nine patients in cardiogenic shock (18%), infarct related artery (IRA): RCA 22x, LAD 21x, LCX 5x, CABG 1x, single vessel disease 27x, multiple vessel disease 22x. Acute results: Initial IRA-TIMI flow 0 in 28 patients, 1 in twelve patients, 2 in 9 patients; after rescue-PTCA TIMI flow 1 in one patient, 2 in two patients, 3 in 46 patients (procedural success 94%). Hospital mortality 8.2% (four patients), all in cardiogenic shock. Early reocclusion rate 10%. Bleeding complications 14%, no fatal complications. Long-term results: Observation period 2.5 years in 42 patients (0.5-6.5 years). Three more deaths. Total mortality 14% (7/49). Angiographic follow-up: Ejection fraction initially 50%; 53% after 3 months. Repeat revascularization in 43% (15/35): Re-PTCA in 8/35, surgery in 6/35 patients, 1x transplantation. 80% of the patients were free from angina or heart failure. CONCLUSIONS: Rescue-PTCA in acute myocardial infarction has a high procedural success rate with a low hospital mortality. It is the treatment of choice for patients in cardiogenic shock. Transportation to an interventional center is safe. The reintervention rate is comparably high. The long-term results are good.

Immunohistochemical video-microdensitometry of myocardial collagen type I and type III.

Collagen is an essential part of the cardiac interstitium. Collagen subtypes, their location, total amount and the architecture of the fibrillar network are of functional importance. Architecture in terms of density of the fibrillar network is assumed to be reflected by the intensity of immunohistochemical staining of collagen. The aim of this study was to evaluate a video-based microdensitometric method for quantifying density expressed as absorbance of collagen subtypes I and III stained with an indirect immunoperoxidase method in myectomy specimens of patients with hypertrophic obstructive cardiomyopathy. Various factors influencing the immunohistochemical staining product and the technical properties of the image analysis system were investigated. Linearity between collagen concentration and the absorbance of the immunohistochemical staining product was demonstrated for collagen I using a dot-blot technique. Immunohistochemical collagen staining and density measurement were easily reproducible. The cardiac disability of the patients was assessed according to the New York Heart Association (NYHA) criteria. There was a significant increase in collagen type I density with higher NYHA class, whereas no significant association was found for total collagen area fraction. Thus, video-based microdensitometry gives further insight into the structural remodelling of myocardial collagens and reveals their significance in the process of heart failure in hypertrophic cardiomyopathy.

Are 18 doses of WHO/MDT sufficient for multibacillary leprosy; results of a trial in Malawi.

A trial comparing 18 monthly and 30 monthly doses of the World Health Organization-recommended multidrug therapy (WHO/MDT) in 305 multibacillary leprosy patients in Malawi is described. Patients were randomly allocated to one of the two regimens at the time of taking the 18th supervised dose of WHO/MDT. The mean follow-up period was 3 years (maximum 6 years). No relapse was observed in either group. The cumulative probabilities of remaining slit-skin smear positive were significantly higher among patients receiving only the 18 monthly doses of WHO/MDT, but reached zero at month 60 of follow up. The percentage of patients who developed new disabilities during the trial period was similar in both groups. However, the overall percentage of patients who developed new disabilities (50/305, 16.4%) remains disturbingly high. On the whole, the results of the trial argue in favor of 18 monthly doses of WHO/MDT taken within 24 months as being sufficient for the treatment of multibacillary leprosy.

Does the introduction of WHO-MDT influence trends in the incidence of leprosy?--the Malawian experience.

There has been an average annual decline in detection rates of all types of leprosy in Malawi of around 11.6% between 1977 and 1991. There was no obvious acceleration or slowing down of this decline following the introduction of WHO/MDT in 1983-84. Disability ratios stayed at the same level of about 11% during the 15 years covered by this paper suggesting that patients did not self-report earlier after 1983-84 which might have masked an underlying accelerated decline in detection rates. Thus it is concluded that the influence of WHO/MDT on the pattern of leprosy over a period of time, in a country like Malawi, is so far not noticeably different from any influence dapsone monotherapy might have had.

Four-year follow-up results of a WHO-recommended multiple-drug regimen in paucibacillary leprosy patients in Malawi.

An evaluation of a World Health Organization-recommended multidrug therapy (WHO/MDT) in 499 paucibacillary leprosy patients is described. Patients were followed for 48 months after completion of treatment. Overall relapse rates after treatment were found to be 6.5 per 1000 person years (95% confidence interval 3.4-11.4). There were 12 relapses. A relative lack of cell-mediated immunity, as suggested by number of lesions, clinical classification and lepromin test results, and poor compliance with the dapsone component of WHO/MDT, appeared to be associated with a marginally increased risk of relapse. Severe type 1 reactions after completion of treatment occurred in 17 (3.5%) patients, 15/17 during the first 12 months of follow-up. Overall, 12 (2.5%) patients developed new disabilities during or after WHO/MDT.

