[Soft palate chronic lymphocytic leukemia]. / Leucémie lymphoïde chronique vélaire.

INTRODUCTION: Forty percent of non-Hodgkin lymphoma (NHL) are located in extranodal sites. The palatal location of chronic lymphocytic leukemia (CLL) is usually observed at a late stage of the disease. CASE: We report the case of a 62-year-old male patient managed for 8 years for CLL, having presented with a soft palatal tumor in the last 2 years. The diagnosis of CLL was made by immunohistochemistry. The patient was given 6 courses of chemotherapy combining fludarabine, cyclophosphamide, and rituximab. DISCUSSION: The diagnosis of CLL requires immunohistochemistry. Chemotherapy is the first line treatment. The complication may be an aggressive lymphoma (Richter).

[Sarcoïdose in patient with chronic hepatitis C treated with pegylated interferon]. / Sarcoïdose chez un patient traité par interféron pégylé pour une hépatite chronique C.

Induced sarcoïdosis during therapy with interferon for chronic viral hepatitis C involves mainly by isolated cutaneous lesions or with lung lesions. Systemic forms are very rare. We report an observation. A 50-year-old patient developed a systemic sarcoïdosis two months after the end of treatment for hepatitis C with pegylated interferon and ribavirin with lung, joint and hepatic manifestations. After starting corticosteroid therapy, the evolution was favourable. Induced sarcoïdosis by interferon therapy is rare, treatment necessitates stopping interferon, and sometimes corticosteroid therapy.

Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration.

Altered alpha- and beta-adrenergic receptor signaling is associated with cardiac hypertrophy and failure. Stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 have been reported to mediate cardioprotection after injury through the mobilization of stem cells into injured tissue. However, little is known regarding whether SDF-1/CXCR4 induces acute protection following pathological hypertrophy and if so, by what molecular mechanism. We have previously reported that CXCR4 physically interacts with the beta-2 adrenergic receptor and modulates its downstream signaling. Here we have shown that CXCR4 expression prevents beta-adrenergic receptor-induced hypertrophy. Cardiac beta-adrenergic receptors were stimulated with the implantation of a subcutaneous osmotic pump administrating isoproterenol and CXCR4 expression was selectively abrogated in cardiomyocytes using Cre-loxP-mediated gene recombination. CXCR4 knockout mice showed worsened fractional shortening and ejection fraction. CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases whereas fibrosis increases. In addition, CXCR4 expression was rescued with the use of cardiotropic adeno-associated viral-9 vectors. CXCR4 gene transfer reduced cardiac apoptotic signaling, improved mitochondrial function and resulted in a recovered cardiac function. Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo.

Efficient transduction of vascular smooth muscle cells with a translational AAV2.5 vector: a new perspective for in-stent restenosis gene therapy.

Coronary artery disease represents the leading cause of mortality in the developed world. Percutaneous coronary intervention involving stent placement remains disadvantaged by restenosis or thrombosis. Vascular gene therapy-based methods may be approached, but lack a vascular gene delivery vector. We report a safe and efficient long-term transduction of rat carotid vessels after balloon injury intervention with a translational optimized AAV2.5 vector. Compared with other known adeno-associated virus (AAV) serotypes, AAV2.5 demonstrated the highest transduction efficiency of human coronary artery vascular smooth muscle cells (VSMCs) in vitro. Local delivery of AAV2.5-driven transgenes in injured carotid arteries resulted in transduction as soon as day 2 after surgery and persisted for at least 30 days. In contrast to adenovirus 5 vector, inflammation was not detected in AAV2.5-transduced vessels. The functional effects of AAV2.5-mediated gene transfer on neointimal thickening were assessed using the sarco/endoplasmic reticulum Ca(2+) ATPase isoform 2a (SERCA2a) human gene, known to inhibit VSMC proliferation. At 30 days, human SERCA2a messenger RNA was detected in transduced arteries. Morphometric analysis revealed a significant decrease in neointimal hyperplasia in AAV2.5-SERCA2a-transduced arteries: 28.36±11.30 (n=8) vs 77.96±24.60 (n=10) µm(2), in AAV2.5-green fluorescent protein-infected, P<0.05. In conclusion, AAV2.5 vector can be considered as a promising safe and effective vector for vascular gene therapy.

