Inhalable dust measurements as a first approach to assessing occupational exposure in the pharmaceutical industry.

Occupational exposure to active ingredients in the pharmaceutical industry has been the subject of very few published studies. Nevertheless, operations involving active powdered drugs or dusty operations potentially lead to operator exposure. The aim of this study was to collect occupational exposure data in the pharmaceutical industry for production processes involving powdered active ingredients. While the possibility of assessing drug exposure from dust level is examined, this article focuses on inhalable dust exposure, without taking chemical risk into account. A total of 377 atmospheric (ambient and personal) samples were collected in nine drug production sites (pharmaceutical companies and contract manufacturing organizations) and the dust levels were assessed. For each sample, relevant contextual information was collected. A wide range of results was observed, both site- and operation-dependent. Exposure to inhalable dust levels varied from 0.01 mg/m(3)to 135 mg/m(3). Though restricted to dust exposure, the study highlighted some potentially critical situations or operations, in particular manual tasks (loading, unloading, mechanical actions) performed in open systems. Simple preventive measures such as ventilation, containment, and minimization of manual handling should reduce dust emissions and workers' exposure to inhalable dust.

Identification of the SH3 domain of GAP as an essential sequence for Ras-GAP-mediated signaling.

Guanosine triphosphatase activating protein (GAP) is an essential component of Ras signaling pathways. GAP functions in different cell types as a deactivator and a transmitter of cellular Ras signals. A domain (amino acids 275 to 351) encompassing the Src homology region 3 (SH3) of GAP was found to be essential for GAP signaling. A monoclonal antibody was used to block germinal vesicle breakdown (GVBD) induced by the oncogenic protein Ha-ras Lys12 in Xenopus oocytes. The monoclonal antibody, which was found to recognize the peptide containing amino acids 275 to 351 within the amino-terminal domain of GAP, did not modify the stimulation of the Ha-Ras-GTPase by GAP. Injection of peptides corresponding to amino acids 275 to 351 and 317 to 326 blocked GVBD induced by insulin or by Ha-Ras Lys12 but not that induced by progesterone. These findings confirm that GAP is an effector for Ras in Xenopus oocytes and that the SH3 domain is essential for signal transduction.

CB2 receptors as new therapeutic targets for liver diseases.

Cannabinoid type-1 (CB1) and type-2 (CB2) receptors belong to the family of G protein-coupled receptors and mediate biological effects of phyto-derived and endogenous cannabinoids. Whereas functions of CB1 receptor have been extensively studied, the CB2 receptor has emerged over the last few years as a critical player in regulation of inflammation, pain, atherosclerosis and osteoporosis. Therefore, although still at a preclinical stage, the development of selective CB2 molecules has gained of interest as new targets in drug discovery. Recent data have unravelled a key role of CB2 receptors during chronic and acute liver injury, including fibrogenesis associated to chronic liver diseases, ischaemia-reperfusion-induced liver injury, and hepatic encephalopathy associated to acute liver failure. This review summarizes the latest advances on the recently identified role of CB2 receptors in the pathophysiology of liver diseases.

Long-term results of valve replacement with the St. Jude Medical prosthesis.

To assess with truly long follow-up the long-term results of valve replacement with the St. Jude Medical prosthesis (St. Jude Medical, Inc., St. Paul, Minn.), we reviewed the case histories of the first 1112 patients undergoing 1244 valve replacements with this valve between June 12, 1978, and June 12, 1987: 690 male (62%) and 422 female patients, mean age 56 years. A total of 773 patients (69%) had the aortic valve replaced, 207 (19%) the mitral valve, and 132 (12%) the aortic and mitral valves. There were 42 hospital deaths (3.8%). Follow-up was 97.5% complete (8988 patient-years). There were 213 late deaths. Ninety-one (43%) were considered valve-related: sudden death, n = 27; anticoagulant-related hemorrhage, n = 22; thromboembolism, n = 19; prosthetic valve endocarditis, n = 13; valve thrombosis, n = 9; and noninfectious perivalvular leak, n = 1. Overall actuarial survival, including hospital mortality, was 68% +/- 6% (95% confidence limits) 14 years after the operation. Linearized rates of late valve-related events were as follows: thromboembolism, 1.09% per patient-year; anticoagulant-related hemorrhage, 0.94% per patient-year; prosthetic valve endocarditis, 0.32% per patient-year; valve thrombosis, 0.33% per patient-year; and perivalvular leak, 0.19% per patient-year. Actuarial freedom, at 14 years, from thromboembolism was 89% +/- 3%, anticoagulant-related hemorrhage 83% +/- 8%, valve thrombosis 97% +/- 1%, and reoperation 95% +/- 3%. Actuarial freedom from all valve-related deaths and valve-related morbidity and mortality, at 14 years, was 84% +/- 6% and 61% +/- 8%, respectively. We conclude that, because of its low thrombogenicity, low incidence of valve-related events, and low valve-related mortality, the St. Jude Medical valve is one of the best performing mechanical prosthesis currently available. Nevertheless, the late valve-related complications and deaths illustrate that the quest for a "perfect" prosthesis remains unfulfilled.

