Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial.

BACKGROUND: On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia. METHODS: Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918. FINDINGS: 408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0·56 [95% CI 0·46-0·69], p<0·0001); 87% were alive versus 83%, respectively (0·67 [0·48-0·92]; p=0·01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0·0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0·0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group. INTERPRETATION: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche.

A new LC/MS method for specific determination of human systemic exposure to bisphenol A, F and S through their metabolites: Application to cord blood samples.

Due to restriction of the use of BPA, several structural analogues such as BPS and BPF have been proposed for its replacement in many consumer products. This has increased the prevalence of BPS and BPF in urine from tested cohorts. However, these substitutes have similar endocrine disrupting properties to BPA, particularly on reproductive and metabolic functions, which suggests that fetal exposure to these analogues could be of concern for human health. Bisphenols (BPs) are mainly metabolized to glucuronides (BP-Gs), which are considered as inactive but provide a relevant marker of fetal exposure during pregnancy. In most instances, these metabolites are indirectly quantified after hydrolysis and measurement of the corresponding native BPs, which may lead to bias due to spurious BPs contamination during blood collection and/or analyses. We have developed a new method for direct quantification of BP-Gs, which has the advantage of not being affected by errors related to the presence of BPs. First, BP-Gs were extracted from plasma by anion exchange solid phase extraction. They were then labelled with dansyl chloride, using experimentally-optimized incubation conditions, after which the dansyl derivatives were injected into an on-line SPE-UHPLC/MS/MS system. The performance of the method, in terms of sensitivity, precision and accuracy, was evaluated in plasma over a concentration range of 0.05-5 ng/mL. The intra- and inter-day CV% precision were lower than 20% with accuracies ranging from 93% to 115%. The limit of quantification was set at 0.05 ng/mL. The method was then applied to measure BP-Gs in forty-four cord plasma samples. Although no BPF-G was found, BPA-G and BPS-G was determined in almost half of the cord plasma samples with concentration ranges nd-0.089 ng/mL and nd-0.586 ng/mL, respectively.

Dynamic organization of developing Purkinje cells revealed by transgene expression.

The cerebellum has many properties that make it a useful model for investigating neural development. Purkinje cells, the major output neurons of the cerebellar cortex, have drawn special attention because of the availability of biochemical markers and mutants that affect their development. The spatial expression of L7, a protein specific for Purkinje cells, and L7 beta Gal, a gene expressed in transgenic mice that was constructed from the L7 promoter and the marker beta-galactosidase, delineated bands of Purkinje cells that increased in number during early postnatal development. Expression of the transgene in adult reeler mutant mice, which show inverted cortical lamination, and in primary culture showed that the initial expression of L7 is intrinsic to Purkinje cells and does not depend on extracellular signals. This may reflect an underlying developmental map in cerebellum.

Prescription of drugs during pregnancy: a study using EFEMERIS, the new French database.

BACKGROUND: Because of the limited data concerning drug risks in pregnancy, health professionals are often deprived of relevant and sufficient information related to prescribing or dispensing during pregnancy. However, previous studies have emphasised the widespread French prescription of several drugs (sometimes "typically French") which have not been assessed in pregnant women. OBJECTIVES: The aim of the present study was to create the first French database of drugs prescribed and dispensed during pregnancy and the outcome of these pregnancies. METHODS: This feasibility study concerns pregnant women who gave birth to a baby between 1 July 2004 to 30 June 2005 in Haute-Garonne and who are registered in the French Health Insurance Service. Data sources include (1) the French Health Insurance Database (drugs prescribed during pregnancy), (2) the Mother and Child Protection Centre Database (newborn health at birth and 9 months after) and (3) the Antenatal Diagnostic Centre Database (medical pregnancy interruptions). RESULTS: The database is composed of 10,174 "mother-outcome" pairs. The prevalence rate of congenital anomalies was 2.2%. Pregnant women were prescribed 11.3 +/- 8.2 different drugs. Among the 20 most frequently prescribed drugs, around half of them have not been evaluated in pregnant women. CONCLUSIONS: The first results of this study show that implementation of a French database on prescription of drugs and pregnancy outcomes is feasible. Compared with several databases available in other countries, EFEMERIS provides exact data on period of exposure to drugs, pregnancy terminations, and follow up of the baby 9 months after birth. Recording these data would make it possible to assess the risk of malformations due to a greater number of drugs and would contribute to international drug evaluation studies.