SERCA2a gene transfer prevents intimal proliferation in an organ culture of human internal mammary artery.

Coronary restenosis, a major complication of percutaneous balloon angioplasty, results from neointimal proliferation of vascular smooth muscle cells (VSMCs). The sarco/endoplasmic reticulum calcium ATPase 2a isoform (SERCA2a), specific to contractile VSMCs, has been reported previously to be involved in the control of the Ca(2+)-signaling pathways governing proliferation and migration. Moreover, SERCA2a gene transfer was reported to inhibit in vitro VSMC proliferation and to prevent neointimal thickening in a rat carotid injury model. The aim of this study was to evaluate the potential therapeutic interest of SERCA2a gene transfer for prevention of in-stent restenosis using a ex vivo model of human left internal mammary artery (hIMA) intimal thickening. Left hIMAs, obtained at the time of aorto-coronary bypass surgeries, were subjected to balloon dilatation followed by infection for 30 min with adenoviruses encoding either human SERCA2 and green fluorescence protein (GFP) or control gene (ß-galactosidase, ß-gal) and GFP. Proliferation of subendothelial VSMCs and neointimal thickening were observed in balloon-injured hIMA maintained 14 days in organ culture under constant pressure and perfusion. SERCA2a gene transfer prevented vascular remodeling and significantly (P<0.01, n=5) reduced neointimal thickening in injured arteries (intima/media ratio was 0.07±0.01 vs 0.40±0.03 in ß-gal-infected arteries). These findings could have potential implications for treatment of pathological in-stent restenosis.

A calcium-sensitive promoter construct for gene therapy.

Targeting diseased cells is a challenging issue in both pharmacological and biological therapeutics. Gene therapy is emerging as a novel approach for treating rare diseases and for illnesses for which there is no other alternative. An important limitation of gene therapy has been the off-target effects and therefore efforts have been focused on increasing the specificity of gene transfer to the targeted organ. Here, we describe a promoter containing six nuclear factor of activated T cells (NFAT) consensus sequences, which is as efficient as the cytomegalovirus (CMV) promoter to drive expression in vascular smooth muscle cells both in vitro and in vivo. In contrast to the CMV promoter it is activated in a Ca(2+)-dependent manner after endoplasmic reticulum depletion and allows the transgene expression only in proliferative/diseased cells. Overexpression of sarco/endoplasmic reticulum (SR/ER) Ca(2+) ATPase 2a under the control of this NFAT promoter inhibits restenosis after angioplasty in rats. In conclusion, this promoter may be useful for gene therapy in vascular proliferative diseases and other diseases involving upregulation of the NFAT pathway.

Calcium cycling proteins and their association with heart failure.

Heart failure (HF) has reached epidemic proportions in the United States and is one of the most important challenges to public health. Severe congestive HF is associated with substantial morbidity and mortality. HF afflicts approximately 5 million patients and contributes to 3 million hospitalizations and 300,000 deaths yearly. Late-stage HF has a poor prognosis, and therapeutic options are limited. Defective excitation­contraction (EC) coupling in HF may result from altered density or function of proteins relevant for Ca2+ homeostasis.

Delivery of gelfoam-enabled cells and vectors into the pericardial space using a percutaneous approach in a porcine model.

Intrapericardial drug delivery is a promising procedure, with the ability to localize therapeutics with the heart. Gelfoam particles are nontoxic, inexpensive, nonimmunogenic and biodegradable compounds that can be used to deliver therapeutic agents. We developed a new percutaneous approach method for intrapericardial injection, puncturing the pericardial sac safely under fluoroscopy and intravascular ultrasound (IVUS) guidance. In a porcine model of myocardial infarction (MI), we deployed gelfoam particles carrying either (a) autologous mesenchymal stem cells (MSCs) or (b) an adenovirus encoding enhanced green fluorescent protein (eGFP) 48 h post-MI. The presence of MSCs and viral infection at the infarct zone was confirmed by immunoflourescence and PCR. Puncture was performed successfully in 16 animals. Using IVUS, we successfully determined the size of the pericardial space before the puncture, and safely accessed that space in setting of pericardial effusion and also adhesions induced by the MI. Intrapericardial injection of gelfoam was safe and reliable. Presence of the MSCs and eGFP expression from adenovirus in the myocardium were confirmed after delivery. Our novel percutaneous approach to deliver (stem-) cells or adenovirus was safe and efficient in this pre-clinical model. IVUS-guided delivery is a minimally invasive procedure that seems to be a promising new strategy to deliver therapeutic agents locally to the heart.