Polyclonal antibodies against the rat NK1 receptor: characterization and localization in the spinal cord.

We have developed antibodies against the NK1 receptor and have investigated its cellular distribution. Rabbit polyclonal antibodies were generated against peptide (19-32) of the rat brain NK1 receptor. They were very specific to the NK1 site as shown by ELISA against various epitopes of NK1, NK2 and NK3 receptors and by immunoblotting of proteins from bacteria transfected with rat brain NK1 receptor cDNA and from rat cortex. Determining how immunostained NK1 receptors are distributed in the rat spinal cord made it possible to identify the cellular structures on which NK1 receptors are located and where they form synapses with SP terminals. In the superficial layers of the dorsal horn, the NK1 receptors appeared mainly of dendritic nature and were, like SP, abundant. In the deep layers of the dorsal horn and in the ventral horn, they were associated mostly with cell bodies.

Bronchial revascularization in double-lung transplantation: a series of 8 patients. Bordeaux Lung and Heart-Lung Transplant Group.

Donor airway ischemia is the main cause for defective tracheal or bronchial healing after double-lung transplantation. Anatomical studies and bronchial arteriograms have shown that the right intercostal bronchial artery is constant (95% of instances) and provides an important blood supply to the distal trachea, the carina, and the right bronchial tree as well as to the left side through a subcarinal and periadventitial anastomostic network. To maintain this important bilateral bronchial circulation, it is of capital importance not to mobilize the arteries individually and to avoid large dissections around the carina. Both bronchi can thus be revascularized by indirect aortic reimplantation using a bypass graft to a single aortic patch that includes the origin of the right intercostal bronchial artery. Furthermore, the origin of other vessels (a common trunk and left arteries) can be found within a short distance of the right intercostal bronchial artery and possibly be contained within the same aortic patch. From a series of 56 lung transplantations, 8 patients underwent restoration of the bronchial vascularization using a recipient saphenous vein graft between the donor bronchial arteries and the anterior aspect of the recipient's ascending aorta. A lower tracheal anastomosis was performed. Bronchial arterial blood supply was evaluated both by endoscopy and by arteriography at about the 15th postoperative day. The bronchial circulation was visualized at this time in five of seven arteriographies, and this was associated with excellent tracheal healing in all 8 patients.

Lung transplantation with bronchial revascularisation. Surgical anatomy, operative technique and early results.

Ischaemic anastomotic complications are an important cause of mortality and morbidity after lung transplantation. Anatomical studies have demonstrated that the pattern of bronchial arterial supply is relatively constant and therefore amenable to attempts at revascularisation. From May 1990, 10 patients who had a double lung transplantation (tracheal anastomosis) and 1 patient who had a right lung transplantation underwent concomitant bronchial revascularisation. There were two early and one late deaths. There were no anastomotic complications. Regular endoscopic examination showed satisfactory healing in all patients. Early angiography showed patent grafts in 7 of 9 patients. At a mean follow-up of 11 months (range 6-17 months) 8 patients are well and leading a normal life. This report describes the anatomical basis, technical aspects and early results of a promising operative procedure in the field of lung transplantation.

Results of carotid endarterectomy in patients 75 years of age and older.