Diagnosis of congenital toxoplasmosis: prenatal and neonatal evaluation of methods used in Toulouse University Hospital and incidence of congenital toxoplasmosis.

The aim of this study was to determine the incidence of congenital toxoplasmosis (CT) and to assess the performances of prenatal and neonatal diagnoses. From 1994-2005, in Toulouse University Hospital, France, amniocentesis was performed on 352 pregnant women who were infected during pregnancy. All women were treated with spiramycin and pyrimethamine-sulfadoxine when prenatal diagnosis was positive. Among the 275 foetuses with follow-up, 66 (24%) were infected. The transmission rates of Toxoplasma gondii were 7%, 24% and 59% in the first, second and third trimesters, respectively. The sensitivity and specificity of PCR on amniotic fluid (AF) were 91% and 99.5%, respectively. One case was diagnosed by mouse inoculation with AF and six cases were diagnosed by neonatal or postnatal screening. The sensitivity and specificity of PCR on placentas were 52% and 99%, respectively. The sensitivity of tests for the detection of specific IgA and IgM in cord blood was 53% and 64%, respectively, and specificity values were 91% and 92%. In conclusion, PCR performed on AF had the highest levels of sensitivity and specificity for the diagnosis of CT. This permits an early diagnosis of most cases and should be recommended.

Encoding of temporal features of auditory stimuli in the medial nucleus of the trapezoid body and superior paraolivary nucleus of the rat.

Neurons in the superior paraolivary nucleus (SPON) of the rat respond to the offset of pure tones with a brief burst of spikes. Medial nucleus of the trapezoid body (MNTB) neurons, which inhibit the SPON, produce a sustained pure tone response followed by an offset response characterized by a period of suppressed spontaneous activity. This MNTB offset response is duration dependent and critical to the formation of SPON offset spikes [Kadner A, Kulesza RJ Jr, Berrebi AS (2006) Neurons in the medial nucleus of the trapezoid body and superior paraolivary nucleus of the rat may play a role in sound duration coding. J Neurophysiol. 95:1499-1508; Kulesza RJ Jr, Kadner A, Berrebi AS (2007) Distinct roles for glycine and GABA in shaping the response properties of neurons in the superior paraolivary nucleus of the rat. J Neurophysiol 97:1610-1620]. Here we examine the temporal resolution of the rat's MNTB/SPON circuit by assessing its capability to i) detect gaps in tones, and ii) synchronize to sinusoidally amplitude modulated (SAM) tones. Gap detection was tested by presenting two identical pure tone markers interrupted by gaps ranging from 0 to 25 ms duration. SPON neurons responded to the offset of the leading marker even when the two markers were separated only by their ramps (i.e. a 0 ms gap); longer gap durations elicited progressively larger responses. MNTB neurons produced an offset response at gap durations of 2 ms or longer, with a subset of neurons responding to 0 ms gaps. SAM tone stimuli used the unit's characteristic frequency as a carrier, and modulation rates ranged from 40 to 1160 Hz. MNTB neurons synchronized to modulation rates up to approximately 1 kHz, whereas spiking of SPON neurons decreased sharply at modulation rates >or=400 Hz. Modulation transfer functions based on spike count were all-pass for MNTB neurons and low-pass for SPON neurons; the modulation transfer functions based on vector strength were low-pass for both nuclei, with a steeper cutoff for SPON neurons. Thus, the MNTB/SPON circuit encodes episodes of low stimulus energy, such as gaps in pure tones and troughs in amplitude modulated tones. The output of this circuit consists of brief SPON spiking episodes; their potential effects on the auditory midbrain and forebrain are discussed.

[Frequency, persistence and recurrence of HPV lesions of the uterine cervix in HIV-seropositive women]. / Fréquence, persistance et récidive des lésions à HPV du col utérin chez les patientes séropositives pour le VIH.

