[Digital necrosis revealing lung cancer: Case-report and review of the literature]. / Nécroses des orteils révélant un cancer bronchique : cas clinique et revue de la littérature.

We report the case of a 51-year-old patient who presented necrosis affecting all of the toes in a context of confusion and declining general health. The etiology work-up disclosed a lung mass. Biopsy and search for extension led to the diagnosis of adenocarcinoma with liver metastasis. Unfortunately, symptomatic treatment of the digital necrosis did not lead to improvement and the patient was given palliative care. Digital necrosis generally affects the fingers. Localization on the toes is atypical and few cases have been reported in the literature.

Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease.

We sought to identify the molecular basis of the autosomal dominant form of Kufs disease, an adult onset form of neuronal ceroid lipofuscinosis. We used a combination of classic linkage analysis and Next Generation Sequencing to map and identify mutations in DNAJC5 in a total of three families. We analyzed the clinical manifestations in 20 individuals with mutation in DNAJC5. We report here the mapping and the identification of a p.L116del mutation in DNAJC5 segregating with the disease in two distinct American families, as well as a p.L115R mutation in an additional family. The age of onset and clinical manifestations were very homogeneous among mutation positive individuals, including generalized tonic-clonic seizures, myoclonus, ataxia, speech deterioration, dementia, and premature death. A few individuals also exhibited parkinsonism. DNAJC5, which encodes the cysteine string protein (CSPα), a presynaptic protein implicated in neurodegeneration, causes autosomal dominant Kufs disease. The leucine residues at positions 115 and 116 are hotspots for mutations and result in a homogeneous phenotype of progressive myoclonus epilepsy with onset around 30 years old.

Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 mutations.

OBJECTIVE: Two unrelated families were ascertained in which sisters had infantile onset of epilepsy and developmental delay. Mutations in the protocadherin 19 (PCDH19) gene cause epilepsy and mental retardation limited to females (EFMR). Despite both sister pairs having a PCDH19 mutation, neither parent in each family was a heterozygous carrier of the mutation. The possibility of parental mosaicism of PCDH19 mutations was investigated. METHODS: Genomic DNA from peripheral blood was obtained and sequenced for PCDH19 mutations. Parentage was confirmed by markers. RESULTS: Both sister pairs have a mutation in PCDH19. Sister pair 1 has a missense mutation, c.74T>C, L25P, while sequence analysis indicates both of their parents are negative for the mutation. Diagnostic restriction enzyme analysis detected low-level mosaicism of the mutation in their mother. Sister pair 2 are half-sisters who share a mother and each has the missense PCDH19 mutation c.1019 A>G, N340S. The sequence chromatograph of their mother shows reduced signal for the same mutation. These data indicate maternal somatic and gonadal mosaicism of the PCDH19 mutation in both sister pairs. Phenotyping is suggestive of, and PCDH19 mutation detection is diagnostic for, the disorder EFMR in the affected girls. CONCLUSIONS: We show that gonadal mosaicism of a PCDH19 mutation in a parent is an important molecular mechanism associated with the inheritance of EFMR. This should be considered when providing genetic counseling for couples who have one affected daughter as they may risk recurrence of affected daughters and having sons at risk of transmitting EFMR.

Leflunomide in rheumatoid arthritis in daily practice: treatment discontinuation rates in comparison with other DMARDs.

OBJECTIVE: To evaluate the treatment discontinuation rate of leflunomide in rheumatoid arthritis (RA) in comparison with the discontinuation of other disease modifying anti-rheumatic drugs (DMARDs), in daily practice, in a single center and during the same period of time. STUDY DESIGN: 3-year, retrospective, monocenter. PATIENTS: RA patients for whom leflunomide or another DMARD was initiated between 1998 and 2001 (several DMARDs could be initiated for a given patient during this period). Collected data: For each patient, demographic and disease data. For each treatment course, date of initiation, if relevant date of discontinuation and reason for discontinuation. ANALYSIS: Percentage of patients discontinuing treatment over time (life table method; Kaplan-Meier), comparison between leflunomide and the "any other DMARD" or methotrexate groups using the Log-Rank test. RESULTS: During the study period, 515 DMARDs were initiated in 285 patients. Leflunomide was initiated in 161 patients who were older and had a longer disease duration than the other treated patients (59 +/- 13 years and 14 +/- 9 years versus 54 +/- 15 years and 11 +/- 10 years in the leflunomide group and other DMARDs group respectively). Discontinuation rate of leflunomide after 1 year was 56.7%, mainly because of adverse drug reactions (41.6%). The discontinuation rate whatever the reason and for toxicity was higher for leflunomide than for other DMARDs studied. However discontinuation for inefficacy was similar in both groups. CONCLUSION: This study conducted in conditions of daily practice when leflunomide was first available suggests a higher discontinuation rate of leflunomide because of adverse events when compared to other DMARDs.