From April 1980 to September 1989, 69 patients over 75 years of age (mean 78 years, range 75 to 86) underwent 81 carotid endarterectomies. Twenty three percent were asymptomatic, 56.5% had symptoms appropriate to lesion location and 20.5% had a non hemispheric syndrome. Nine patients required an associated procedure (combined cardiac surgery 6 pts; vascular surgery 3 pts). Perioperative mortality was 3.7%. The combined early lethal and non lethal stroke rate was 6.1%. Actuarial survival, at 10 years, was 58.4% +/- 10, and the incidence of freedom from stroke at 10 years was 86.2% +/- 5. Despite the fact that the hospital mortality of patients over 75 years undergoing carotid endarterectomy is more than three times that of patients operated on under 75 years of age (1.2%), the combined stroke and neurologic mortality rate is similar to that of patients under 75 years (5.3%). Carotid surgery in patients over 75 years of age does not increase life expectancy but does improve the quality of survival which depends mainly on cardiac events.

[Anatomical bases for bronchial arterial revascularization in double lung transplantation]. / Bases anatomiques de la revascularisation artérielle bronchique dans les transplantations bi-pulmonaires.

A study of the bronchial arterial blood supply was conducted to facilitate in surgical attempts of bronchial revascularization in double lung transplantation. This study consisted of 20 cadaveric anatomical dissections of the bronchial arterial blood supply as well as a retrospective review of 50 bronchial arteriograms. The right bronchial tree was supplied by an artery originating from the right intercostal bronchial arterial trunk in 76 to 95% of the cases. This artery also supplied the distal trachea and the carina in over 80% of cases as well as the proximal left bronchial tree via a network of small collaterals found in the subcarinal compartment and adventitial tissues located on the anterior surface of the descending aorta. A common arterial trunk for both the right and left bronchial trees was found in 12 of the 20 dissections (60%). Left bronchial arteries were much smaller and less consistent. Proximity of the bronchial arteries orifices was frequently observed: in 10 of the 20 dissections it allowed simultaneous reperfusion of more than one vessel. To maintain the vascular anastomotic network in between the right and left trees, extensive vascular dissection and carinal resections are prohibited. This will allow revascularization of the whole tracheal bronchial tree via the supply of the origin of the RICBA.

[Perforation and rupture of the esophagus. Apropos of 35 cases]. / Les perforations et ruptures de l'oesophage. A propos de trente-cinq cas.

A series of 35 oesophageal perforations from the period 1980-1987 is reported. Sixteen perforations followed oesophageal endoscopy, 10 were spontaneous, 8 were due to foreign bodies and one was post-operative. The delay in reaching the right diagnosis was less than 24 hours in 18 cases and more than 24 hours in 17 cases. Oesophageal leak was demonstrated in 86% of our cases by contrast study; in the others by rigid oesophagoscopy. Perforation occurred in the cervical oesophagus in 6 patients, thoracic oesophagus in 28 and abdominal oesophagus in 2 (one had a double perforation). Three patients were managed non operatively and survived. Cervical oesophagostomy and oesophageal diversion were used in 4 patients as primary treatment because of perforation occurring in caustic burn cases (2 cases, both survived) or late severe sepsis (2 cases, both died). Two patients with neoplastic stricture were treated by oesophago-jejunal bypass without resection and partial oesophago-gastrectomy respectively: both survived. Direct suture and closure of the perforation were performed in 26 patients. Two died, one because of oesophageal leak. Post-operative localized leaks developed in 5 other patients without any mortality and 4 healed with conservative management. The overall mortality rate was 11% (4 patients). All had a delayed diagnosis (more than 48 hours). We suggest that even in patients with delayed diagnosis of a non-malignant oesophageal perforation, direct suture and closure should be attempted under protection of functional oesophageal diversion and "contact drainage" to canalize a possible post-operative localized leak. Good oesophageal diversion can be achieved by naso-oesophageal suction and gastric suction through gastrostomy or with oesogastric antireflux procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings.