[Interstitial pneumonia related to mesalamine]. / Pneumopathie interstitielle induite par la mésalazine.

We report the case of a 57-year-old woman with ulcerative colitis since eight years who developed a diffuse interstitial pneumonia linked to mesalazine (oral and enemas). The adverse drug-related effect to mesalazine was strongly suggested regarding improvement upon discontinuation and relapse after reinstitution of mesalazine. To date, after 8 years, the patient has not any respiratory symptom which is another argument for the adverse drug-related effect to mesalazine.

[Citrobacter freundii spondylitis and sickle cell disease: a case in Morocco]. / Spondylite a Citrobacter freundii et drépanocytose: une observation au Maroc.

Infectious complications of sickle cell disease are common and can be serious and difficult to diagnose. Epidemiological aspects of these infections are well documented. The most common germ in children is pneumococcus followed by Haemophilus influenzae and minor salmonella. In adults gram-negative germs including minor salmonella are the most frequent. The purpose of this report is to describe a case of a Citrobacter freundii spondylitis with prevertebral abscess extending to dorsal and lumbar spinal areas. Diagnosis was made during work-up for persistent vaso-occlusive manifestations. Treatment consisted of percutaneous lumbar drainage associated with antibiotherapy.

[Pyomyositis: an infectious complication in systemic lupus erythematous]. / La pyomyosite : une complication infectieuse du lupus érythémateux systémique.

Pyomyositis is a primary pyogenic muscular infection. It has been originally described in the tropics. Presenting signs and symptoms are not specific. It is frequently misdiagnosed in the early stages. We report the case of a 47-year-old woman with systemic lupus erythematosus treated with corticosteroids who presented a thigh pyomyositis evidenced by echography and MRI. Outcome was uneventful after antibiotics and surgical drainage. Pyomyositis is increasingly described among immunocompromised people, including lupus patients treated with corticosteroids.

[Primary non-Hodgkin's lymphoma of the adrenals. A case report]. / Lymphome malin non hodgkinien primitif de la surrénale. A propos d'un cas.

Bilateral primary non-Hodgkin's lymphoma (NHL) of the adrenals is uncommon. Less than 70 cases have been described in the literature. The symptoms of disease are variable and depend on the tumor size and the presence of adrenal insufficiency . We report a case of large diffuse B-cell adrenal lymphoma discovered in a 40-year-old woman presenting bilateral lumbar pain. Hormonal exploration demonstrated adrenal insufficiency. Imaging explorations showed a large and bilateral adrenal mass. Percutaneous CT-guided biopsy of the adrenal and search for extension revealed primary bilateral adrenal lymphoma. After glucocorticoid substitution, treatment was based on a CHOP regimen chemotherapy; outcome was unfavourable after the second cure; the patient died from septic shock. The diagnosis of primary adrenal non-Hodgkin lymphoma should be investigated in patients with a rapidly growing bilateral adrenal mass associated with adrenal insufficiency.

[A case of myopathy associated with hypothyroidism and hyperprolactinaemia]. / Un cas de myopathie révélant une hypothyroïdie périphérique avec syndrome tumoral hypophysaire.

