Further characterization of morphologically defined typical and atypical CLL: a clinical, immunophenotypic, cytogenetic and prognostic study on 390 cases

We analysed a group of 390 patients, diagnosed with chronic lymphocytic leukaemia (CLL). Cases were subclassified as morphologically typical and atypical CLL according to the criteria of the FAB proposal. Typical CLL cases were mostly diagnosed at a low-risk stage (Binet A/Rai 0), required no immediate treatment and expected a long survival; atypical CLL cases mostly presented at a more advanced risk stage (Binet B/Rai I–II), usually required immediate treatment and their survival was shorter. Moreover, clinical staging was of prognostic significance in typical but not in atypical cases.   In typical CLL, del(11q) was the most common chromosomal abnormality (21%) whereas in atypical CLL trisomy 12 was found in about 65% of the cases documented with an abnormal karyotype. Although chromosomal abnormalities were associated with a poor survival in typical CLL, they are of no prognostic significance in atypical CLL.   Based on these data, we conclude that subtyping CLL by morphology enables the identification of two groups of cases, each characterized by a specific clinical presentation, different cytogenetic abnormalities and prognostic parameters. We speculate that these two groups may represent two related, but different, diseases with different prognostic parameters and a different survival.     

Long-term carriage, and transmission of methicillin-resistant Staphylococcus aureus after discharge from hospital.

The purpose of this study was to determine whether patients who become carriers of methicillin-resistant Staphylococcus aureus (MRSA) during their stay in hospital, remain colonized after discharge. Thirty-six patients colonized with MRSA during one of three outbreaks at Utrecht University Hospital (1986-89) were screened 2 or 3 years after they had become carriers. Patients were also interviewed to determine factors contributing to persistent carriage, such as antibiotics, re-admissions to the hospital, presence of skin lesions and chronic diseases. At the same time transmission of MRSA to family members was determined. The epidemic MRSA strain was still found in three patients (8%). One was a cystic fibrosis patient who had had frequent re-admissions to the hospital and had received several course of antibiotic treatment. Both of the other patients had skin lesions: a fistula and a colostomy respectively. None of the 44 family members of the patients was colonized or infected with MRSA. We conclude that long-term MRSA carriage occurs with low frequency and is comparable to persistent carriage of methicillin-sensitive Staphylococcus aureus (MSSA). Transmission of MRSA to healthy individuals in an antibiotic-free environment is a rare event.     

Safety aspects of non-ionic surfactant vesicles: a toxicity study related to the physicochemical characteristics of non-ionic surfactants.

Two different toxicity models were used to assess the relationship between the physicochemical properties of non-ionic surfactant vesicles (NSVs), and the safety of these vesicles for topical drug administration. The vesicles used in this study consisted of polyoxyethylene alkyl ethers (CnEOm) in which the number of C atoms (n) varied between 12 and 18 and the number of oxyethylene units (m) between 3 and 7. The physicochemical properties of the vesicles are described in terms of hydrophilic-lipophilic balance (HLB) values, and critical micelle concentrations (CMC), and the rigidity of the bilayers as determined by the gel-liquid transition temperatures and the cholesterol content of the bilayers. The first toxicity model, comprising the measurement of the ciliary beat frequency, is a tool to assess the safety of intranasally applied formulations. Studies using this ciliotoxicity model revealed that by increasing the length of the alkyl chain of the surfactant, a decrease in toxicity was observed. The opposite correlation was found if the length of the polyoxyethylene headgroup was increased. Furthermore, it was observed that gel-state vesicles produce less of an effect on the ciliary beat frequency than liquid state vesicles. The second toxicity model, comprising the determination of cell proliferation of human keratinocytes, is a method to assess skin irritancy. In contrast to the ciliotoxicity model the length of the polyoxyethylene headgroup and of the alkyl chains did not seem to have an effect on the safety of the vesicles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Individual chaperones required for Yop secretion by Yersinia.

Pathogenic yersiniae secrete anti-host proteins called Yops, by a recently discovered Sec-independent pathway. The Yops do not have a classical signal peptide at their N terminus and they are not processed during membrane translocation. The secretion domain is nevertheless contained in their N-terminal part but these domains do not resemble each other in the different Yops. We have previously shown that YopE secretion requires SycE, a 15-kDa acidic protein acting as a specific cytosolic chaperone. Here we show that the gene downstream from yopH encodes a 16-kDa acidic protein that binds to hybrid proteins made of the N-terminal part of YopH and either the bacterial alkaline phosphatase or the cholera toxin B subunit. Loss of this protein by mutagenesis led to accumulation of YopH in the cytoplasm and to a severe and selective reduction of YopH secretion. This protein thus behaves like the counterpart of SycE and we called it SycH. We also engineered a mutation in lcrH, the gene upstream from yopB and yopD, known to encode a 19-kDa acidic protein. Although this mutation was nonpolar, the mutant no longer secreted YopB and YopD. The product of lcrH could be immunoprecipitated together with cytoplasmic YopD. lcrH therefore seems to encode a YopD-specific chaperone, which we called SycD. Determination of the dependence of YopB on SycD requires further investigation. SycE, SycH, and SycD appear to be members of a new family of cytosolic chaperones required for Yop secretion.     