Chronic liver diseases represent a major health problem due to cirrhosis and its complications. During the last decade, endocannabinoids and their receptors have emerged as major regulators of several pathophysiological aspects associated with chronic liver disease progression. Hence, hepatic cannabinoid receptor 2 (CB(2)) receptors display beneficial effects on alcoholic fatty liver, hepatic inflammation, liver injury, regeneration and fibrosis. Cannabinoid receptor 1 (CB(1)) receptors have been implicated in the pathogenesis of several lesions such as alcoholic and metabolic steatosis, liver fibrogenesis, or circulatory failure associated with cirrhosis. Although the development of CB(1) antagonists has recently been suspended due to the high incidence of central side effects, preliminary preclinical data obtained with peripherally restricted CB(1) antagonists give real hopes in the development of active CB(1) molecules devoid of central adverse effects. CB(2) -selective molecules may also offer novel perspectives for the treatment of liver diseases, and their clinical development is clearly awaited. Whether combined treatment with a peripherally restricted CB(1) antagonist and a CB(2) agonist might result in an increased therapeutic potential will warrant further investigation.

[The endocannabinoid system as a novel target for the treatment of liver fibrosis]. / Le système endocannabinoïde, une nouvelle cible pour le traitement de la fibrose hépatique.

The cannabinoid system comprises specific G protein-coupled receptors (CB1 and CB2), exogenous (marijuana-derived cannabinoids) and endogenous (endocannabinoids) ligands, and a machinery dedicated to endocannabinoid synthesis and degradation. Studies over two decades have extensively documented the crucial role of the cannabinoid system in the regulation of a variety of pathophysiological conditions. However, its role in liver pathology has only been recently unravelled, probably given the low expression of CB1 and CB2 in the normal liver. We have recently demonstrated that CB1 and CB2 receptors display opposite effects in the regulation of liver fibrogenesis during chronic liver injury. Indeed, both receptors are up-regulated in the liver of cirrhotic patients, and expressed in liver fibrogenic cells. Moreover, CB1 receptors are profibrogenic and accordingly, the CB1 antagonist rimonabant reduces fibrosis progression in three experimental models. In keeping with these results, daily cannabis smoking is a risk factor for fibrosis progression in patients with chronic hepatitis C. In contrast, CB2 display antifibrogenic effects, by a mechanism involving reduction of liver fibrogenic cell accumulation. These results may offer new perspectives for the treatment of liver fibrosis, combining CB2 agonist and CB1 antagonist therapy.

Evidence for an excitonic insulator phase in 1T-TiSe2.

We present a new high-resolution angle-resolved photoemission study of 1T-TiSe2 in both its room-temperature, normal phase and its low-temperature, charge-density wave phase. At low temperature the photoemission spectra are strongly modified, with large band renormalizations at high-symmetry points of the Brillouin zone and a very large transfer of spectral weight to backfolded bands. A calculation of the theoretical spectral function for an excitonic insulator phase reproduces the experimental features with very good agreement. This gives strong evidence in favor of the excitonic insulator scenario as a driving force for the charge-density wave transition in 1T-TiSe2.

Photoemission of a quantum cavity with a nonmagnetic spin separator.

Quantum well states are a consequence of confinement in a quantum cavity. In this study we investigate with photoemission the influence of the interface electronic structure on the quantum well state energy dispersion in ultrathin Mg(0001) films on W(110). Coupling between the sp-derived quantum well states and the substrate across the interface becomes manifest in a deviation from free electronlike dispersion behavior. Most importantly, we observe a marked level splitting, which is interpreted as due to the Rashba effect at the interface. Such an interfacial electron beam splitting on materials with strong spin-orbit coupling is an essential ingredient for novel spintronic devices. The combination of a quantum cavity with a heavy, electron reflecting substrate reveals spin-splitting effects in ultrathin films without conventional magnetism being involved.

Synthetic-aperture experiment in the visible with on-axis digital heterodyne holography.

We have developed a new on-axis digital holographic technique, heterodyne holography. The resolution of this technique is limited mainly by the amount of data recorded on two-dimensional photodetectors, i.e., the number of pixels and their size. We demonstrate that it is possible to increase the resolution linearly with the amount of recorded data by aperture synthesis as done in the radar technique but with an optical holographic field.

Numerical heterodyne holography with two-dimensional photodetector arrays.

We present an original heterodyne holography method for digital holography that relies on two-dimensional heterodyne detection to record the phase and the amplitude of a field. The technique has been tested on objects as much as 13 mm in size. Consistency checks were performed, and high-resolution images were computed. We show the requirement for a spatial filter to select properly sampled near-axis photons. Heterodyne holography is superior to off-axis digital holography for both field of view and resolution.