UNLABELLED: We report a case of a serious myopathy related to hypothyroidism with pituitary enlargement and hyperprolactinemia. CASE REPORT: Mr D.L 33 years old man suffering from myalgia, muscular weakness and cramps for six months. The laboratory check-up revealed a high serum creatin phosphokinase level, an autoimmune hypothyroidism, hyperprolactinemia and pituitary enlargement. The electromyogram was normal and the muscle biopsy showed no obvious inflammation. The outcome was favourable under L. thyroxin. DISCUSSION: The frequency of myopathy during hypothyroidism ranges from 30 to 80%. The main symptoms related are weakness, muscular cramps and myalgia. However, hyperprolactinemia and pituitary enlargement described in this case are due to reactional mechanism. These several hypothyroid manifestations improve remarkably under L.thyroxin. CONCLUSION: Proximal myopathy may rarely be displayed as the sole manifestation of hypothyroidism. Therefore, it is recommended that hypothyroid myopathy should be taken into account during differential diagnosis of proximal muscle weakness.

[Orbital involvement in IgD Kappa myeloma]. / Atteinte de l'orbite au cours d'un myélome à IgD Kappa.

INTRODUCTION: IgDkappa myeloma accounts for less than 2% of all myeloma cases. Orbital involvement is uncommon in myeloma and the authors suggest a possible predilection for IgD myeloma to involve the orbit. CASE REPORT: A 67-year-old women was admitted for diffuse bone pain and painful ptosis of the right eye. The symptoms had progressed over approximately 1 year and were associated with a severe decline in general health. The biochemical, hematological, and radiological investigations suggested the diagnosis of an IgD kappa myeloma. Orbital x-ray showed destruction of the greater and lesser right wing of the sphenoid bone. Treatment was polychemotherapy. The course of the disease was very rapid and death occurred within 17 months from renal failure and amyloidosis. DISCUSSION: Orbital involvement by myeloma occurs in 0.3% of cases and the majority are unilateral. The typical orbital symptoms include ptosis, diplopia, loss of vision, and pain. This was not considered to contribute to poor prognosis but may affect the functional prognosis.

[Hypoparathyroidism associated with systemic lupus erythematosus: a case]. / Association lupus systémique et hypoparathyroïdie: à propos d'un cas.

UNLABELLED: Hypoparathyroidism is very rarely diagnosed in patients with lupus. CASE: A 39-year-old women had systemic lupus erythematosus known for 3 years. She was admitted for a paresthesia of the lower limb, depression, insomnia and 5 kg weight loss. The laboratory tests revealed hypoparathyroidism and no sign of disease activity. Treatment with oral calcium and vitamin D resulted in correction of the hypocalcemia and QT prolongation. DISCUSSION: The combined diagnosis lupus-hypoparathyroidism has very rarely been reported. We suggest there may be a common underlying pathological process linking the two diseases. The occurrence of these diseases in the same individual may be related to an underlying genetic predisposition or secondary to the generalized autoimmune disease process.

[Evaluation of bone mineral density in hyperthyroid patients before and after medical therapy]. / Evaluation de la densité minérale osseuse chez les patients hyperthyroïdiens, et après contrôle de l'hyperthyroïdie par traitement médical.

Osteoporosis is a common complication of hyperthyroidism, but it is not often evaluated. The aim of this study is to examine bone mineral density (BMD) (dual energy X-ray absorptiometry: DEXA) in lumbar spine (L1-L4), femoral neck (FN) and Ward's triangle (TW) in 45 hyperthyroid patients (group A: n 25 active hyperthyroidism, group B: n 20 controlled hyperthyroidism on medical therapy, after a mean of 7 months of euthyroidism), compared to control group (group C: n 22). These 3 groups are adjusted by age, sex, menopausal status and BMI. In hyperthyroid patients (group A), as compared to the control group, we noticed a significant reduction of BMD (z score) in different sites, more markedly in the lumbar spine (p L1-L4: 0,005; p FN: 0,011; p TW: 0,019). In group A, no differences were found between BMD values after adjustment for Z score whatever the menopausal status (p L: 0.12; p FN: 0.33; p TW: 0.09) and degree ofhyperthyroidism (p L: 0.48; p FN: 0.41; p TW: 0.21). The degree of BMD in group B patients was different from that of patients in group A (p L: 0.37; p FN: 0.28; p TW: 0.31). and was significantly lower than in those of group C except for the TW (p L: 0.009; p CF: 0.038; p TW: 0.068). We conclude that it is important to consider that after reaching euthyroidism hyperthyroidism patients present a bone risk.