Walking exercise in patients with intermittent claudication. Experience in routine clinical practice.

BACKGROUND: In patients with intermittent claudication, exercise in the form of walking is effective in reducing pain and maximising achievable walking distance. However, data are lacking on the implementation of walking exercise in these patients. AIMS: To explore the current behaviour and views of patients with intermittent claudication towards taking walking exercise. DESIGN OF STUDY: Postal questionnaire and focus group meetings. SETTING: Two academic general practice networks (Utrecht and Maastricht Universities) in The Netherlands. METHOD: Three hundred and seventy-five patients with intermittent claudication, selected from the files of general practitioners participating in two academic general practice networks, were sent a postal questionnaire; 216 (58%) were returned. Nine of these responders also attended a focus group meeting. RESULTS: Seventy per cent (151/216) of the patients reported having received advice about walking exercise. If specified, the advice given most often recommended walking in the local neighbourhood (56%, 84/151). Fifty-two per cent (113/216) of all patients actually performed walking exercise and only 32%of them received any kind of supervision. Among the barriers for taking walking exercise, 'comorbidity', 'lack of (specific) advice' and 'lack of supervision' were often mentioned. Among the stimuli to start and continue walking, 'following the doctor's advice', 'relief of complaints' and 'a better general condition' were often mentioned by patients. CONCLUSIONS: Walking exercise was not carried out by almost half of patients with intermittent claudication in this study. Lack of specific advice and supervision were found to be important barriers to taking walking exercise.     

The presence of an HLA-identical sibling donor has no impact on outcome of patients with high-risk MDS or secondary AML (sAML) treated with intensive chemotherapy followed by transplantation: results of a prospective study of the EORTC, EBMT, SAKK and GIMEMA Leukemia Groups (EORTC study 06921).

This report used the framework of a large European study to investigate the outcome of patients with and without an HLA-identical sibling donor on an intention-to-treat basis. After a common remission-induction and consolidation course, patients with an HLA-identical sibling donor were scheduled for allogeneic transplantation and patients lacking a donor for autologous transplantation. In all, 159 patients alive at 8 weeks from the start of treatment were included in the present analysis. In total, 52 patients had a donor, 65 patients did not have a donor and in 42 patients the availability of a donor was not assessed. Out of 52 patients, 36 (69%) with a donor underwent allogeneic transplantation (28 in CR1). Out of 65 patients, 33 (49%) received an autograft (27 in CR1). The actuarial survival rates at 4 years were 33.3% (s.e. = 6.7%) for patients with a donor and 39.0% (s.e. = 6.5%) for patients without a donor (P = 0.18). Event-free survival rates were 23.1% (s.e. = 6.2%) and 21.5% (s.e. = 5.3%), respectively (P = 0.66). Correction for alternative donor transplants did not substantially alter the survival of the group without a donor. Also, the survival in the various cytogenetic risk groups was not significantly different when comparing the donor vs the no-donor group. This analysis shows that patients with high-risk myelodysplastic syndrome and secondary acute myeloid leukemia may benefit from both allogeneic and autologous transplantation. We were unable to demonstrate a survival advantage for patients with a donor compared to patients without a donor.     

Specific antibody responses to three schistosome-related carbohydrate structures in recently exposed immigrants and established residents in an area of Schistosoma mansoni endemicity

By the use of surface plasmon resonance spectroscopy, immunoglobulin G (IgG) subclass and IgM antibodies against three schistosome-derived carbohydrate structures, FLDN (Fucalpha1-3GalNAcbeta1-4GlcNAcbeta1-3Galalpha1), LDN-DF [GalNAcbeta1-4(Fucalpha1-2Fucalpha1-3)GlcNAcbeta1], and LDNF [GalNAcbeta1-4(Fucalpha1-3)GlcNAcbeta1-3Galalpha1], were measured in 184 previously unexposed Kenyan immigrants who moved into the Masongaleni area, where Schistosoma mansoni is endemic. They were sampled within their first year of exposure and again 2 years later. A cohort selected out of the original residents of the area, who had been exposed for many years, served as controls. Associations with responses to S. mansoni worm, egg (SEA), and cercarial (CERC) antigens were examined. In addition, we measured responses to keyhole limpet hemocyanin, a glycoprotein which carries glycan epitopes that are also expressed by schistosomes. Specific IgG1 responses were most pronounced against FLDN and LDN-DF and strongly associated with those previously measured to SEA and CERC. Similarly to previously published age profiles of IgG1 and IgG2 responses to SEA, levels of IgG1 against LDN-DF decreased with age. In contrast, specific IgM responses against the three schistosome-derived carbohydrate structures were most marked against LDNF. Our results indicate that, of the three glycan structures tested, the acute response against schistosome glycoconjugate antigens in young children is mainly directed against the LDN-DF epitope. The response to LDN-DF in older individuals and the responses to the two other epitopes were similar in the two cohorts, suggesting that these antigens are recognized in the early stages of infection and that the immune response persists. The biological significance of these observations needs further elucidation.