OBJECTIVE: The aim of this study was to determine the frequency, persistence and risk of recurrence of human papillomavirus (HPV) lesions of the uterine cervix in human immunodeficiency virus (HIV)-infected women. PATIENTS AND METHODS: To determine the frequency of such lesions, we compared 148 HIV-positive patients with 4862 HIV-negative patients who had a cervical smear test in Toulouse university hospital. To determine the persistence and recurrence rate of the lesions, we prospectively followed 63 of the HIV-positive patients. Their follow-up was compared with that of 227 of the HIV-negative patients. RESULTS: Abnormal smears were much more frequent in HIV-positive patients (42 versus 5%, P<0.001). Persistence or aggravation of the lesions was also greater in HIV-positive patients (82 versus 43%, P<0.001). Lastly, the recurrence rate of dysplastic lesions after treatment was significantly higher in HIV-positive patients (64 versus 11%, P<0.001). DISCUSSION AND CONCLUSION: As the frequency, persistence and risk of recurrence of cervical HPV lesions are very high in HIV-positive women, close gynecological surveillance of these patients is indispensable. Surveillance must not be restricted to the uterine cervix because of the frequency of multifocal lesions: vagina, vulva, perineum and anus. It must also be adapted to the severity of immunodeficiency and the patient's history.

Acute steroid myopathy: a highly overlooked entity.

BACKGROUND: Myopathy in patients being treated with corticosteroids is known primarily among chronically treated patients or in critically ill and mechanically ventilated patients receiving corticosteroids, often in high doses. AIM: To highlight the entity of acute, early onset corticosteroid-treatment-associated myopathy and its characteristics. DESIGN AND METHODS: Reporting our experience with four patients and reviewing all published reports of myopathy developing ≤14 days of initiating corticosteroid-treatment. RESULTS: Acute corticosteroid myopathy (ASM) exists, though the syndrome appears to be rare. It is characterized by unpredictability and heterogeneity, sometimes developing within 1-3 days, after a single dose, which may not be high and administered by varied routes. Proximal limb muscle weakness is the most common form, but distal limb, bulbar and respiratory muscles may be involved. Steroid cessation often leads to improvement/resolution, but irreversibility may occur. CONCLUSIONS: A high index of suspicion for the possibility of ASM is necessary to ensure drug discontinuation and recovery. This is particularly true since the entity is not widely recognized and its symptoms are often erroneously interpreted as due to the patient's underlying disease.

Parotid gland involvement, the presenting sign of high grade non-Hodgkin lymphoma in two patients with Gaucher disease and sicca syndrome.

Increased risk of haematological malignancies has been described in Gaucher disease patients; however, high-grade lymphoma has been rarely observed. We report two patients with Gaucher disease and sicca syndrome diagnosed with aggressive lymphoma involving the parotid gland. A 29-year-old woman with Gaucher disease developed tumour of the left parotid gland. She reported chronic arthralgias, xerostomia and xerophthalmia. Parotid gland biopsy disclosed diffuse large B-cell lymphoma. No lymphadenopathy was found. Bone biopsy revealed focal lymphomatous infiltration consistent with stage IV disease. MACOP-B chemotherapy regimen (cyclophosphamide, adriamycin, methotrexate, bleomycin, vincristine, prednisone) resulted in complete remission for 15 years. A 76-year-old patient with Gaucher disease suffered from dry-mouth feeling. He developed a left parotid gland tumour. CT scan disclosed diffuse lymphadenopathy, pleural effusion and multiple lung nodules. A cervical lymph node biopsy revealed mantle cell lymphoma. Fine-needle aspiration of the parotid gland showed lymphoma cells. Immunochemotherapy with fludarabine, cyclophosphamide and rituximab resulted in complete remission. Accumulation of the glucocerebroside in Gaucher disease activates macrophages, inducing release of pro-inflammatory cytokines which may be involved in the pathogenesis of second malignancy. Patients with Gaucher disease bear an increased risk of haematological malignancies; however, aggressive lymphoma has been described only occasionally. In both our patients the presenting sign of lymphoma was tumour of the parotid gland. The patients suffered from sicca syndrome, which increases risk for developing lymphoma. The underlying Gaucher disease and sicca syndrome might be implicated as immunological triggers for lymphoma occurrence and its propensity for the parotid gland in these patients.

[Transabdominal cervico-isthmic cerclage in the management of cervical incompetence in high risk women]. / Cerclage par voie abdominale pour la prise en charge des incompétences cervicales chez les femmes à haut risque.

