Modulation of the functional interfaces between retroviral intasomes and the human nucleosome.

Infection by retroviruses as HIV-1 requires the stable integration of their genome into the host cells. This process needs the formation of integrase (IN)-viral DNA complexes, called intasomes, and their interaction with the target DNA wrapped around nucleosomes within cell chromatin. To provide new tools to analyze this association and select drugs, we applied the AlphaLISA technology to the complex formed between the prototype foamy virus (PFV) intasome and nucleosome reconstituted on 601 Widom sequence. This system allowed us to monitor the association between both partners and select small molecules that could modulate the intasome/nucleosome association. Using this approach, drugs acting either on the DNA topology within the nucleosome or on the IN/histone tail interactions have been selected. Within these compounds, doxorubicin and histone binders calixarenes were characterized using biochemical, in silico molecular simulations and cellular approaches. These drugs were shown to inhibit both PFV and HIV-1 integration in vitro. Treatment of HIV-1-infected PBMCs with the selected molecules induces a decrease in viral infectivity and blocks the integration process. Thus, in addition to providing new information about intasome-nucleosome interaction determinants, our work also paves the way for further unedited antiviral strategies that target the final step of intasome/chromatin anchoring. IMPORTANCE In this work, we report the first monitoring of retroviral intasome/nucleosome interaction by AlphaLISA. This is the first description of the AlphaLISA application for large nucleoprotein complexes (>200 kDa) proving that this technology is suitable for molecular characterization and bimolecular inhibitor screening assays using such large complexes. Using this system, we have identified new drugs disrupting or preventing the intasome/nucleosome complex and inhibiting HIV-1 integration both in vitro and in infected cells. This first monitoring of the retroviral/intasome complex should allow the development of multiple applications including the analyses of the influence of cellular partners, the study of additional retroviral intasomes, and the determination of specific interfaces. Our work also provides the technical bases for the screening of larger libraries of drugs targeting specifically these functional nucleoprotein complexes, or additional nucleosome-partner complexes, as well as for their characterization.

Characteristics and prognosis of patients with angiographic stent thrombosis: comparison between drug-eluting and bare-metal stents.

INTRODUCTION: Conflicting data exist on the risk of stent thrombosis with drug-eluting stents (DES) versus bare-metal stents (BMS). Little is known about the potential different characteristics and outcomes of DES versus BMS thrombosis. OBJECTIVE: To compare the characteristics, timing and outcomes of patients with angiographic stent thrombosis according to type of stent implanted. METHODS: The population comprised consecutive patients who underwent BMS or DES implantation (January 2003-April 2007) at Pitié-Salpêtrière Hospital. Data from patients with and without a stent thrombosis were compared to identify predictors of thrombosis. Timing of thrombosis (acute,<24 hours; subacute,<30 days; late,>30 days; very late,>1 year), clinical, angiographic and procedural characteristics, and outcomes were compared between patients with a BMS or DES thrombosis. RESULTS: A total of 3579 patients received a BMS (2815 lesions, 2318 patients) or a DES (1536 lesions, 1261 patients). Documented angiographic stent thrombosis occurred in 52 (1.4%) patients, 16 (1.3%) with a DES and 36 (1.6%) with a BMS. Rates of acute (0.1% versus 0.2%), subacute (1% versus 0.7%), late (both 0.2%) and very late (both 0.2%) thrombosis were similar in patients with BMS and DES thrombosis. Factors predictive of stent thrombosis were similar, including left ventricular failure (P<0.0001), initial percutaneous coronary intervention (PCI) for acute myocardial infarction (P<0.0001), multivessel PCI (P<0.0001), and balloon dilatation before stenting (P<0.04). Eleven (21%) cases of BMS (n=8, 22%) or DES (n=3, 19%) thrombosis arose soon after stopping antiplatelet therapy. Thirteen of 52 (25%) patients died a few hours after the event. Twenty-seven (52%) major adverse cardiac events occurred at 18 months, 7 in patients with a DES and 20 in those with a BMS (44% versus 55%, P=NS). These included 16 deaths (31%), 7 repeat PCIs and 4 myocardial infarctions. There were no independent predictive factors of death after stent thrombosis. CONCLUSIONS: BMS and DES thrombosis are similar in terms of timing of thrombosis, characteristics and outcomes, and share the same risk of late thrombosis after interruption of antiplatelet therapy.