Positional cloning of a cyromazine resistance gene in Drosophila melanogaster.

Cyromazine is an effective insecticide used to control dipteran insects. Its precise mode of action is yet to be determined, although it has been suggested that it interferes with the hormone system, sclerotization of the cuticle, or nucleic acid metabolism. To understand the way in which cyromazine acts, we have positionally cloned a cyromazine resistance gene from Drosophila melanogaster. Six cyromazine resistance alleles had previously been generated by ethyl methanasulphonate treatment. Two of these failed to complement each other and here we identify them as having independent non-sense mutations in CG32743, which is an ortholog of Smg1 of worms and mammals and encodes a phosphatidylinositol kinase-like kinase (PIKK). RNAi experiments confirm that cyromazine resistance can be achieved by knocking down CG32743. These are the first cyromazine resistant mutations identified at the nucleotide level. In mammals Smg1 phosphorylates P53 in response to DNA damage. This finding supports the hypothesis that cyromazine interferes with nucleic acid metabolism.

Should pancreas imaging be recommanded in patients over 50 years when diabetes is discovered because of acute symptoms?

The relationship between diabetes mellitus and cancer of the pancreas is complex and incompletely understood. Nevertheless, it is generally agreed that new-onset diabetes in a patient over 50 Years old is a classical indication of pancreatic cancer. But there is no official directive in France that a scan should routinely be performed in such cases. We have studied 115 patients aged over 50 who were hospitalized for new-onset diabetes (fewer than 30 days) whose instability required insulin treatment. Routine imaging revealed abdominal disorders in 14 patients, 6 (5.2%) of whom were suffering from pancreatic adenocarcinomas. No clinical indication or laboratory test, apart from an unusually severe anorexia, suggested the discovered disorders. We therefore routinely carry out a pancreas scan, preferably by MRI, on all patients over 50 Years old presenting with new-onset diabetes, even if there are not clinical or laboratory indications of cancer. This is the only way in which small pancreatic cancers can be detected, thus providing the best hopes for successful treatment. Unfortunately, too often, this approach also detects only tumors that are already well developed. However, nowadays, it is not conceivable for a clinical team to discharge a patient from hospital with such a serious disease undiagnosed.

Home blood pressure monitoring in diabetic population.

Normalization of blood pressure is today as necessary as an optimal blood glucose control. These targets aim at reducing the negative consequences of hypertension which is particularly frequent and of poor prognosis for these patients. Nevertheless, the definition of the real blood pressure of these patients is uneasy because of the lack of precision of clinical blood pressure measurement. New methods have been developed to address this insufficiency. Home blood pressure monitoring is characterised by good compliance and accuracy, but patient education needs a special training and validated automated devices. This method has to be proposed to the diabetic population as soon as hypertension may be a problem. These patients will contribute to monitor their own blood pressure as they do it with blood glucose control.

[Extreme obesity in Prader-Willi Syndrome (PWS)]. / Obésité extrême au cours d'un syndrome de Willi-Prader.

INTRODUCTION: Prader-Willi Syndrome (PWS) belong to genetic obesities and we report a caricatural observation. DEVELOPMENT: The early onset of (PWS) is characterised by a severe neonatal hypotonia with poor suck reflex--which may lead to tube feeding--and poor weight gain. Later appears insatiable appetite, morbid obesity associated with short stature, dysmorphic syndrome with small hands and behavioural disorders. Although diagnosis is based on clinical features, it must be confirmed by genetic test looking for the characteristic deletion of the chromosome 15q11-q13 region. PWS is the first example in humans of genetic imprinting. CONCLUSION: Today, the challenge in PWS is it early management which may authorise Growth Hormone administration.