Comparative metabolism of methacrylonitrile and acrylonitrile to cyanide using cytochrome P4502E1 and microsomal epoxide hydrolase-null mice.

Methacrylonitrile (MAN) and acrylonitrile (AN) are metabolized via glutathione (GSH) conjugation or epoxide formation. We have recently shown that CYP2E1 is essential for AN epoxidation and subsequent cyanide liberation. Current studies were designed to compare the enzymatic basis of MAN vs. AN metabolism to cyanide using wild-type (WT), CYP2E1-, and mEH-null mice. Mice received a single gavage dose of 0.047, 0.095, 0.19, or 0.38 mmol/kg of MAN or AN, and blood cyanide was measured at 1 or 3 h later. Blood cyanide levels in WT mice treated with AN or MAN were dose and time dependent. At equimolar doses, significantly higher levels of cyanide were detected in the blood of MAN- vs. AN-treated mice. Further, while significant reduction in blood cyanide levels occurred in MAN-treated CYP2E1-null vs. WT mice, AN metabolism to cyanide was largely abolished in CYP2E1-null mice. Pretreatment of mice with 1-aminobenzotriazole (ABT, CYP inhibitor) demonstrated that CYPs other than CYP2E1 also contribute to MAN metabolism to cyanide. Blood cyanide levels in mEH-null mice treated with aliphatic nitriles are generally lower than levels in similarly treated WT mice. Western blot analysis showed that expression of sEH was greater in male vs. female mice. The role of various epoxide hydrolases (EHs) in the production of cyanide from aliphatic nitriles is apparently structure and dose dependent. Regardless of genotype, significantly higher levels of cyanide were measured in the blood of male vs. female mice treated with MAN or AN. In conclusion, these data showed that (1) at equimolar doses, higher blood cyanide levels were detected in mice treated with MAN vs. AN; (2) while CYP2E1 is the only enzyme responsible for AN metabolism to cyanide, other CYPs also contribute to MAN metabolism; and (3) significantly higher levels of cyanide were measured in the blood of male vs. female treated with either nitrile. Higher blood cyanide levels in male vs. female mice and in MAN- vs. AN-treated mice may explain the gender-related differences in the toxicity of these chemicals and the greater potency of MAN vs. AN.

Comparison of germ cell mutagenicity in male CYP2E1-null and wild-type mice treated with acrylamide: evidence supporting a glycidamide-mediated effect.

Acrylamide is an animal carcinogen and probable human carcinogen present in appreciable amounts in heated carbohydrate-rich foodstuffs. It is also a germ cell mutagen, inducing dominant lethal mutations and heritable chromosomal translocations in postmeiotic sperm of treated mice. Acrylamide's affinity for male germ cells has sometimes been overlooked in assessing its toxicity and defining human health risks. Previous investigations of acrylamide's germ cell activity in mice showed stronger effects after repeated administration of low doses compared with a single high dose, suggesting the possible involvement of a stable metabolite. A key oxidative metabolite of acrylamide is the epoxide glycidamide, generated by cytochrome P4502E1 (CYP2E1). To explore the role of CYP2E1 metabolism in the germ cell mutagenicity of acrylamide, CYP2E1-null and wild-type male mice were treated by intraperitoneal injection with 0, 12.5, 25, or 50 mg acrylamide (5 ml saline)(-1) kg(-1) day(-1) for 5 consecutive days. At defined times after exposure, males were mated to untreated B6C3F1 females. Females were killed in late gestation and uterine contents were examined. Dose-related increases in resorption moles (chromosomally aberrant embryos) and decreases in the numbers of pregnant females and the proportion of living fetuses were seen in females mated to acrylamide-treated wild-type mice. No changes in any fertility parameters were seen in females mated to acrylamide-treated CYP2E1-null mice. Our results constitute the first unequivocal demonstration that acrylamide-induced germ cell mutations in male mice require CYP2E1-mediated epoxidation of acrylamide. Thus, CYP2E1 polymorphisms in human populations, resulting in variable enzyme metabolic activities, may produce differential susceptibilities to acrylamide toxicities.