OBJECTIVES: Transabdominal cervico-isthmic cerclage is an alternative to vaginal route for patients with severe cervical incompetence. The purpose of this study is to describe our experience with this technique during pregnancy for high risk women. MATERIALS AND METHODS: We performed a retrospective study including 12 transabdominal cerclages performed between 1988 and 2005. All patients had an history of repeated midtrimester fetal losses or preterm delivery, and 82% already had a prior failed transvaginal cerclage. Fourteen pregnancies were reported. RESULTS: The median gestational age at cerclage placement was 14 weeks (range: 12 to 17). All patients underwent a caesarean section at a mean gestational age of 35 weeks gestation (range: 23 to 38 WG). The fetal survival rate was 93 compared to 17% before the cerclage. There were no significant perioperative or neonatal complications. CONCLUSION: Transabdominal cervico-isthmic cerclage remains a reliable technique for the management of cervical incompetence after a prior failed transvaginal cerclage when vaginal access is difficult. Laparoscopic approach is under development.

Human decidual NK cells: unique phenotype and functional properties -- a review.

Human decidual NK cells are massively recruited at the site of embryonic implantation (decidua basalis). They differ in many ways from their peripheral blood NK cell counterparts in terms of gene expression, phenotype and functionality. The major subpopulation of decidual NK cells is CD56(bright) whereas the minor subset is CD56(dim), contrasting with the peripheral blood NK cells whose major subpopulation is CD56(dim). Decidual NK cell cytolytic function is much reduced despite the presence of several activating receptors and the essential machinery required for lysis. Decidual NK cells produce a number of cytokines that are not normally secreted by peripheral blood NK cells. Human decidual NK cell potential functions at the maternal-fetal interface are not yet clearly established but several hypotheses are being evaluated, including control of extravillous invasion, control of uterine vascular remodeling, and local anti-viral activity.

[Twin delivery: a survey of French obstetrical policies]. / Accouchement des grossesses gémellaires: enquête sur les politiques des maternités françaises.

OBJECTIVES: To describe obstetrical policy variations concerning the delivery management in the case of twins, at term. PATIENTS AND METHODS: A mail survey was undertaken among the medical supervisors of the maternity wards belonging to the AUDIPOG Network (N=170). RESULTS: The participating rate was 73.35%. 124 answers were analysed. Elective caesarean was realized by 0.8% of participants for diamniotic twins and by 57% of cases for monamniotic twins An elective caesarean is planned for respectively 74% of answers if first (J1) and second twin (J2) are in a breech presentation, 81% if J1 is in breech and J2 in cephalic presentation, and 68% if J1 is in breech and J2 in transverse presentation. Delivery with J1 in breech and J2 in cephalic presentation had a higher risk than a delivery of a single breech at term. When J1 and J2 had a breech presentation 73% of participants thought that this delivery is more difficult than a delivery of a single breech at term. However, they were only 17.5% to consider that a delivery of twin with J1 in cephalic and J2 in breech presentation had a higher risk than a single breech delivery. DISCUSSION AND CONCLUSION: Medical policy variations are not extensive except for X-ray pelvimetry and the presence for the delivery of one paediatrician and one anaesthesiologist. An elective caesarean policy for twins is infrequent in France.

Autologous T cells control B-chronic lymphocytic leukemia tumor progression in human-->mouse radiation chimera.

B-chronic lymphocytic leukemia (B-CLL) is characterized by the clonal accumulation of CD5+ B cells. It has been suggested that CLL cells may be regulated by inhibitory and growth-promoting signals exerted by autologous T cells. We have recently described a model for human B-CLL in which peripheral blood mononuclear cells (PBMCs) are transplanted into the peritoneal cavity of lethally irradiated mice radioprotected with bone marrow from mice with severe combined immunodeficiency. In this model, adoptive transfer of low-stage PBMCs leads to marked engraftment of T cells or combined T and CLL cell engraftment, whereas infusion of high-stage PBMCs leads to dominance of CLL cells with a miniscule level of T-cell engraftment. This mutual exclusive pattern of engraftment indicated that T cells might control the expansion of tumor cells in the peritoneum of recipient BALB/c mice. In the present study, we further investigated this question and we demonstrate that in vivo T-cell depletion, using OKT3 antibody, markedly enhances the engraftment of B-CLL cells from patients with early-stage disease. In mice receiving PBMCs from 11 donors with advanced-stage disease, the results were more heterogeneous. In five patients the results were similar to those observed in early stage, whereas in two cases no CLL cell engraftment was found in the absence of T cells. The addition of purified T cells to PBMCs led to a substantial decrease of CLL engraftment in three advanced-stage cases. These results strengthen the working hypothesis that autologous T cells can actively suppress the expansion of the pathological cells in human-->mouse radiation chimera. This effect is prominent in early-stage disease, whereas in advanced stage suppressive and/or stimulatory effects may occur in different patients. The interaction of T cells with tumor cells and the potential of autologous T cell/immune-therapy in CLL can be further explored in this model.

