Modified-release recombinant human TSH (MRrhTSH) augments the effect of (131)I therapy in benign multinodular goiter: results from a multicenter international, randomized, placebo-controlled study.

BACKGROUND: Recombinant human TSH (rhTSH) can be used to enhance (131)I therapy for shrinkage of multinodular goiter (MG). OBJECTIVE, DESIGN, AND SETTING: The objective of the study was to compare the efficacy and safety of 0.01 and 0.03 mg modified-release (MR) rhTSH as an adjuvant to (131)I therapy, vs. (131)I alone, in a randomized, placebo-controlled, international, multicenter study. PATIENTS AND INTERVENTION: Ninety-five patients (57.2 ± 9.6 yr old, 85% females, 83% Caucasians) with MG (median size 96.0, range 31.9-242.2 ml) were randomized to receive placebo (group A, n = 32), MRrhTSH 0.01 mg (group B, n = 30), or MRrhTSH 0.03 mg (group C, n = 33) 24 h before a calculated activity of (131)I. MAIN OUTCOME MEASURES: The primary end point was a change in thyroid volume (by computerized tomography scan, at 6 months). Secondary end points were the smallest cross-sectional area of the trachea; thyroid function tests; Thyroid Quality of Life Questionnaire; electrocardiogram; and hyperthyroid symptom scale. RESULTS: Thyroid volume decreased significantly in all groups. The reduction was comparable in groups A and B (23.1 ± 8.8 and 23.3 ± 16.5%, respectively; P = 0.95). In group C, the reduction (32.9 ± 20.7%) was more pronounced than in groups A (P = 0.03) and B. The smallest cross-sectional area of the trachea increased in all groups: 3.8 ± 2.9% in A, 4.8 ± 3.3% in B, and 10.2 ± 33.2% in C, with no significant difference among the groups. Goiter-related symptoms were effectively reduced and there were no major safety concerns. CONCLUSION: In this dose-selection study, 0.03 mg MRrhTSH was the most efficacious dose as an adjuvant to (131)I therapy of MG. It was well tolerated and significantly augmented the effect of (131)I therapy in the short term. Larger studies with long-term follow-up are warranted.

Autoimmune polyendocrine syndrome type 1 in north-western France: AIRE gene mutation specificities and severe forms needing immunosuppressive therapies.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS1) has been poorly evaluated in France. We focused on the north-western part of the country to describe clinical phenotypes, especially severe forms of the disease, and AIRE gene mutations. METHODS: Clinical and immunological data were collected, and pathological mutations were identified by DNA sequencing. RESULTS: Nineteen patients were identified with APS1. Clinical manifestations varied greatly, showing 1-10 components. Mucocutaneous candidiasis, adrenal failure, hypoparathyroidism, alopecia and other severe infections were the most frequent components. Four patients had severe forms, needing immunosuppressive therapy: 2 for hepatitis; 1 for severe malabsorption, and 1 for a T cell large granular lymphocytic leukemia. These therapies were very effective but caused general discomfort. One patient died of septicemia. Four different AIRE gene mutations were identified, and a 13-bp deletion in exon 8 (c.967-979del13) was the most prevalent. There was at least one allele correlating with this mutation and alopecia occurrence (p = 0.003). No novel mutation was detected. CONCLUSION: APS1 appears to be rare in north-western France. We identified 4 cases with a severe form needing immunosuppressive therapy. The AIRE gene mutations are more like those found in north-western Europe than those found in Finland.

Pronuclear morphology differs between women more than 38 and women less than 30 years of age.

Pronuclear morphology has been reported as a good tool for studying embryo development and euploidy. Comparing two groups of women with different aneuploidy risk, women more than 38 years old (n = 28) known to be at high risk of aneuploidy, and women under 30 years old (n = 35), this study investigated whether pronuclear morphology could be used routinely as an alternative to preimplantation genetic screening (PGS) in countries where PGS is prohibited. Pronuclear morphology was evaluated for 301 zygotes and related to embryo quality and pregnancy outcome. For the older women, an increased frequency of zygotes with abnormal polar body and pronuclei alignment was observed, i.e. type gamma, with 93% aneuploidy risk (26.0 versus 15.1% P < 0.05) and fewer zygotes with a good development prognosis (36.4 versus 47.8%; P < 0.05). A1alpha configuration was associated with good implantation rate and was not related to day 2 embryo quality. This configuration was less frequent in the group of women more than 38 years old and among non-pregnant women under 30 years, compared with pregnant women under 30 years old. Pronuclear morphology seemed linked to age, but not associated with embryo quality. A larger study allowing correlation analysis is necessary to confirm the value of these criteria and the link to a woman's age.

