Influence of chimeric human-bovine fibers on adenoviral uptake by liver cells and the antiviral immune response.

Human adenoviruses (HAdV) are widely used for in vitro and in vivo gene transfer. Viral hepatotropism, inflammatory responses and neutralization by pre-existing antibodies (NAbs) are obstacles for clinical applications of HAdV vectors. Although the multifactorial events leading to innate HAdV toxicity are far from being elucidated, there is a consensus that the majority of intravenously injected-HAdV vectors is sequestered by Kuppfer cells, probably independently of coagulation factors. In this study, we show that the adenoviral-associated humoral and innate cytokine immune responses are significantly reduced when HAdV-5 vector carrying human bovine chimeric fibers (HAdV-5-F2/BAdV-4) is intravenously injected into mice. Fiber pseudotyping modified its interaction with blood coagulation factors, as FIX and FX no longer mediate the infection of liver cells by HAdV-5-F2/BAdV-4. As a consequence, at early time points post-infection, several cytokines and chemokines (IFN-gamma, IL-6, IP-10, MCP-1, RANTES and MP1beta) were found to be present at lower levels in the plasma of mice that had been intravenously injected with HAdV-5-F2/BAdV-4 compared with mice injected with the parental vector HAdV-5. Moreover, genetic modification of the fiber allowed HAdV-5-F2/BAdV-4 to partially escape neutralization by NAbs.

The adenovirus type 3 dodecahedron's RGD loop comprises an HSPG binding site that influences integrin binding.

Human type 3 adenovirus dodecahedron (a virus like particle made of twelve penton bases) features the ability to enter cells through Heparan Sulphate Proteoglycans (HSPGs) and integrins interaction and is used as a versatile vector to deliver DNA or proteins. Cryo-EM reconstruction of the pseudoviral particle with Heparan Sulphate (HS) oligosaccharide shows an extradensity on the RGD loop. A set of mutants was designed to study the respective roles of the RGD sequence (RGE mutant) and of a basic sequence located just downstream. Results showed that the RGE mutant binding to the HS deficient CHO-2241 cells was abolished and unexpectedly, mutation of the basic sequence (KQKR to AQAS) dramatically decreased integrin recognition by the viral pseudoparticle. This basic sequence is thus involved in integrin docking, showing a close interplay between HSPGs and integrin receptors.

[Adenoviruses structure]. / Structure des ad�novirus.

Adenoviruses are double stranded DNA non enveloped viruses. Although these viruses are widely studied for gene therapy and anticancer applications, fundamental knowledge of these viruses, especially from a structural point of view is lacking. This is probably partly responsible for the limited success of the first clinical trials.With these viruses, one of the main conditions necessary to use adenoviruses for therapeutic application is structural modification of the virus. Indeed, one has to retarget the virus to specific tissues and/or remove all the immunogenic loops present on the outside of the virus in order to limit the host immune response. To make these changes rationally, the structure of the capsid has to be known at atomic resolution. Today, electron microscopy is the only tool that enables us to have access to the structure of the entire virus, but only at intermediate resolution. Because the atomic structures of the adenovirus major capsid proteins are known, one can combine these structures with the electron microscopy based envelope to calculate a model of the capsid at quasi-atomic resolution. These kinds of models are useful to visualize and understand the complexity of the virus. Nevertheless, the structure of the entire capsid at atomic resolution will really be necessary to use the virus in a safe way.

Development of the dodecahedral penton particle from adenovirus 3 for therapeutic application.

The subviral dodecahedral particle of adenovirus 3, which assembles spontaneously in insect cells expressing the viral penton base protein, shows promise as a vector for drug delivery. Its ability to gain cell entry has been demonstrated and recent structural analysis has outlined details of the interfaces between penton bases and the importance of proteolysis of the penton base N terminus for assembly, providing a basis for understanding particle assembly and stability. Here, work in manipulating the assembly status of the dodecahedron by changing buffer conditions and subsequent success in passively encapsidating a marker molecule is described. This represents an important stage towards development of the dodecahedral particle for use as a delivery vehicle capable of targeting therapeutic molecules to specific cell types.

Protein transduction into human cells by adenovirus dodecahedron using WW domains as universal adaptors.