[Is rapid intrapartum vaginal screening test of group B streptococci (GBS) during partum useful in identifying infants developing early-onset GBS sepsis in postpartum period?]. / Test de dépistage rapide intra partum du portage vaginal de streptocoque du groupe B (SGB) pour le repérage des nouveau-nés à risque d'infection néonatale précoce à SGB. Étude observationnelle analytique dans une maternité de type III.

INTRODUCTION: Group B streptococcus (GBS) is the most common infectious agent responsible for early-onset bacterial sepsis (EOS) in term newborns. French prevention of perinatal GBS disease guidelines recommend screening for maternal vaginal GBS colonization at the 9th month of pregnancy, and use of intrapartum antibiotic prophylaxis (IAP) in case of detected GBS vaginal colonization. Peripheral bacterial sampling (gastric aspiration, ear, or meconium) and measurement of C-reactive protein (CRP) are performed in asymptomatic newborns in case of infectious risk factors and/or incomplete IAP. OBJECTIVE: The aim of this study was to investigate the relation between a rapid intrapartum screening test for GBS during labor in term parturients and infants developing GBS EOS and in comparison to current recommendations. METHODS: We conducted an observational analytic single-center study, with use of a rapid intrapartum GBS screening test, at Toulouse University Hospital. RESULTS: A total of 1416 mother-newborn dyads were prospectively included between 31/01/2012 and 17/08/2012. Vaginal GBS colonization was found at the 9th month of pregnancy in 148 mothers (10.6 %), and 176 mothers (12.5 %) were screened positively at delivery using intrapartum GBS rapid polymerase chain reaction assay (GBS PCR) (P=0.025). No confirmed neonatal GBS EOS was found. Nine infants had suspected GBS EOS because of a positive peripheral bacterial finding and elevated CRP. In these infants, seven pregnant mothers were GBS-positive with GBS PCR assay during labor, and four women were positive on prenatal culture at the 9th month of pregnancy. The diagnostic values of the two tests highlighted a nonsignificant superiority of intrapartum GBS PCR assay (AUC=0.83 [0.68-0.97] vs. 0.67 [0.50-0.84]), (P=0.057). The negative predictive value was improved with intrapartum PCR assay (negative likelihood ratio [LR]: 0.3 [0.1-0.9] vs. 0.6 [0.4-1.1]). Intrapartum GBS PCR assay provided its best positive predictive value in the absence of complete AIP and without other infectious factors (positive LR: 21.3 [15.4-29.5]). CONCLUSION: These results suggest that the intrapartum GBS PCR assay offers a better predictive value of GBS EOS than the usual vaginal culture swab at the 9th month but requires confirmation by large studies.

Characterization of an alternatively spliced AATYK mRNA: expression pattern of AATYK in the brain and neuronal cells.

The AATYK gene encodes a tyrosine kinase whose expression is up-regulated during the apoptosis and differentiation of 32Dcl3 myeloblastic cells. Because high levels of AATYK mRNA have also been detected in the brain, and because these transcripts differ in size from that observed in the 32Dcl3 cell line, it was of interest to determine whether this gene encodes mRNAs that are alternatively spliced and whether these mRNAs are expressed in a tissue-specific manner. We have isolated a novel, alternatively spliced AATYK mRNA using cDNA library screening and RT-PCR, whose expression is readily detected in the brain but not myeloid cells. Western blot analysis revealed that the AATYK protein was expressed in virtually all regions of the adult rat brain in which neurons are present, including olfactory bulb, forebrain, cortex, midbrain, cerebellum and pons. Immunohistochemical labeling of adult brain sections showed the highest levels of AATYK expression in the cerebellum and olfactory bulb. Expression of AATYK was also up-regulated as a function of RA-induced neuronal differentiation of p19 embryonal carcinoma cells, supporting a role for this protein in mature neurons and neuronal differentiation.