[Direct determination or estimated value of plasma ionized calcium : indications and limits]. / Dosage direct du calcium ionisé plasmatique ou estimation par calcul: intérêts et limites.

Calcium plays a fundamental role in many essential for life functions. Ionized calcium (Ca(++) ) represents free fraction and 50% of the total calcium in the plasma is accepted as its physiologically active form. On almost all laboratories, only total calcium is routinely measured, and ionized calcium concentration is calculated based on calcium, protein or albumin concentrations for many plasma sample or with others parameters like pH. Since 1935, the literature was abounted with "correction" formulae of varying degree of sophistication. Many laboratories routinely use correction formulae to either calculate an "adjusted" or "corrected" total calcium, or "ionized" fraction is calculated,but these determinations lack of accuracy or precision. Errors associated with the measurement of the other variables contribuate to the difficulty in producing a useful correction formulae. Direct measurement of ionized calcium by potentiometry is the method of choice for this assay. Improvements in ion selective electrodes (ISE) technology make possible the routine clinical measurement of Ca(++). However this technology implies several obligations for its use, particulary in blood ampling, storage and transport. In this review, characteristics of different available analysers are described. We think that Ca(++) should be systematically performed and not calculated in pathological situations where an possible alteration of the calcium metabolism is found especially in multiple myeloma in which paraprotein may bind calcium.

[Hip arthroplasty in genetic hemochromatosis. Report of 5 cases]. / L'atteinte coxofémorale dans l'hémochromatose génétique. A propos de cinq observations.

INTRODUCTION: Half of the patients with genetic hemochromatosis will have arthritis. Two of these articular involvements are well-known: the arthropathy involving the phalangeal and the metacarpophalangeal joints of the hand, useful for diagnosis, and hip arthropathy. Iron deposits seem to be involved in articular cartilage destruction. EXEGESIS: We report five cases of patients with hemochromatosis hip involvement. Hip arthropathy revealed hemochromatosis in one case and appeared despite efficient phlebotomies in another case. Three of these patients required hip arthroplasty. CONCLUSION: Hip arthropathy remains a frequent but unknown event in genetic hemochromatosis (12.5%) and it involves the functional prognosis.

Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and gamma-irradiation.

Integrin-mediated cellular adhesion to extracellular matrix (ECM) components is an important determinant of chemotherapeutic response of human myeloma cells. Here, we demonstrate that when K562 chronic myelogenous leukemia (CML) cells are adhered to fibronectin (FN), they become resistant to apoptosis induced by the BCR/ABL inhibitors AG957 and STI-571, as well as DNA damaging agents and gamma-irradiation. This phenomenon, termed cell adhesion-mediated drug resistance (CAM-DR), was induced by adhesion through the alpha5beta1 (VLA-5) integrin. Phosphotyrosine analysis demonstrates that anti-apoptotic signaling through integrins in K562 cells is independent of the tyrosine kinases activated by BCR/ABL, with the possible exception of an unknown 80 kDa protein. Cytoprotection of FN-adhered CML cells indicates that tumor-ECM interactions may be critical for the emergence of drug-resistant tumor populations and treatment failure in this disease. Antagonists of beta1 integrin-mediated adhesion or corresponding signal transduction elements may sensitize CML cells to chemotherapy and prevent resistance to the novel BCR/ABL kinase inhibitors being used for the treatment of this disease.

CLAN, a novel human CED-4-like gene.

Proteins governing cell death form the basis of many normal processes and contribute to the pathogenesis of many diseases when dysregulated. Here we report the cloning of a novel human CED-4-like gene, CLAN, and several of its alternatively spliced isoforms. These caspase-associated recruitment domain (CARD)-containing proteins are expressed at varying degrees in normal human tissues and may contribute to a number of intracellular processes including apoptosis, cytokine processing, and NF-kappa B activation. The CARD of the CLAN proteins binds a number of other CARD-containing proteins including caspase-1, BCL10, NOD2, and NAC. Once their physiologic functions are uncovered, CLAN proteins may prove to be valuable therapeutic targets.

Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR).