Ectopic hyperprolactinaemia in a woman with a mesocolic perivascular epithelioid cell tumor ("PEComa").

Ectopic prolactin secretion remains exceptional and originates mainly from malignant tumors. We report the case of a 47-year-old woman who presented amenorrhea leading to unravel important hyperprolactinaemia (269 ng/mL) with no hypothalamo-pituitary mass on magnetic resonance imaging (MRI). Pelvic imaging revealed the presence of a large pelvic mass that originated from the mesocolon. After complete surgical extraction, histological examination was in favour of a "perivascular epithelioid cell tumor" (PEComa). Prolactin levels normalized after surgical extraction and remained normal after a 3-year follow-up, totally free of tumour recurrence and/or metastasis. This suggests that hyperprolactinaemia was most likely related to the PEComa, despite negative reactions with antiprolactin antibodies at immunohistochemistry. Alternatively to a direct prolactin secretion by the tumor, one could hypothesize that the tumour secreted a prolactin stimulating factor or a dopamine antagonist that could not be identified. In conclusion, in face of an important hyperprolactinaemia without any hypothalamic-pituitary mass, it remains important to search for an ectopic prolactin production, such as a PEComa.

Beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8.

CONTEXT: Mutations of the monocarboxylate transporter 8 (MCT8) gene determine a distinct X-linked phenotype of severe psychomotor retardation and consistently elevated T(3) levels. Lack of MCT8 transport of T(3) in neurons could explain the neurological phenotype. OBJECTIVE: Our objective was to determine whether the high T(3) levels could also contribute to some critical features observed in these patients. RESULTS: A 16-yr-old boy with severe psychomotor retardation and hypotonia was hospitalized for malnutrition (body weight = 25 kg) and delayed puberty. He had tachycardia (104 beats/min), high SHBG level (261 nmol/liter), and elevated serum free T(3) (FT(3)) level (11.3 pmol/liter), without FT(4) and TSH abnormalities. A missense mutation of the MCT8 gene was present. Oral overfeeding was unsuccessful. The therapeutic effect of propylthiouracil (PTU) and then PTU plus levothyroxine (LT(4)) was tested. After PTU (200 mg/d), serum FT(4) was undetectable, FT(3) was reduced (3.1 pmol/liter) with high TSH levels (50.1 mU/liter). Serum SHBG levels were reduced (72 nmol/liter). While PTU prescription was continued, high LT(4) doses (100 microg/d) were needed to normalize serum TSH levels (3.18 mU/liter). At that time, serum FT(4) was normal (16.4 pmol/liter), and FT(3) was slightly high (6.6 pmol/liter). Tachycardia was abated (84 beats/min), weight gain was 3 kg in 1 yr, and SHBG was 102 nmol/liter. CONCLUSIONS: 1) When thyroid hormone production was reduced by PTU, high doses of LT(4) (3.7 microg/kg.d) were needed to normalize serum TSH, confirming that mutation of MCT8 is a cause of resistance to thyroid hormone. 2) High T(3) levels might exhibit some deleterious effects on adipose, hepatic, and cardiac levels. 3) PTU plus LT(4) could be an effective therapy to reduce general adverse features, unfortunately without benefit on the psychomotor retardation.

[Severe Graves' acropachy and dermopathy. Three case reports]. / Acropachye et dermopathie basedowiennes severes. Trois observations.

INTRODUCTION: Traditionally described, severe Graves' acropachy and tibial myxoedema are now only encountered in certain severe forms of Graves' disease, where they can be difficult to diagnose and hence delay the initiation of treatment. OBSERVATIONS: Three patients presented with severe ophthalmopathy, pretibial myxoedema and acropachy of different clinical forms. DISCUSSION: In supplement to the usual biopsies and X-rays, bone scintigraphy provides early diagnosis of acropachy. The severity of the immune disease, the episodes of hypothyroidism and cigarette smoking are the 3 main factors contributing to these extra-thyroid manifestations of Graves' disease. There is currently no treatment that can permanently resolve the functional and aesthetic problems of dermopathy and acropachy.