[Sleep-related breathing disorders and normal or high-tension glaucoma: 35 patients with polysomnographic records]. / Troubles respiratoires nocturnes et glaucome à pression normale ou élevée. A propos de 35 patients hospitalisés pour polysomnographie.

PURPOSE: To look for early stage glaucoma symptoms in patients referred for sleep-related breathing disorders or sleep apnea syndrome. PATIENTS AND METHOD: Thirty-five patients between October 2001 and April 2002 consecutively admitted for polysomnographic evaluation were investigated. Each patient had complete ophthalmologic examination before the nocturnal record. A blue-on-yellow Humphrey computerized perimetry test was given, and a standard perimetry with a color vision test if abnormalities were found. The criteria studied were intraocular pressure, optic nerve cupping and aspect, visual field indices and visual field aspect, which were compared to the respiratory disturbance index. Twenty-seven subjects were included in this analysis, nine women and 18 men. RESULTS: In eight patients, the respiratory disturbance index was higher than 10. All intraocular pressures were normal. Visual field defects were found in two patients with both standard and blue-on-yellow perimetry, and in 12 patients with only blue-on-yellow perimetry. Mean deviation and visual field aspect correlated well with the respiratory disturbance index (p=0.026, p=0.033). Other visual field indices were not correlated with the respiratory disturbance index. CONCLUSION: In this study, we found visual field alterations with blue-on-yellow computerized perimetry that did not exist with standard perimetry. The visual field defects were more frequent when the respiratory disturbance index was poor.

[Absence of nephro-protective effect of acetylcysteine in patients with chronic renal failure investigated by coronary angiography]. / Absence d'effet néphroprotecteur de l'acetylcystéine chez les patients avec insuffisance rénale chronique explorés par coronarographie.

Recent studies have suggested that an oral dose of acetylcysteine could play a prophylactic role in the prevention of nephrotoxicity from iodine contrast media in patients affected by chronic renal failure. Between June 2001 and September 2002 we selected 120 patients with a basal plasma creatinine level greater than 1.36 mg/dl investigated by coronary angiography. The treatment group included 60 patients who received 600 mg of acetylcysteine in the morning and evening before the day of the examination together with intravenous saline hydration. The control group patients received hydration alone. The clinical characteristics of the groups were comparable as well as the basal plasma creatinine level: 2.01+/-1.1 mg/dl in the acetylcysteine group and 1.81+/-0.69 in the control group. The plasma creatinine level was measured 24 and 48 hours after coronary angiography. The respective changes in plasma creatinine level at 24 and 48 hours were 0.12+/-0.29 and 0.02+/-0.29 mg/dl in the acetylcysteine group and 0.06+/-0.29 and 0.07+/-0.43 mg/dl in the control group (NS). Acute renal failure caused by the contrast medium, defined by an increase of 25% in the plasma creatinine level compared to the basal value, occurred in 3 patients from the acetylcysteine group and 2 patients from the control group. The only predictive factor for acute renal failure was the quantity of contrast medium (316+/-141 vs 173+/-115 ml, p<0.05). In conclusion, acute renal failure caused by contrast medium is rare in sufficiently hydrated patients with moderate chronic renal failure when a low dose of contrast medium is used. Our study does not confirm a prophylactic effect of acetylcysteine in the prevention of nephrotoxicity from contrast media following coronary angiography in patients with moderate chronic renal failure.

[Value of combined coronary angioplasty and coronary angiography]. / Intérêt de l'angioplastie coronaire dans le même temps que la coronarographie.