Long-term (29 years) results of reconstructive surgery in rheumatic mitral valve insufficiency.

BACKGROUND: Results of conservative surgery are well established in degenerative mitral valve (MV) insufficiency. However, there are controversies in rheumatic disease. This study is the evaluation of one center for rheumatic MV insufficiency based on a functional approach. METHODS AND RESULTS: From 1970 to 1994, 951 patients with rheumatic MV insufficiency were operated on with the reconstructive techniques elaborated by Alain Carpentier. Aortic valve diseases were excluded. Mean age was 25.8 years (4 to 75), and sinus rhythm was present in 63%. The functional classification used was type I, normal leaflet motion, 71 patients (7%); type II, prolapsed leaflet, 311 patients (33%); and type III, restricted leaflet motion, 345 patients (36%). The combined lesion of prolapse of the anterior leaflet and restriction of the posterior was present in 224 patients (24%). Surgical techniques used were implantation of a prosthetic ring in 95%, shortening of the chords and leaflet enlargement with autologous pericardium, and commissurotomy. Hospital mortality rate was 2%. The mean follow-up was 12 years (maximum, 29 years): 8618 patients per year. Actuarial survival was 89+/-19% at 10 years and 82+/-18% at 20 years. The rate of thromboembolic events was 0.4% patients per year (33 events), with 3 deaths. Freedom from reoperation was 82+/-19% at 10 years and 55+/-25% at 20 years. The main cause (83%) of reoperation was progressive fibrosis of the MV. The actuarial rate of reoperation was 2% patients per year and was correlated to the degree of preoperative fibrosis. CONCLUSIONS: Conservative surgery of rheumatic MV insufficiency has a low hospital mortality rate and an acceptable rate of reoperation. The results are excellent regarding the minimal risk of thromboembolic events.

Very long-term results (more than 20 years) of valve repair with carpentier's techniques in nonrheumatic mitral valve insufficiency.

BACKGROUND: Mitral valve repair is considered the gold standard in surgery of degenerative mitral valve insufficiency (MVI), but the long-term results (>20 years) are unknown. METHODS AND RESULTS: We reviewed the first 162 consecutive patients who underwent mitral valve repair between 1970 and 1984 for MVI due to nonrheumatic disease. The cause of MVI was degenerative in 146 patients (90%) and bacterial endocarditis in 16 patients (10%). MVI was isolated or, in 18 cases, associated with tricuspid insufficiency. The mean age of the 162 patients (104 men and 58 women) was 56+/-10 years (age range 22 to 77 years). New York Heart Association functional class was I, II, III, and IV in 2%, 39%, 52%, and 7% of patients, respectively. The mean cardiothoracic ratio was 0.58+/-0.07 (0.4 to 0.8), and 72 (45%) patients had atrial fibrillation. Valve analysis showed that the main mechanism of MVI was type II Carpentier's functional classification in 152 patients. The leaflet prolapse involved the posterior leaflet in 93 patients, the anterior leaflet in 28 patients, and both leaflets in 31 patients. Surgical technique included a Carpentier's ring annuloplasty in all cases, a valve resection in 126 patients, and shortening or transposition of chordae in 49 patients. During the first postoperative month, there were 3 deaths (1.9%) and 3 reoperations (2 valve replacements and 1 repeat repair [1.9%]). Six patients were lost to follow-up. The remaining 151 patients with mitral valve repair were followed during a median of 17 years (range 1 to 29 years; 2273 patient-years). The 20-year Kaplan-Meier survival rate was 48% (95% CI 40% to 57%), which is similar to the survival rate for a normal population with the same age structure. The 20-year rates were 19.3% (95% CI 11% to 27%) for cardiac death and 26% (95% CI 17% to 35%) for cardiac morbidity/mortality (including death from a cardiac cause, stroke, and reoperation). During the 20 years of follow-up, 7 patients were underwent surgery at 3, 7, 7, 8, 8, 10, or 12 years after the initial operation. Valve replacement was carried out in 5 patients, and repeat repair was carried out in 2 patients. At the end of the study, 65 patients remained alive (median follow-up 19 years). Their median age was 76 years (age range 41 to 95 years). All except 1 were in New York Heart Association functional class I/II. CONCLUSIONS: Mitral valve repair using Carpentier's technique in patients with nonrheumatic MVI provides excellent long-term results with a mortality rate similar to that of the general population and a very low incidence of reoperation.