Strip test for bedside detection of interleukin-6 in cervical secretions is predictive for impending preterm delivery.

Inflammatory cytokines in amniotic fluid are markers of prematurity which could characterize preterm labour of infectious origin. To avoid amniocentesis, we analyzed IL-6, IL-8, IL-10, and IL-13 by RT-PCR in cervical secretions (CS) of 307 women with preterm labour. IL-6 was detected in 26.3% patients who delivered at less than 34 weeks (specificity: 95.8%). In addition, IL-6 was associated with delivery within 7 days (specificity: 91.6%). To render the detection more rapid and cheaper, a strip test was designed and evaluated comparatively with RT-PCR in 76 women. This bedside strip test was twice more sensitive than RT-PCR, with little decrease in specificity.

[Prospective study of the causes for destruction of labile blood products during 1999 at a University Hospital Center]. / Etude prospective des causes de destruction des produits sanguins labiles, au cours de l'année 1999 dans un CHU.

The destruction of the blood cell product (BCP) is a situation which is hard to accept in the present context of transfusional safety which aims at covering the transfusional needs in the most appropriate way. In our University Hospital, 500 BCP out of 20,000 are destroyed per year, which represent a cost of 100,000 $. A prospective research was carried out from January 1st to December 31st 1999 in order to analyse the causes of the destruction of the BCP and to differentiate the inevitable destructions for the patient's security from the avoidable destructions which might have benefited from corrective measures. For each group of simultaneously destroyed BCP, an information note specified the patient's pathology, the reasons for the prescription, the number and the type of transfused and destroyed BCP in the same day, the time spent between distribution and return, and the causes of destruction. In 1999, a total of 483 LBP out of 19,802 which were distributed, have been returned and destroyed, that is to say 2.4% for a 99.3% traceability which involved 242 patients. Among these destroyed BCP, 28.3% came from inevitable causes--death or acute intensive care which needed a lot of transfusions--69.7% were categorised as being related to avoidable causes depending on the organisation of transport and care, unadapted safety measures. The corrective measures to be taken, concern the improvement of transport procedures, the set-up of a nominative BCP reservation system in the Blood Center, the scheduling of the BCP deliveries from the blood bank, and a better adaptation of the safety measures to the transfusional needs.

Improving the efficiency of a user-driven learning system with reconfigurable hardware. Application to DNA splicing.

This paper describes a new approach to problem solving by splitting up problem component parts between software and hardware. Our main idea arises from the combination of two previously published works. The first one proposed a conceptual environment of concept modelling in which the machine and the human expert interact. The second one reported an algorithm based on reconfigurable hardware system which outperforms any kind of previously published genetic data base scanning hardware or algorithms. Here we show how efficient the interaction between the machine and the expert is when the concept modelling is based on reconfigurable hardware system. Their cooperation is thus achieved with an real time interaction speed. The designed system has been partially applied to the recognition of primate splice junctions sites in genetic sequences.

Carpentier-Edwards pericardial bioprosthesis in aortic or mitral position: a 12-year experience.

BACKGROUND: The first generation of pericardial valves was withdrawn from the market for a high rate of premature failure. With an original design, Carpentier-Edwards pericardial valves promised improved results. METHODS: Seven hundred eighty-seven patients who underwent isolated aortic valve replacement and 182 patients who underwent isolated mitral valve replacement between July 1984 and December 1995 with Carpentier-Edwards pericardial bioprostheses in our institution were followed up. The patients' mean age was 68.3 (aortic valve replacement, AVR) and 63.9 (mitral valve replacement, MVR) years. All but five AVR patients were followed up for an average of 4.7 years after operation, with a total follow-up of 3,624 patient-years. All patients with MVR were followed up for an average of 5.3 years after operation, with a total follow-up of 969 patient-years. RESULTS: After 12 years, actuarial survival rate is 53% for AVR and 54% for MVR. Freedom from valve-related complications for aortic versus mitral valve replacement is, respectively, 68% and 55%, freedom from valve-related death is 84% and 85%, freedom from thromboembolism 87% and 94%, and freedom from endocarditis 97% and 94%. The behavior of the aortic valve is better than that of the mitral valve: freedom from reoperation is 92% and 76%, respectively; freedom from valve failure is 94% and 78%. Age is an important factor, especially in the mitral position: freedom from valve failure is 52% in patients younger than 60 years and 100% in patients older than 60 years. CONCLUSIONS: With a low rate of valve-related events at 12 years and a low rate of structural deterioration, this prosthesis is a reliable choice for AVR and in patients over 60 years for MVR. A more durable mitral bioprosthesis is needed for patients younger than 60 years.