Combined coronary angioplasty and coronary angiography is performed in most catheter laboratories and has become a routine procedure. The aim of this study was to assess its clinical results and economic value. This was a retrospective monocenter study performed over an 11 year period (1990-2000) which included 2,727 patients requiring coronary angioplasty after coronary angiography. The angioplasty procedure was performed at the same time as angiography (combined, n = 1,809) or after angiography (deferred, n = 631). Patients admitted for acute coronary syndromes not stabilised by pharmacological interventions were excluded from the study. The comparison of these two modes of angioplasty was based on primary success rates, complications, duration of hospital stay and hospital costs. The combined procedure was used progressively more frequently over the study period, increasing from 54% to 88% in 2000. The hospital clinical results (Success and complication rates) were comparable in the two groups. The predictive factors of failure were the year of the angioplasty procedure and occlusive lesions on multivariate analysis. The combined procedure was associated with a shorter hospital stay than deferred angioplasty (8.2 +/- 6.1 days versus 15.0 +/- 8.0 days, p = 0.0001) and with lower costs. The authors conclude that combined coronary angiography-angioplasty is as effective and as safe as deferred angioplasty. It is associated with a shorter hospital stay and lower hospital costs.

[Comparison between Greenbaum's parabulbar anesthesia and Ripart's subtenon anesthesia in the anterior segment surgery]. / Comparaison de l'anesthésie parabulbaire selon Greenbaum et l'anesthésie sous-ténonienne de Ripart dans la chirurgie du segment antérieur.

PURPOSE: To compare two methods of sub-tenon anesthesia in 80 surgical procedures (phakoemulsification, glaucoma and combined surgery) in a prospective, single-surgeon study. MATERIALS AND METHODS: Forty patients requiring anterior segment surgery in each eye were randomised to receive subtenon anaesthesia by either Greenbaum's method (using a flexible plastic cannula) or Ripart's method (using a 23G hypodermic needle). Randomization dictated the mode of anaesthesia for the first eye, the other technique being used for the second eye. Anaesthesia consisted of 1.5ml lidocaïne 2% and 1.5ml bupivacaïne 0.5% in all cases, and was performed by the same surgeon (EDLM) immediately before surgery. Type of surgical procedure, duration, complications, presence of sub-conjunctival haemorrhage, were assessed by the surgeon, who also graded chemosis (0-3), nuclear hardness (1-4), and ocular akinesia (0-2) for each patient. Pain was scored subjectively by each patient (0-10) during the injection, peroperatively and postoperatively. RESULTS: Chemosis was significatively higher with Greenbaum's method than Ripart's method (p<0.01) and was sometimes undesirable for the surgeon. There was no difference in the pain score during the injection, preoperatively or postoperatively. Pain was usually very light and did not correlate with the duration of surgery. There was no akinesia in the majority of cases with either method, but the surgeon was sometimes limited by the akinesia of the medial rectus muscle and often by that of the inferior rectus muscle with elevation of the globe. CONCLUSION: Greenbaum's method and Ripart's method are two subtenon anesthesic techniques characterized by an immediate, intense and prolonged analgesia (sometimes 60mn). Complete akinesia is rare and this is sometimes limiting. Chemosis was more often associated with Greenbaum's method, but Ripart's method carries the potential for needle-related complications.

[New techniques of interventional cardiology]. / Nouvelles techniques de cardiologie interventionnelle.

Balloon coronary angioplasty for coronary stenosis has a success rate of over 90%, but secondary restenosis occurs in 30 to 40% of the patients. In addition, long calcified, ulcerated and distal lesions cannot be treated with the balloon technique. New techniques are thus needed and are currently under clinical evaluation. Stents are metallic meshes designed as vascular prostheses to maintain the arterial lumen open. Currently, stents are indicated in case of acute coronary occlusion during the angioplasty procedure and more rarely in case of elastic recoil after dilatation. First intention stents can reduce the rate of restenosis by about one-fourth, although use is limited due to the risk of thrombosis. The rotablator has a fine elliptoid tip which rotates at 180,000 rpm. When inserted into the area of stenosis, the rotablator attacks preferentially hard resistant material and is thus indicated for calcified lesions. It should not be used in large arteries or if a thrombus is visible on the angiography. Primary success rate is 95% and recoil does not exceed 5%. But this method still is not the final solution since the rate of restenosis is 44%, and even 54% for calcified lesions. In directional arthrectomy the tip of the catheter carries a metal cylinder with a lateral window which can be positioned on the lesion. Atheromatous material is then cut off with a rotating knife and trapped in the catheter's reservoir. This new system gives results which are currently similar to those for conventional angioplasty. The potential role of transluminal laser atherectomy, an effective but costly technique, is yet to be established. These new devices offer great potential, but their impact will depend to a great extent on the experience of the cardiology team and must be evaluated in comparison with the results of the classical balloon angioplasty.