Epidemiology and ethnic aspects of B cell chronic lymphocytic leukemia in Israel.

Chronic lymphocytic leukemia (CLL) represents 30% of all leukemias in Caucasians. In East Europe and USA the disease incidence is high while in Asia and Africa CLL is rare. The present study deals with 302 cases of B cell CLL and related disorders; 207 patients originating from Europe and America (Ashkenazi Jews) and 95 descendants from Asia, The Mediterranean or Africa (Sephardic Jews). The patients were recruited during 1975-1996 in a single center covering the Hashfela region -- a Southern area of Israel with a current population of 430000 inhabitants. Incidence of the disease, clinical pattern, biological parameters, prognosis and outcome were investigated and compared in both ethnic groups. The results of this study show a high incidence of CLL in Israel. The mean annual age-adjusted incidence 4.3 per 100000 person-year is among the highest reported values. Our study confirms previous data on the prevalence of CLL in Ashkenazi compared to Sephardic Jews. The rise in CLL rate in the reviewed period occurred in both populations, mainly in the Sephardic group. The relative risk for Ashkenazies compared to Sephardics decreased from 6.0 in the 1975-1979 period to 2.4 in 1990-1996. A high rate of CLL was found in new immigrants from the former USSR with 26 cases de novo diagnosed and 11 prevalent cases not included in this series among approximately 60000 new immigrants in the ara over the last 8 years. No differences were found in clinical, laboratory and immunological parameters at the time of diagnosis in the two ethnic groups. The follow-up showed a similar pattern in the disease evolution. A preliminary study of immunoglobulin heavy chain rearrangement performed in 14 patients showed no significant differences in JH hybridization in the early stages of the disease, but more aberrations in advanced CLL in the Ashkenazi group. Our findings suggest that ethnic origin of the patients itself does not affect the biological and clinical behavior of this disease.

Grb7 expression and cellular migration in chronic lymphocytic leukemia: a comparative study of early and advanced stage disease.

Grb7, a noncatalytic intracellular adaptor protein involved in cell migration, is overexpressed in certain invasive and metastatic solid tumors. We found a highly significant difference in the level of expression of Grb7 between chronic lymphocytic leukemia (CLL) cells obtained from stage I and stage IV patients (P<0.001). Using semiquantitative RT-PCR, we detected high levels of Grb7 in 88% of stage IV patients vs only 18% in stage I patients. A corresponding increase was found in the in vitro migration of stage IV CLL cells in comparison to stage I cells. The statistically significant difference in the expression of Grb7 between stage IV and stage I patients was preserved even when tested specifically in the ZAP70-positive group (P<0.01). These findings show that Grb7 levels reflect the severity of the disease, and may be used, in conjunction with ZAP70, to predict disease progression.

Verapamil inhibits B-cell proliferation and tumor necrosis factor release and induces a clinical response in B-cell chronic lymphocytic leukemia.

Four B-CLL patients, treated with verapamil for cardiac problems, showed substantial reduction of lymphadenopathy in one, a 3- and 5-year stabilization of B-CLL in two patients, and a dramatic decrease in lymphocyte count, lymphadenopathy and splenomegaly in one stage IV patient. We therefore studied the effects of verapamil on B-CLL cells in vitro. In 13 samples we observed that verapamil strongly inhibited in vitro proliferation of pokeweed mitogen (PWM) stimulated and unstimulated cells. Using a cytotoxic bioassay, we found that verapamil markedly inhibited the spontaneous and PMW-induced release of tumor necrosis factor (TNF) by B-CLL cells. These findings suggest that verapamil may block B-CLL cell proliferation through inhibition of TNF release and thereby may contribute to the management of B-CLL.