The tumor cell environment may influence drug response through interactions with the extracellular matrix (ECM). We recently reported that adhesion of myeloma cells to fibronectin (FN) via beta1 integrins is associated with a cell adhesion mediated drug resistance (CAM-DR). Activation of beta1 integrins is known to influence both apoptosis and cell growth. We hypothesized that the FN mediated cytoprotection may be in part due to perturbations in cell cycle progression. In this report we demonstrate that adhesion of myeloma cells to FN results in a G1 arrest associated with increased p27kip1 protein levels and inhibition of cyclin A and E associated kinase activity. Disruption of cells from FN adhesion resulted in a rapid recruitment of cells into S phase, a decrease in p27kip1 levels, and reversion to a drug sensitive phenotype. Treatment of cells with p27Kip1 antisense oligonucleotides did not affect FN adhesion; however, p27Kip1 protein levels were reduced and cells became sensitive to cytotoxic drugs. These studies demonstrate that beta1 mediated adhesion of myeloma cells to FN regulates p27kip1 levels and that p27kip1 levels are causally related to CAM-DR. Disruption of beta1 integrin mediated FN adhesion may represent a potential target for the potentiation of drug induced apoptosis.

Integrin-mediated drug resistance in multiple myeloma.

Drug resistance remains a major obstacle to the treatment of many hematopoietic malignancies such as multiple myeloma. Although much research has been focused on acquired resistance phenotypes, we believe that de novo drug resistance mechanisms may be an important component in protecting cells from initial drug exposure. It is now realized that many of the biological processes associated with this disease, including cell survival, may come as a result of the direct interactions of malignant plasma cells with the bone marrow microenvironment. This review examines the role of cell adhesion to one bone marrow component, fibronectin (FN), and the impact it may have on response to cytotoxic drugs. We discuss the influence of the integrin VLA-4 (alpha4beta1) on cell adhesion mediated drug resistance (CAM-DR) as well as the effects of chronic drug exposure on integrin function. Data presented here demonstrates that drug selection can make a non-adherent cell line adherent to FN through inside-out integrin activation and consequently cause a decrease in sensitivity to drug. We also speculate on the possible mediators of this intrinsic mechanism of drug resistance which may, along with the integrins themselves, become promising therapeutic targets in cancer treatment.

Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines.

Integrin-mediated adhesion influences cell survival and may prevent programmed cell death. Little is known about how drug-sensitive tumor cell lines survive initial exposures to cytotoxic drugs and eventually select for drug-resistant populations. Factors that allow for cell survival following acute cytotoxic drug exposure may differ from drug resistance mechanisms selected for by chronic drug exposure. We show here that drug-sensitive 8226 human myeloma cells, demonstrated to express both VLA-4 (alpha4beta1) and VLA-5 (alpha5beta1) integrin fibronectin (FN) receptors, are relatively resistant to the apoptotic effects of doxorubicin and melphalan when pre-adhered to FN and compared with cells grown in suspension. This cell adhesion mediated drug resistance, or CAM-DR, was not due to reduced drug accumulation or upregulation of anti-apoptotic Bcl-2 family members. As determined by flow cytometry, myeloma cell lines selected for drug resistance, with either doxorubicin or melphalan, overexpress VLA-4. Functional assays revealed a significant increase in alpha4-mediated cell adhesion in both drug-resistant variants compared with the drug-sensitive parent line. When removed from selection pressure, drug-resistant cell lines reverted to a drug sensitive and alpha4-low phenotype. Whether VLA-4-mediated FN adhesion offers a survival advantage over VLA-5-mediated adhesion remains to be determined. In conclusion, we have demonstrated that FN-mediated adhesion confers a survival advantage for myeloma cells acutely exposed to cytotoxic drugs by inhibiting drug-induced apoptosis. This finding may explain how some cells survive initial drug exposure and eventually express classical mechanisms of drug resistance such as MDR1 overexpression.

[Contribution of chemotherapy in the treatment of cancer of the cavum (UCNT): apropos of 47 cases]. / Apport de la chimiothérapie dans le traitement du cancer du cavum (UCNT): à propos de 47 patients.

The authors present, from a 47 patients retrospective study, the place of BAC chemotherapy in the treatment of undifferenciated nasopharyngeal carcinoma. Twenty three patients treated with exclusive radiation therapy are compared with 24 patients treated with three courses of BAC chemotherapy prior to and after radiation therapy. The procedure using associated chemotherapy permits to increase the 5 years survival rate up to 20% more and to obtain a 100% primary response of the tumor. This encouraging results should be confirmed by a prospective randomized study about a great number of patients.