[The styloid bone and carpal protuberance]. / Os styloïdeum et carpe bossu.

Dorsal carpal protuberance of the wrist is frequently caused by the presence of a styloideum bone. We report a case illustrating this pathophysiological hypothesis. This pathology is often confused with synovial cyst emphasizing the importance of a lateral view of the hand in 30 degrees supination. Computed tomography sections are also helpful showing the exact nature of the protuberance. A cuneiform resections of the joint line can leave to complete symptom relief.

[Coronary angioplasty, a privileged method of myocardial revascularization of the elderly]. / L'angioplastie coronaire, méthode privilégiée de revascularisation myocardique du sujet âgé.

Coronary angioplasty is a myocardial revascularisation technique of choice in the elderly, avoiding the need for general anesthesia as well as the complications of thoracotomy and extracorporeal circulation. Used in a continuous series of 62 patients, it provided a 79% primary success rate in this situation, where reaching the coronary artery and penetrating the stenosis may be difficult. Femoral complications (hematoma, false aneurysm) are commoner in this age group, but appear to be beneficially influenced by the replacement of heparin by ticlopidine peri-operatively. With 24 months follow-up, the proportion of patients free of any major cardiac event and NYHA classes I and II is 66%, actuarial survival rate without infarction is 76%. These results would tend to restrict the indications for bypass after the age of 75 to cases of stenosis of the left main coronary artery, failure of angioplasty or multi-vessel atheroma with a "culprit lesion" inaccessible to dilatation.

[Oculo-palpebral complication of vaccination. Review of the literature]. / Les complications oculo-palpébrales des vaccinations. Revue de la littérature.

Post-vaccination eyes and eyelid complications are seldom seen. Clinically different, they are not only due to the small-pox vaccination which is no longer performed but may also be seen with various kinds of viral vaccines as well as bacterial vaccines except for polymyelitis and tetanus. We believe that vaccination contraindications, direction for use and propylactic treatment are useful.

[Third angioplasty, and after that?]. / La troisième angioplastie, et après?

The authors studied retrospectively a series of 39 patients with a documented second restenosis after coronary angioplasty between January 1987 and November 1992, 33 of whom (31 men, 2 women) underwent a third procedure. The artery dilated was the left anterior descending (n = 17 including 9 proximal stenoses), the right coronary (n = 10), the left circumflex or its branches (n = 5) and the left main stem (n = 1). The lesions were confirmed to one vessel in 25 cases (75%) and affected two vessels in 8 cases (25%). The third angioplasty procedure was performed on a single artery in all cases. The average left ventricular ejection fraction was 60% (43%-75%). The diameter of the dilated artery was over 3.25 mm in 24% of cases (8/33). The primary success rate was 100% without any complications. The average period between the first and second angioplasties was 16 +/- 10 weeks, and between the second and third angioplasties 19 +/- 12 weeks. Angioplastic controls of the 3rd angioplasty were performed in 25 cases (75%). A third restenosis (n = 7) was treated by surgical bypass (n = 1), repeat angioplasty (n = 4), endocoronary stenting (n = 1) or medically (n = 1), with a global follow-up of 22 months (2-56 months), 2 patients underwent coronary bypass grafting, 2 have residual angina (contralateral lesion which could not be dilated), 1 had an infarct in the territory of an undilated artery, and 28 (85%) were asymptomatic. The restenosis rate after the third angioplasty procedure was 28% (7/25).(ABSTRACT TRUNCATED AT 250 WORDS)

[Preservation of a foot by shortening tibial osteotomy after a circumferential electric burn to the leg]. / Sauvetage d'un pied après brulure électrique circonférentielle de la jambe par ostéotomie tibiale de raccourcissement.