An efficient screening assay for the rapid and precise determination of affinities between leucine zipper domains.

The protein products of the jun and fos oncogenes require a functional protein-protein interaction domain, called the "leucine zipper domain", to exert their transcriptional regulatory activity. A scintillation proximity assay was developed in which the biotinylated leucine zipper domain of the Jun protein (275-315) was immobilized on streptavidin-coated microfluorospheres and in which the leucine zipper domain of the Fos protein (160-200) was used as free, labeled ligand. The Fos leucine zipper peptide specifically bound to the Jun leucine zipper peptide, and for the first time, a dissociation constant (Kd = 110 +/- 12 nM in PBS/0.1% Tween) could be determined. Optimal heterodimer formation was reached at neutral pH. Both acidic and alkaline pH decreased the association of the peptides which was, furthermore, completely abolished by 500 mM NaCl, confirming that charged residues are critical for heterodimerization. A commercially obtained recombinant Jun protein competed as efficiently as the Jun leucine zipper peptide for binding to the Fos peptide, confirming the feasibility of using the two leucine zipper peptides to study the interactions between the two transcription factors. We also injected leucine zipper peptides individually into Xenopus oocytes to study whether they would interfere with the activity of the Fos/Jun heterodimer in vivo. Both peptides blocked selectively insulin-mediated oocyte maturation with an IC50 in the range of 15 ng per oocyte. In conclusion, the scintillation proximity assay described here may be used to investigate protein-protein interactions mediated by leucine zipper structures and to identify compounds that inhibit leucine zipper association.

[Left thoracotomy in the excision of cancers of the cardia and the lower third of the esophagus. Apropos of a series of 210 cases]. / La thoracophrénotomie gauche dans l'exérèse des cancers du cardia et du tiers inférieur de l'oesophage. A propos d'une série de 210 cas.

From January 1 1980 to December 1993, 210 patients underwent exeresis of a cancer of the cardia or the lower third of the oesophagus. There were 193 males and 17 females (mean age 63.5 years, range 18-84). Cancers were in an advanced stage in 56.6% (stage 0, 0.95%; stage 1, 9.04%; stage 3, 43.3%; stage 4, 6.19%). Postoperative morbidity was 21% and hospital mortality was 3.81%. Actuarial survival rate at 1, 3, 5 and 10 years were 64.1%, 23.9%, 17.7% and 12.8% respectively. The advent of the CT scan, better patient selection and improved nutrition management and postoperative care have greatly improved hospital mortality (7 deaths for 118 operations before 1987, i.e. 5.93% and 1 death for 92 operations since 1987, i.e. 1.08%. Creating a circumferential instead of radial phrenotomy and the possibility of raising the anastomosis to upper thorax or in combination with left access and cervicotomy have led to excellent immediate results and confirm our choice in this method.

[Non-esterified fatty acids and alpha 1-fetoprotein are the modulators of uterine binding of estrogens during development in the rat]. / Les acides gras non estérifiés et l'alpha 1-foetoprotéine sont les modulateurs de la fixation utérine des oestrogènes au cours du développement du rat.

We studied the effects of different classes of non-esterified fatty acids (NEFA) on the binding of natural and synthetic estrogens by uterine cytosolic receptors. The role of alpha 1-fetoprotein (AFP) in this process was also studied. Saturated fatty acids, irrespective of their concentration, slightly increased (120%) E2 binding to the 4S and 8S uterine cytosolic receptors. The effect of unsaturated fatty acids was dependent on their concentration: at 0.5 X 10(-4) M unsaturated NEFA potentiated the E2 binding to the receptor. At a higher concentration (2.0 X 10(-4) M), the NEFAs were highly inhibitory. This inhibition was dependent on the degree of unsaturation of the fatty acids. Tritiated arachidonic acid interacted directly with the 4S and 8S cytosol receptor. Furthermore, we demonstrated a double competition between murine AFP and the 8S receptor for estrogens and unsaturated NEFA. The effect of these hydrophobic ligand exchanges between transport proteins and receptors on the modulation of the action of estrogen is discussed.