BACKGROUND: Direct protein transduction is a recent technique that involves use of peptide vectors. In this study, we demonstrate that adenovirus dodecahedron (Dd), a virus-like particle devoid of DNA and able to penetrate cells with high efficiency, can be used as a vector for protein delivery. METHODS: Taking advantage of Dd interaction with structural domains called WW, we have elaborated a universal adaptor to attach a protein of interest to this vector. RESULTS: A tandem of three WW structural domains derived from the Nedd4 protein enables the formation of stable complexes with Dd, without impairing its endocytosis efficiency. Our protein of interest fused to the triple WW linker is delivered by the dodecahedron in 100% of cells in culture with on average more than ten million molecules per cell. CONCLUSION: These data demonstrate the great potential of adenovirus dodecahedron in combination with WW domains as a protein transduction vector.

Structure of the dodecahedral penton particle from human adenovirus type 3.

The sub-viral dodecahedral particle of human adenovirus type 3, composed of the viral penton base and fiber proteins, shares an important characteristic of the entire virus: it can attach to cells and penetrate them. Structure determination of the fiberless dodecahedron by cryo-electron microscopy to 9 Angstroms resolution reveals tightly bound pentamer subunits, with only minimal interfaces between penton bases stabilizing the fragile dodecahedron. The internal cavity of the dodecahedron is approximately 80 Angstroms in diameter, and the interior surface is accessible to solvent through perforations of approximately 20 Angstroms diameter between the pentamer towers. We observe weak density beneath pentamers that we attribute to a penton base peptide including residues 38-48. The intact amino-terminal domain appears to interfere with pentamer-pentamer interactions and its absence by mutation or proteolysis is essential for dodecamer assembly. Differences between the 9 Angstroms dodecahedron structure and the adenovirus serotype 2 (Ad2) crystallographic model correlate closely with differences in sequence. The 3D structure of the dodecahedron including fibers at 16 Angstroms resolution reveals extra density on the top of the penton base that can be attributed to the fiber N terminus. The fiber itself exhibits striations that correlate with features of the atomic structure of the partial Ad2 fiber and that represent a repeat motif present in the amino acid sequence. These new observations offer important insights into particle assembly and stability, as well as the practicality of using the dodecahedron in targeted drug delivery. The structural work provides a sound basis for manipulating the properties of this particle and thereby enhancing its value for such therapeutic use.

Synthesis, cellular localization, and quantification of penton-dodecahedron in serotype 3 adenovirus-infected cells.

Adenovirus penton is a non-covalent complex composed of the penton base and fiber proteins, localized at the twelve vertices of the icosahedral virus capsid. In cells infected by adenovirus serotype 3 (Ad3), penton is found not only in the virus capsid but also self-assembled in dodecahedra formed through interactions between the twelve penton bases. In this study, the intracellular trafficking of penton proteins from the cytoplasm to the nucleus has been followed, and the nuclear re-arrangement induced by viral infection has been observed by electron microscopy of ultrathin sections. The amount of dodecahedra has been assessed in relation to the number of Ad3 infectious virions produced during the Ad3 replication cycle. It appears that dodecahedra are produced in a large excess over viral infectious particles and that they are located intranuclearly along the nuclear membrane of Ad3-infected cells at late times of infection.

[Bariatric surgery in France: results of a nationwide prospective survey]. / La chirurgie de l'obésité en France: résultats d'une enquête prospective nationale.

AIM: To compare the actual practice of bariatric surgery in France with the guidelines of scientific societies regarding surgical indications and followup. METHODS: This a prospective descriptive transversal study performed within a two month period (December 2002 - January 2003) in all patients for which a consent demand has been sent to the Medical Insurance Services (examined by an administrative consultant) and/or patients operated on for morbid obesity (with or without administrative consent). RESULTS: One thousand and three patients have been examined by an administrative consultant before obesity surgery and 1238 patients have been operated in 263 centres including 79 public (non-profit) centres and 184 private centres. In 16.7 % of the cases, there were wrong indications according to recognized criteria (BMI<35 kg/m(2) or lack of comorbidities for BMI between 35 and 39) or even contraindications because of other diseases. Patient informed consent was retrieved in only 54 % of medical files and follow up protocol was done in only 47 % of the cases. Because of several missing data, the practice of bariatric surgery followed the guidelines in only 34 % of cases. In hospital morbidity rate was 5 %. Two patients died postoperatively (mortality rate 0.2 %). CONCLUSIONS: This study demonstrates that the practice of bariatric surgery needs to be improved in France.

[Virus and heparan sulphate: from adsorption mechanism to cellular entry]. / Virus et héparane sulfate : des mécanismes d'adsorption cellulaire à l'entrée virale.