[Evaluation of the actual traceability of labile blood products using medical records]. / Evaluation de la traçabilité effective des produits sanguins labiles à partir des dossiers médicaux.

The traceability of blood products is an essential part of haemovigilance and transfusion safety. A pilot survey assessed the actual traceability by analysing transfusion information collected from medical records of a representative sample of 390 labile blood products transfused in a French university hospital. Transfusion and distribution forms were missing in 2.3% and 6.9% respectively. Availability and validity of transfusion information varied according to the nature of the expected information, elements of patients' records and types of wards. The location where the transfusion was performed was false or ambiguous in 38% of cases in surgery. Crude traceability, evaluated by the feedback of validated distribution forms, was estimated at 85.2% whereas actual traceability was estimated at 81.9% (SD 1.7%). High availability (98.7%) of at least one of the two sheets of the distribution form in medical records, or in the blood bank, revealed that a significant improvement of traceability should come from a better compliance to the rules of information transmission. The actual traceability differed significantly according to clinical services (worse in surgery) and was lower in case of autologous or absence of previous transfusion. An analysis of markers of good traceability should suggest efficient evolution of organization and information systems. This pilot study shows the relevance and feasibility of this kind of survey which could interestingly be performed on a large national representative random sample.

Large outbreak of Salmonella enterica serotype paratyphi B infection caused by a goats' milk cheese, France, 1993: a case finding and epidemiological study.

OBJECTIVE: To assess the magnitude of a nationwide outbreak of infection with Salmonella enterica serotype paratyphi B and identify the vehicle and source of infection. DESIGN: A case finding study of S paratyphi B infection between 15 August and 30 November 1993; a pair matched case-control study; an environmental investigation at a processing plant that produced a raw goats' milk cheese incriminated in the outbreak; phage typing and genotyping of food and human S paratyphi B isolates. SETTING: France, 15 August to 30 November 1993. SUBJECTS: 273 patients with S paratyphi B infection; 59 pairs of cases and controls matched for age, sex, and city of residence. MAIN OUTCOME MEASURES: Numbers of cases and incidence rates by region of residence and age; matched odds ratios for dairy food preferences. RESULTS: Among the 273 cases there was one death; 203 (78%) strains belonged to phage type 1 var 3. The incidence of infection was greatest in the region where goats' milk cheese is commonly produced. Comparison of cases and controls showed a 12-fold greater risk of illness (95% confidence interval 1.6 to 92.3) from eating brand A unpasteurised goats' milk cheese. S paratyphi B isolates of phage type 1 var 3 were recovered from cheese A, goats' milk at the plant processing cheese A, and goats' milk supplied to the plant by a single farm. Genotypic IS 200 typing of food and human 1 var 3 phage type isolates showed a common IS 200 pattern. CONCLUSION: This outbreak emphasises the potential health hazards of widely distributed unpasteurised milk products in France and the need for their close bacterial monitoring.

High speed pattern matching in genetic data base with reconfigurable hardware.

Homology detection in large data bases is probably the most time consuming operation in molecular genetic computing systems. Moreover, the progresses made all around the world concerning the mapping and sequencing of the genome of Homo Sapiens and other species have increased the size of data bases exponentially. Therefore even the best workstation would not be able to reach the scanning speed required. In order to answer this need we propose an algorithm, A2R2, and its implementation on a massively parallel system. Basically, two kinds of algorithms are used to search in molecular genetic data bases. The first kind is based on dynamic programming and the second on word processing, A2R2 belongs to the second kind. The structure of the motif (pattern) searched by A2R2 can support those from FAST, BLAST and FLASH algorithms. After a short presentation of the reconfigurable hardware concept and technology used in our massively parallel accelerator we present the A2R2 implementation. This parallel implementation outperforms any kind of previously published genetic data base scanning hardware or algorithms. We report up to 25 million nucleotides per scanning seconds as our best results.