Four-year follow-up results of a WHO-recommended multiple-drug regimen in paucibacillary leprosy patients in Malawi

An evaluation of a World Health Organization-recommended multidrug therapy (WHO/MDT) in 499 paucibacillary leprosy patients is described. Patients were followed for 48 months after completion of treatment. Overall relapse rates after treatment were found to be 6.5 per 1000 person years (95 percent confidence interval 3.4-11.4). There were 12 relapses. A relative lack of cell-mediated immunity; as suggested by number of lesions; clinical classification and lepromin test results; and poor compliance with the dapsone component of WHO/MDT; appeared to be associated with a marginally increased risk of relapse. Severe type 1 reactions after completion of treatment occurred in 17 (3.5 percent ) patients; 15/17 during the first 12 months of follow-up. Overall; 12 (2.5 percent ) patients developed new disabilities during or after WHO/MDT

Disabilities in leprosy patients ascertained in a total population survey in Karonga District, northern Malawi.

This paper describes the pattern of disability among 1654 leprosy patients ascertained between 1973 and 1987 in Karonga District, Northern Malawi. Approximately 20% of patients identified prior to 1980 had some disability at registration, but this percentage fell to approximately 10% with the introduction of total population surveys in the Lepra Evaluation Project. The proportion of patients with disabilities at registration increased with age, was higher among males than females, was higher among borderline and lepromatous than tuberculoid patients, and was higher for passively than for actively detected patients. The risk of developing disabilities among patients without any disabilities at registration was approximately 5 per 1000 person years, and appeared to be slightly higher after the completion of treatment than during treatment.

Disabilities in leprosy patients ascertained in a total population survey in Karonga District; northern Malawi

This paper describes the pattern of disability among 1654 leprosy patients ascertained between 1973 and 1987 in Karonga District; Northern Malawi. Approximately 20 percent of patients identified prior to 1980 had some disability at registration; but this percentage fell to approximately 10 percent with the introduction of total population surveys in the Lepra Evaluation Project. The proportion of patients with disabilities at registration increased with age; was higher among males than females; was higher among borderline and lepromatous than tuberculoid patients; and was higher for passively than for actively detected patients. The risk of developing disabilities among patients without any disabilities at registration was approximately 5 per 1000 person years; and appeared to be slightly higher after the completion of treatment than during treatment

Preliminary appraisal of a WHO-recommended multiple drug regimen in paucibacillary leprosy patients in Malawi.

A study was undertaken within the framework of the LEPRA Evaluation Project and the LEPRA Control Project in Malawi (Central Africa) to study the incidence rates of type 1 reactions and of relapses in paucibacillary leprosy patients treated with the current World Health Organization-recommended multiple drug regimen (WHO/MDT). Of 503 patients recruited into the study, 488 were reviewed at the end of treatment and 480 have now been followed for 1 year after completion of treatment. At the end of treatment the skin lesions had completely disappeared in 27.4%, but were judged to be still active in 4.3%. During the follow-up period two patients were found with new active skin lesions, giving a relapse rate of 4.17 (2 of 480) per 1000 person years during the first year after completion of WHO/MDT (95% confidence interval 1.14 to 15.06 per 1000 person years). The incidence rate of marked type 1 reaction (renewed inflammation in previously inactive lesions) during the first year after completion of WHO/MDT was 47.8 per 1000 person years in self-reporting patients but zero in patients identified by active case finding. Data are presented which suggest that the incidence rate of late type 1 reactions is closely related to the classification and stage of the disease at detection.

Hapten-specific antibodies in allergic contact dermatitis in the guinea pig.

A guinea pig model was used to investigate the potential role of hapten-specific antibodies in allergic contact dermatitis. Hapten-specific antibodies of both the IgG1, IgG2 and IgM (sub)classes could be readily detected by ELISA in sera obtained after single or repeated exposure to the allergens 2,4-dinitrochlorobenzene (DNCB) or 4-ethoxymethylene-2-phenyloxazolone. Experiments in which animals were strongly boostered with Freund's complete adjuvant support previous reports that hapten-specific antibodies are able to transfer contact skin reactions with a delayed time course into naive recipients. In contrast, epicutaneous sensitization procedures never allowed transfer of such reactivity. Upon transfer of immune sera to previously sensitized animals, existing allergic contact dermatitis was unaffected, except for a distinct suppression of induration, but not erythema, in the DNCB system. In actively sensitized animals, antibody-related suppression of induration was never observed. Hapten-specific hyposensitivity, as induced by repeated epicutaneous exposure, was also not related to circulating antibody levels. Our findings do not support the view that hapten-specific antibodies should be reconsidered as playing a potentially important role in allergic contact dermatitis.