Heparan sulphates are complex polysaccharides that belong to a class of molecules called glycosaminoglycans. Linked to different core proteins, they are ubiquitously expressed at most cells' surface. These molecules interact with a huge number of distinct proteins and regulate their biological activities. In particular different viruses make use of heparan sulphate interactive properties to dock themselves at the surface of their cellular targets. This interaction enables the viruses to concentrate at the close proximity of others molecules that act as co-receptors, and as such increases viral entry. Recent progresses in the structural characterisation of glycosaminoglycans have helped to understand the relationship between the structure of these molecules and their ability to recognise viral capside or envelope glycoproteins. These works also showed the direct role of these molecules in viral tropism and mechanism of entry, and suggest medical applications as biotechnological strategies.

[A comparison of the management of severe high blood pressure between 1999 and 2003 in France]. / Comparaison des prises en charge de l'hypertension artérielle sévère en France entre 1999 et 2003.

AIM: To measure the change in blood-pressure control in two populations of patients with severe high blood pressure between 1999 and 2003. METHOD: The French National Healthcare Fund performed two observational, cross-sectional surveys on the medical management of high blood pressure, the first in 1999 and the second in 2003. Each survey enrolled patients aged between 20 and 80 years old who filed a first-time request for exemption from co-payments for this long-term disorder. Study data was collected by the health fund's salaried physician advisors who directly examined the patients and from information gathered from each patient's attending physician. Adequate blood pressure control was defined according to the guidelines set out by the ANAES in 1997 and determined by calculating the average of the last three blood pressure figures recorded by the patient's attending physician (systolic [SBP] and diastolic [DBP] arterial blood pressures). RESULTS: 10,665 patients were enrolled in the 1999 survey and 2,584 were enrolled in the 2003 survey. The average age was 63.1 +/- 0.2 years in 1999 and 64.4 +/- 0.4 years in 2003. The proportion of diabetic patients in the two surveys remained stable: 27.5% +/- 1.0 in 1999 and 28.4% +/- 1.7 in 2003. Between 1999 and 2003, the percentage of patient who were treated for hypercholesterolemia increased from 44.0% +/- 1.1 to 54.3% +/- 1.9. Between 1999 and 2003, the proportion of patients who were considered well-controlled (SBP and DBP < 140/90 mmHg) or, if older than 60 years with isolated systolic high blood pressure (DBP < 90 mmHg and SBP < or = 160 mmHg) increased almost 5% points, going from 40.8% +/- 1.1 in 1999 to 45.5% +/- 1.9 in 2003. In diabetic patients, in whom the cut-off threshold is 130/85 mmHg, 6.7% +/- 1.1 were considered well-controlled in 1999 while 5.4% +/- 1.7 were deemed well-controlled in 2003. The proportion of well-controlled patients in the sub-group of hypertensive patients with renal failure (cut-off thresholds: 125/75 mmHg) remained relatively stable between 1999 and 2003: 5.2% [2.5; 7.9] versus 2.8% [0.5; 8.6]. CONCLUSION: There was a significant increase in the proportion of well-controlled hypertensive patients between 1999 and 2003. This increase occurred at the same time as a number of initiatives (scientific societies, federal government as well as the National Health Fund) intended to sensitize physicians to the need to obtain adequate blood pressure control.

The prevalence and cost of diabetes in metropolitan France: what trends between 1998 and 2000?*.

OBJECTIVES: Our aim was to update available data concerning the prevalence and cost of diabetes in metropolitan France. METHODS: We performed a retrospective study using patient reimbursement data from all the 128 local health offices (CPAM) in metropolitan France. We selected patients who received reimbursements for an oral hypoglycemic agent or insulin. Thus, 704,423 patients were studied by using 1998 data and 1,145,603 patients were studied by using data from 2000. The expenditures studied represented the total amount reimbursed by national health insurance to diabetic patients. The cost differential which could be attributed to diabetes was calculated by determining the difference between costs generated by diabetic patients to those generated by the rest of the population of the same age. RESULTS: Between 1998 and 2000, the prevalence of diabetes treated in the population of affiliates covered by the general scheme increased from 2.78% to 2.96%. The total amount paid by the general scheme for care to diabetic patients (related to diabetes or not) was 5.710 billion euros in 2000 compared to 4.862 billion euros in 1998. The amount which can be attributed to diabetes alone can be estimated to be 2.414 billion euros in 2000 compared to 2.021 billion euros in 1998. After considering the impact of the increase in the number of treated diabetics, a modification in the modalities of medical care probably accounts for 183 million euros of the cost increase. Medical equipment (self blood glucose monitoring devices, reagent strips, finger lancets...) accounts for 39.3% (72 million euros) of this cost differential, medications account for 34.4% (63 million euros) and nursing care 16.9% (31 million euros). There was no change in the cost of diabetes with relation to expenses for medical consultations.