[Postoperative re-expansion causing unilateral pulmonary edema]. / Oedème pulmonaire unilatéral de réexpansion postopératoire.

A case of re-expansion pulmonary oedema is reported. A 7-year-old girl, after having been operated on for a lung tumour, had a postoperative haemothorax combined with atelectasis of the left upper lobe. After she had recovered from the first dose of chemotherapy, the thoracotomy wound was reopened to remove the partially organised and lysed haemothorax, as well as the very thickened pleura. The patient developed clinical signs of pulmonary oedema very shortly after the end of the anaesthetic (tachypnoea, cyanosis, a decrease in oxygen saturation when FIO2 < 1, pink frothy secretions in the endotracheal tube). End-inspiratory crepitations became audible in the left lung field only. The chest film showed left-sided diffuse nodular alveolar opacities. The girl was again ventilated, with + 5 cmH2O positive end-expiratory pressure. She was extubated 36 h later, and discharged a few days later without any sequela. This case was the first to be described in a child after pleural surgery. The death rate, estimated from a literature survey, is about 20%.

Intensive treatment of stage III-IV aggressive malignant lymphomas (protocol TPL-84).

BACKGROUND: Much progress has been made in the last ten years in the treatment of non Hodgkin's lymphomas by increasing drug schedules and by using non cross-resistant regimens. METHODS: So we decided in 1984 to test a new multiple drug protocol (Tours-Poitiers-Limoges = TPL protocol) which used a sequence of three courses of classical high-dose induction therapy, three courses of consolidation therapy using Teniposide, Cytosine Arabinoside, L Asparaginase and high-dose Methotrexate, and three courses of late intensification using the same drugs as induction therapy. Results. Thirty-eight patients younger than 60 years were included. Complete remission was obtained in 27 patients (71%). The median follow-up was 3 years and 9 months with one third of CR patients having been followed beyond 5 years. Seven patients relapsed (26% of CR patients) and one died of toxicity in complete remission. At present 22 patients (58%) are in complete remission, 19 in first CR, 1 in first CR after allogenic bone marrow transplantation, and 2 in second prolonged CR after autologous bone marrow transplantation. The median survival time is 48 months and the actuarial disease-free survival curve seems to have a plateau at 48.5%, with no relapse after 24 months. CONCLUSIONS: These results confirm the efficacy of alternating high-dose conventional chemotherapy in the treatment of intermediate and high-grade NHL, with about half of the patients being cured. However, more intensive chemotherapy regimens are needed to improve cure rates.

The TAM regimen prior to allogeneic and autologous bone marrow transplantation for high-risk acute lymphoblastic leukemias: a cooperative study of 62 patients.

A total of 62 patients with high-risk acute lymphoblastic leukemia (ALL) were treated with fractionated total body irradiation, high-dose cytosine arabinoside and melphalan followed by bone marrow transplantation (BMT). Thirty-six patients received allogeneic and 26 autologous BMT. Eight patients were treated in CR1, 36 in CR2 (first relapse occurring on therapy for 32), seven in further CR, 10 in relapse (five early first relapse, four second relapse and one fourth relapse) and one with refractory ALL. Severe toxicity occurred in 26 of the 62 patients (42%) and 14 died (22.5%) from non-leukemic causes. The actuarial event-free survival at 3.6 years was 28% after autologous BMT and 52% after allogeneic BMT with actuarial relapse rates of 62% and 35%, respectively. The results of this pilot study seem promising for this group of poor risk ALL, but the relapse rate remains high after autologous BMT and needs to be improved.

Nosocomial legionnaires' disease in a bone marrow transplant unit.

We report the outcome of nosocomial legionnaires' disease in three patients who were isolated in the same sterile unit after allogeneic bone marrow transplantation. In all three cases the disease presented with dramatic pulmonary symptoms, and diagnosis was ascertained by direct immunofluorescence on bronchoalveolar fluids. None of the patients underwent seroconversion. This report draws attention to: (1) the fact that bacteriological filters do not ensure absolute security; (2) the need for frequent monitoring of the two factors governing legionella growth, water temperature and chlorination; and (3) the effectiveness of quinolones as a curative and prophylactic treatment of legionnaires' disease in transplanted patients avoiding pharmacological cyclosporin interaction.