A patient presented with circumferential loss of skin substance of lower quarter of leg. The patient's advanced age and the poor local conditions could have produced an aleatory result for a flap graft. It was therefore decided to perform a shortening tibial osteotomy as a conservative surgical procedure.

[Dysfunction of aortocoronary bypass. Prognosis]. / Dysfonction des pontages aorto-coronaires. Etude pronostique.

From 1978 to 1988, 108 patients with at least one occluded or stenosed aorto-coronary bypass graft (over 75% stenosis) underwent coronary angiography on average 31 months after the initial coronary bypass surgery. The occluded or stenosed coronary graft was either a saphenous vein (n = 126 including 9 sequentials) or internal mammary artery (n = 5). The bypassed artery was the left anterior descending (n = 66), right coronary (n = 40), left marginal (n = 25) or diagonal (n = 9). The number of occluded or stenosed grafts by patient was 1.2. The left ventricular ejection fraction was 55% (range 25 to 77%). During a mean follow-up period of 60 months after coronary angiography, there were 14 cardiac deaths and 15 non-lethal myocardial infarctions. Treatment comprised 12 angioplasties, 26 new bypass grafts and 3 cardiac transplantations. The 8 year actuarial survival was 84%. The survival without infarction at 8 years was 69%. Survival was significantly decreased to 72% when the occluded or stenosed graft was located on the left anterior descending artery. The survival without infarction at 8 years was 52% in the patients with dysfunction of left anterior descending artery grafts and 89% when the diseased graft was located on another artery (right coronary, left marginal, diagonal). Therefore, the data of this retrospective study show that coronary graft dysfunction on the right coronary, left marginal or diagonal arteries do not greatly influence life expectancy in the medium term after coronary bypass surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

[Congenital mitral and tricuspid double stenosis]. / Double sténose tricuspide et mitrale congénitale.

The authors report the case of a child followed up from the age of 4 months to the age of 15 for asymptomatic congenital heart disease. Initial clinical examination showed the presence of a systolic murmur and a diastolic rumble in the xiphoid area with signs of right atrial dilatation-hypertrophy. During follow-up, an apical diastolic rumble was detected with left atrial dilatation from the age of 3. Doppler echocardiography carried out recently showed double mitral and tricuspid valve stenosis with two-dimensional appearances of doming of both valves and moderate transvalvular pressure gradients with slight elevation of pulmonary artery pressures on the Doppler study. The very early detection of the malformation and the continuous follow-up of this patient indicate the congenital and not rheumatic origin of this double valve stenosis.

[Dental pain and cardiac pain]. / Douleurs dentaires et douleurs cardiaques.

Some aching troubles encountered in heart disease can affect the jaw and patients can visit a dentist for this reason. The severity of this affection needs a quick diagnostic for preserving the patient's life.

[Unilateral Purtscher's retinopathy and seat belts]. / Rétinopathie de Purtscher unilatérale et ceinture de securité.

The authors report 2 cases of unilateral PURTSCHER'S retinopathia who became at the time of a car injury. They discuss about different possible mechanisms of this affection mainly a security belt wearing and tough slow down.

[Fetal death caused by myocarditis and isolated congenital auriculoventricular block]. / Mort foetale par myocardite et bloc auriculo-ventriculaire congénital isolé.

A 26-year old woman gave birth, at term, to a child with isolated complete heart block. A second pregnancy was interrupted by foetal death. Among other immunological abnormalities, this young woman had an antibody resembling the anti-SS-B antibody. At pathological examination the foetus' heart was found to be free of malformation but presented with subacute myocarditis associated with microcalcifications of the conductive tissue. Such findings suggest that an incipient myocarditis may either result in foetal death or lead to fibrosis of conduction pathways with isolated complete heart block.