Adenovirus dodecahedron allows large multimeric protein transduction in human cells.

Adenovirus dodecahedron is a virus-like particle composed of only two viral proteins of human adenovirus serotype 3 that are responsible for virus attachment and internalization. We show here that this dodecameric particle, devoid of genetic information, efficiently penetrates human cells and can deliver large multimeric proteins such as immunoglobulins.

Controlled transgene expression by E1-E4-defective adenovirus vectors harbouring a "tet-on" switch system.

BACKGROUND: The "tet switch system" was originally described under the tet-off configuration with its components encoded by two separate plasmids. Since then, many virus vectors harbouring tet-off components have been designed and their regulation by tetracycline is widely reported. On the contrary, tet-on regulation by viral vectors is poorly documented. METHODS: E1-E4-defective adenoviruses harbouring either rtTA or the luciferase gene under a minimal inducible promoter (TK* or CMV*) or both components in a single genome were produced. Using either a double or a single virus strategy, induction of luciferase expression was investigated in various cell lines, in mice muscle and in rat brain. RESULTS: Over 400-fold induction can be reached with PC12 and NHA cells using a double virus strategy. Comparison of the background activity of different minimal inducible promoters revealed a significant difference between TK* and CMV* promoters both with the cell culture and the in vivo experiments. Interestingly, a single virus strategy permitted an induction exceeding 600-fold with human astrocyte primary cells. Moreover, the E1-E4-defective adenovirus-mediated tet-on system can be quickly switched off and turned back on again. Depending on the cell line, the level of rtTA derived by the single virus strategy differed, resulting in different efficiencies. Experiments performed in rat striatum and mouse muscle confirmed the importance of rtTA expression and minimal promoter used on both doxycycline-independent expression and induction efficiency. Under appropriated rtTA expression, a 32-fold induction is observed in mouse muscle. CONCLUSIONS: In the recombinant adenovirus context, the CMV* but not the TK* promoter is sensitive to transcriptional interference resulting in high doxycycline-independent expression. By paying attention to the rtTA expression, moderate and high induction can be obtained in vivo and in vitro accordingly.

[Management of severe hypertension in France in 1999 and 2000: intermediate results of a health insurance intervention program]. / Prise en charge de l'HTA sévère en France en 1999 et 2000: bilan intermédiaire du programme d'interventions de l'Assurance maladie.