Preliminary appraisal of a WHO-recommended multiple drug regimen in paucibacillary leprosy patients in Malawi

A study was undertaken within the framework of the LEPRA Evaluation Project and the LEPRA Control Project in Malawi (Central Africa) to study the incidence rates of type 1 reactions and of relapses in paucibacillary leprosy patients treated with the current World Health Organization-recommended multiple drug regimen (WHO/MDT). Of 503 patients recruited into the study; 488 were reviewed at the end of treatment and 480 have now been followed for 1 year after completion of treatment. At the end of treatment the skin lesions had completely disappeared in 27.4 percent ; but were judged to be still active in 4.3 percent . During the follow-up period two patients were found with new active skin lesions; giving a relapse rate of 4.17 (2 of 480) per 1000 person years during the first year after completion of WHO/MDT (95 percent confidence interval 1.14 to 15.06 per 1000 person years). The incidence rate of marked type 1 reaction (renewed inflammation in previously inactive lesions) during the first year after completion of WHO/MDT was 47.8 per 1000 person years in self-reporting patients but zero in patients identified by active case finding. Data are presented which suggest that the incidence rate of late type 1 reactions is closely related to the classification and stage of the disease at detection

Local and systemic desensitization induced by repeated epicutaneous hapten application.

Frequent skin exposure of guinea pigs to the contact sensitizing agents dinitrochlorobenzene or 4-ethoxymethylene-2-phenyloxazolone induced both systemic hyposensitization and local unresponsiveness within 8 weeks. Both phenomena were hapten-specific. Decreased systemic reactivity in repeatedly painted guinea pigs is probably not due to receptor blockade or the development of hapten-specific antibodies, but rather to transient sequestration of hapten-specific effector cells within lymph nodes draining the site of hapten exposure. After discontinuation of allergen exposure, effector cells return into the circulation, as indicated by a reversal of systemic hyporesponsiveness within 5 weeks. The persistence of a cellular infiltrate at the site of repeated application and the hapten-specific unresponsiveness at this site suggest that suppressor cells play a role in local unresponsiveness. Upon discontinuation of allergen exposure, local unresponsiveness rapidly dissolves (within one week). Since the circulation is still depleted of effector cells, residual hyporesponsiveness may persist for longer periods.

Chemosensitivity of human head and neck cancer xenografts in the clonogenic assay and in nude mice.

The potential use of human head and neck (H & N) tumours, growing in athymic nude mice, for preclinical assessment of cytostatic drug sensitivity in a soft agar cloning system was examined. Of 20 H & N tumour xenografts, obtained from 6 different xenograft lines, 17 demonstrated sufficient colony growth to evaluate in vitro drug sensitivity. Moreover, all xenografts provided enough cells to test 8 cytostatic drugs at 3 concentrations each. A dose-dependent inhibition of colony growth was obtained with all drugs tested, except methotrexate. Tumours were considered sensitive when the drug concentration required to inhibit colony formation by 50%, was less than 1/10 of the peak plasma concentration in patients. All H & N tumour lines were resistant to cisplatin, doxorubicin, hydroxyurea, mafosfamide (an in vitro active analogue of cyclophosphamide) and methotrexate. Bleomycin was active in 1/6 and 5-fluorouracil in 6/6 of the H & N tumour lines tested. In 32 cases the in vitro data of the H & N tumour lines and a chemosensitive rat rhabdomyosarcoma were compared directly with in vivo results obtained in nude mice. The clonogenic assay correctly predicted sensitivity in 4/6 (66.7%) and resistance in 21/26 (80.8%) of the cases. A lack of correlation was noted for methotrexate, 5-fluorouracil and cyclophosphamide. In vitro culture of human H & N xenografts may provide a means for a rapid and large scale screening to identify new drugs active against H & N malignancies. In addition the clonogenic assay may help to select drugs for subsequent testing in the nude mouse xenograft model. The lack of correlation for some drugs in the present study indicates that there are some limitations in the use of xenograft tumour material for in vitro testing of new drugs.

Intradermal administration of 4-hydroperoxy-cyclophosphamide during contact sensitization potentiates effector T cell responsiveness in draining lymph nodes.

4-Hydroperoxy-cyclophosphamide (4-HPCY) is an in vitro active form of cyclophosphamide. In a previous study, using an in vivo contact sensitivity model in the guinea pig, we demonstrated that intradermal injection of small amounts (50-200 micrograms) of 4-HPCY at the sensitization site resulted in strong potentiation of contact hypersensitivity (Boerrigter and Scheper, 1984). It was postulated that 4-HPCY induces a local decrease of feedback control within the draining antigenically stimulated lymph nodes. The present data are in support of this view: Lymph node hyperplasia induced by contact sensitization (to dinitrochlorobenzene or oxazolone) was further enhanced by 4-HPCY treatment. The paracortical area was preferentially enlarged. 4-HPCY-treated lymph nodes showed an augmentation of hapten-specific T effector cell function as determined in transfer experiments. The response of such lymph node-derived cells to the T cell mitogen PHA was enhanced. Although 4-HPCY treatment resulted simultaneously in a decrease in responsiveness of draining lymph node-derived cells to the B cell mitogen lipopolysaccharide, anti-hapten antibody production was not affected. The present study demonstrates that important similarities exist between the effects of local 4-HPCY treatment and systemic cyclophosphamide pretreatment on the immune response. As systemic treatment with a high dose of cyclophosphamide is known to have serious side effects, the present local protocol provides a new attractive and versatile strategy for T cell immunopotentiation.