AIM: Within the framework of its long-term public health program aimed at improving the clinical management of hypertension (HBP), the French health care funds performed two nationwide surveys concerning affiliates who were recently waived from making co-payments for severe hypertension. The aim was to measure the difference between observed clinical management and benchmark care, defined by the 1997 ANAES guidelines (National Agency for Accreditation and Health Evaluation), at the onset (May 1999) and during the program (November 1999) in order to detect any changes in clinical management between the two study periods, the timeframe corresponding to the intervention period. METHODS: The patient samples used in the two studies involved affiliates aged between 20 and 80 years old living in France or one of its overseas territories who were recently waived from making co-payments (ETM) for severe hypertension (these patients are reimbursed 100% for all care related to the disorder). The evaluation was based on retrospective data furnished by attending physicians. The indicators isolated in order to compare the two study periods were blood pressure control, suggested life-style changes and prescribed drugs. RESULTS: The first survey took place between May and November 1999 and enrolled 10,665 patients (corresponding to a weighted patient population of 50,383) while the second studied 2,649 patients in November 2000. The study population in 1999 was, on the average, younger than the study population in November 2000: 63.1 years +/- 0.2 vs 65.4 years +/- 0.4. Nearly two patients out of three presented at least one other major cardiovascular risk factor in addition to HBP (cigarette smoking, diabetes mellitus or dyslipidemia): 63.9% in 1999 and 64.4% in 2000. Nearly one patient out of seven had associated coronary artery disease: 14.1% in 1999 and 15.3% in 2000 and more than one out of ten had associated cerebro-vascular disease: 12.7% in 1999 and 12.2% in 2000. There were more diabetic patients in the 1999 group than in the 2000 group: 27.5% +/- 1.0 vs 23.9% +/- 1.6. The proportion of patients who had poorly controlled blood pressure (systolic > 140 mmHg or > 160 mmHg in subjects aged between 60 and 80 years with isolated systolic hypertension, or a diastolic > 90 mmHg) did not change: 46.8% +/- 1.1 in 1999 and 45.7% +/- 1.9 in 2000. If the guideline recommendations for diabetics (blood pressure < 130/85) are applied. 85.4% of the diabetic patients were poorly controlled in 1999 and 86.6% in 2000. Similarly, in hypertensive patients with kidney failure (guideline recommendations: < 125/75 mmHg), 94.5% were poorly controlled in 1999 and 96.3% in 2000. Recommended life-style changes (reduction in salt intake, weight loss, lower alcohol consumption, increased physical activity) were not well followed in both studies: in 1999, fewer than one patient out of four completely implemented the desired changes (23.7%) while only 24.5% did so in 2000. Physicians prescribed specifically indicated therapeutic agents considering associated diseases in 68.0% of the patients in 1999 and in 67.6% in 2000. Prescriptions contained a potentially contraindicated drug in 27.3% of the cases in 1999 and in 28.0% in 2000. CONCLUSION: A comparison of the results of the two surveys performed in 1999 and 2000 concerning the management of patients with severe hypertension failed to demonstrate any significant differences in blood pressure control or treatment modalities. While not questioning the value of the interventions of the health funds, these findings illustrate how difficult it is to change clinical practice over a short time period, especially in a disorder involving a number of different elements which include, among others, individual patient behavior. In order to significantly improve clinical management, it will probably be necessary to continue the dialogue between medical advisors of the health care funds (médecins conseils) and clinicians and to renew campaigns aimed at helping patients become more responsible.

[Treatment of severe arterial hypertension: cost of drug prescriptions in accordance with ANAES guidelines]. / Le traitement de L'HTA sévère: coût de la prescription et conformité aux recommandations de L'ANAES.

French national health insurance has carried out two nationwide surveys as part of its programme intended to improve the care given to patients with hypertension, focusing on affiliates diagnosed with severe hypertension entitled to exemption from co-payments (patients are reimbursed 100 per cent for all care related to the corresponding disorder). The objective was to measure the difference between observed care and the quality of care delineated in the guidelines (1997) elaborated by the National Agency for Healthcare Accreditation and Evaluation (ANAES). The before and after comparison was designed to determine whether actual care is in accordance with the guideline's standards. The initial survey took place from 31 May to 12 November 1999 over the entire French territory (metropolitan and overseas departments) and concerned a representative sample of patients whose ages ranged from 20 to 80 years at the time they qualified for exemption from co-payments for severe hypertension. The method used for comparison involved the calculation of a number of different evaluation parameters, the principal one being blood pressure control, using the systolic (PAS) and diastolic (PAD) pressures reported by attending physicians. Other evaluation parameters included the quality of the therapeutic strategy utilized. A total of 10,665 patients were enrolled in the survey by using information gathered from 8377 practicing physicians. Extrapolated to the entire population in 1999, the results can be applied to 50,383 patients. The average age was 63 years and the patients had been treated for hypertension for an average of 9 years. In addition to severe hypertension, 64 per cent of the patients had other significant high-risk factors for cardiovascular disease: 44 per cent had dyslipidemia, 28 per cent had diabetes mellitus, 15 per cent were smokers. In 41 per cent of cases, the patients' blood pressures were well controlled (systolic and diastolic pressures below 140/90 mmHg or, for patients older than 60 years with only isolated systolic hypertension, systolic pressure equal to or lower than 160 mmHg); in 12 per cent of cases the patients' blood pressures were equal to the limit values; in 47 per cent of cases blood pressure was poorly controlled. Diabetics had poorly controlled blood pressure in 85 per cent of cases (systolic or diastolic pressures greater than 130/85 mmHg) and, similarly, 94 per cent of the patients who were in renal failure were poorly controlled (systolic or diastolic pressures greater than 125/75 mmHg). Preferential prescription with a particular therapeutic class, because of an existing comorbidity, was found in 68 per cent of patients whereas potentially contraindicated therapeutic classes were prescribed in 27 per cent. The daily cost of anti-hypertensive drug therapy was estimated at 8.05 francs per day per patient. Extrapolated to the study population in 1999, this represents 148.1 million francs. Less than 1 per cent of this observed cost (1.1 million francs) was economized by prescribing less expensive, alternative drug specialties in spite of the fact that an estimated 9.6 million francs could have been saved if these equivalent, alternative drugs had been prescribed. The potential saving corresponds to 6.5 per cent of the total observed cost. The care given to severely hypertensive patients is sub-optimum when compared with the ANAES guidelines (1997). In public health terms, the most preoccupying feature is poor blood pressure control because it occurs in a patient population with a high cardiovascular risk. These findings fully justify the continuation and amplification of the actions undertaken in this nationwide public health programme concerning the medical care given to hypertensive patients.

[Epidemiology of diabetes in metropolitan France]. / L'épidémiologie du diabète en France métropolitaine.

The statistical analysis of French HealthCare's database, containing total reimbursements to affiliates and a listing of delivered drug prescriptions in the form of specific drug codes, allowed us to update data on the epidemiology of diabetes. This study, performed during the first trimester of 1999 on the entire population of metropolitan France, found an overall prevalence of 2.78 % for diabetes in all affiliates of the regimen (Régime général) stricto sensu (3.06 % in the general population), 0.41 % corresponding to diabetic treated exclusively with insulin (0.44 % in the overall population) and to 0.12 % receiving both insulin and oral hypoglycemic agents concomitantly (0.13 % in the general population). The average age of diabetics, irrespective of the treatment they were receiving, was 63.1 years with a sex ratio M/F of 1.04. These findings confirm epidemiological forecasts which had predicted a significant increase in the prevalence of diabetes over the past few years. The study also confirmed data from the medical literature concerning geographic disparities in the epidemiology of this disease except for the results obtained in the north of France, a region generally thought to have a lower prevalence of diabetes, and which was found to have a prevalence equal to even greater than the national average.

[The cost of diabetes in metropolitan France]. / Le coût du diabète en France métropolitaine.

The statistical analysis of French HealthCare's database, containing total reimbursements to affiliates and a listing of delivered drug prescriptions in the form of specific drug codes, allowed us to update data of the cost of diabetes. This study, realized during the first trimester of 1999, used the combined databases of 110 local healthcare offices (CPAM) among the 128 existing in metropolitan France. French Social Security spent a total of 31.9 billion francs (4.9 billion euros) in care given to diabetics (or 24,137 francs per patient) comprised by 14.2 francs (2.2 billion euros) for in-hospital care and 17.7 billion francs (2.7 billion euros) for outpatient services. The total expenses for diabetic patients represented 4.7% of French Social Security's overall expenses for all its affiliates. The differential cost of diabetes (the difference, at equivalent ages, between cost generated by diabetic patients and those attributable to the remainder of the affiliated population) was estimated, for the generalized health-care regimen (régime général) in 1998, to be 13.3 billion francs (2.0 billion euros). These figures underscore the need to reinforce prevention and screening for end-organ complications since it is generally admitted that the disease's high cost is essentially related to its complications.

[Modalities of follow-up on non-insulin treated diabetics treated in metropolitan France in 1998]. / Les modalités de suivi des diabétiques non insulino traités en France métropolitaine durant l'année 1998.

The statistical analysis of French HealthCare's database allows a retrospective evaluation of the overall clinical care given to diabetics in the light of the guidelines (RBPC) promulgated by the National Agency of Health Accreditation and Evaluation (ANAES). This database contains no information on the stage of the disease process, the completeness of the clinical evaluation (neurological or foot examination) or the results of significant blood tests. We studied the follow-up care given to diabetics whom we were able to identify by isolating reimbursements for hypoglycemic agents using their corresponding drug codes. Considering the time needed for this new drug-coding system to become fully operational, the results can be extrapolated to the entire population of non-insulin treated diabetics. In 1998, almost all follow-up care was provided by general practitioners since only 5.5 % of the patients consulted an endocrinologist during the year studied. Blood sugar was generally monitored with fasting blood sugars rather than HbA1c which was only prescribed in 41.3 % of the patients during the final six months of the period under consideration. Screening and follow-up for degenerative complications were insufficient. Fewer than 40 % of the patients had received reimbursement for an ophtalmological consultation during the preceeding year and fewer than 30 % had an ambulatory resting EKG over the same time period. A certain number of factors were studied in order to determine if they were correlated to better clinical follow-up. The best follow-up was encountered in patients who had a consultation with an endocrinologist at least once during the year, those who were exonerated from co-payments (ALD 30) and finally, those aged between 40 and 59 years (at least with respect to appropriate laboratory tests).