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1.  Clinical features of drusenoid pigment epithelial detachment in age related macular degeneration 
Aim: To analyse clinical features of drusenoid pigment epithelium detachment (PED) in age related macular degeneration.
Methods: 61 eyes of 32 patients with untreated drusenoid PED were followed for an average of 4.6 years (range 1–17 years). Drusenoid PED was defined as ½ disc diameter (DD) of confluent soft drusen under the centre of the macula. All patients underwent visual acuity measurement, biomicroscopic fundus examination, stereoscopic colour photograph, and fluorescein and indocyanine green angiography. Optical coherence tomography was performed in selected cases at the last examination. Kaplan Meier survival analysis was performed to estimate the probability of complications.
Results: Three different natural outcomes were identified: persistence of drusenoid PED (38%), development of geographic atrophy (49%), and choroidal neovascularisation (CNV) (13%). Based on Kaplan Meier survival analysis, drusenoid PED had a 50% of chance of developing geographic atrophy after 7 years. If the drusenoid PED was greater than 2 DD or was associated with metamorphopsia at initial presentation, progression to atrophy or ingrowth of CNV occurred after 2 years (p<0.01).
Indocyanine green angiography confirmed fluorescein angiographic features or ascertained the presence of CNV when fluorescein angiography was equivocal. Optical coherence tomography was helpful in distinguishing coalescent soft drusen from drusenoid PED and disclosed the accumulation of sub or intraretinal fluid in eyes with CNV.
Conclusion: Drusenoid PED size greater than 2 DD and metamorphopsia were risk factors identified at presentation which affected prognosis. The evaluation of the eyes at risk requires the use of all imaging means in order to ascertain the diagnosis of CNV. At long term (over 10 years), geographic atrophy and CNV had occurred in 75% and 25% respectively, with a poor visual outcome.
doi:10.1136/bjo.2003.017632
PMCID: PMC1772148  PMID: 15090415
age related macular degeneration; atrophy; choroidal neovascularisation; drusenoid retinal pigment epithelium detachment; soft drusen
2.  Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C: indirect evidence of a role of hepatitis C virus genotype 3 in steatosis 
Gut  2004;53(3):420-424.
Background and aim: Recent studies suggest that liver steatosis in chronic hepatitis C may be the expression of a direct cytopathic effect of hepatitis C virus (HCV), particularly in patients infected with genotype 3. To investigate this hypothesis, we studied the relationship between steatosis evolution and HCV clearance after antiviral treatment in patients with chronic hepatitis C and paired liver biopsies.
Methods: A total of 151 patients (37 with HCV genotype 3; 114 with HCV non-3 genotypes) were selected according to the following criteria: presence of steatosis at initial biopsy; no antiviral treatment prior to the first biopsy; antiviral treatment received between the two biopsies; body mass index (BMI) <28 kg/m2; absence of excessive alcohol intake; no serum hepatitis B surface antigen or human immunodeficiency virus antibodies; and absence of diabetes mellitus. Evolution of steatosis was examined by comparing steatosis grades between the two biopsies.
Results: Twenty five patients (16.5%) were sustained virological responders (SVR) to antiviral treatment. Steatosis evolution after antiviral treatment was as follows: improvement in 36% of cases; stability in 51%; and worsening in 13%. Steatosis improvement was significantly more frequent in SVR than in non-responders (NR) (64% v 31%; p<0.004). This significant difference occurred in patients infected with genotype 3 (91% v 19%; p<0.0001) but not in those infected with non-3 genotypes (43% v 34%; NS). Among the 25 SVR, improvement in steatosis was significantly more frequent in patients infected with genotype 3 than in those infected with non-3 genotypes (91% v 43%; p<0.04) whereas in NR, improvement in steatosis did not differ between those infected with genotype 3 and non-3 genotypes (19% v 34%; NS). In multivariate analysis, four factors were independently associated with steatosis improvement: sustained virological response to antiviral therapy (odds ratio (OR) 6.06 (95% confidence interval (CI) 1.61–22.9); p = 0.01), severe steatosis (OR 5.50 (95% CI 1.54–19.6); p = 0.01), HCV genotype 3 (OR 2.90 (95% CI 0.85–10.0); p = 0.07), and BMI >25 kg/m2 (OR 0.24 (95% CI 0.08–0.73); p = 0.02).
Conclusions: Our results showed significant improvement in steatosis in patients infected with HCV genotype 3, who achieved sustained viral clearance. This provides further evidence for direct involvement of HCV genotype 3 in the pathogenesis of hepatic steatosis.
doi:10.1136/gut.2002.009936
PMCID: PMC1773974  PMID: 14960527
chronic hepatitis C; steatosis; interferon; hepatitis C virus genotype 3
3.  Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies 
Gut  2003;52(2):288-292.
Background and aims: Steatosis, a frequent histological finding in patients with chronic hepatitis C (CHC), has been suggested to influence liver fibrosis progression. The aim of the present study was to evaluate in patients with CHC and paired liver biopsies the relationship between the evolution of steatosis and that of fibrosis between the two biopsies.
Methods: Ninety six patients were selected according to the following criteria: absence of treatment; absence of cirrhosis at initial biopsy; and serum hepatitis B surface antigen and human immunodeficiency virus antibody negativity. Degrees of necroinflammatory activity, fibrosis, and steatosis grades were assessed in the two biopsies. In addition to histological lesions, parameters studied included the source of infection, duration of infection, body mass index, alcohol intake, alanine aminotransferase levels, hepatitis C virus genotype, and viral load.
Results: The mean interval between the two biopsies was 48 (32) months. Steatosis was found in 54% of patients at first biopsy, and was severe in 9%. Worsening of steatosis was observed in 34% of patients, stability in 50%, and improvement in 16%. Worsening of steatosis was significantly associated with hepatic fibrosis progression in patients with (p=0.03) or without (p<0.03) steatosis at diagnosis. Overall, fibrosis progression was observed in 31% of patients and stability in 69%. In a univariate analysis, fibrosis progression was associated with male sex (p=0.05), worsening of histological activity (p=0.04), and worsening of steatosis (p=0.0003). In a multivariate analysis, the only factor independently associated with fibrosis progression was worsening of steatosis (worsening v improvement/stability: odds ratio 4.7 (95% confidence interval 1.3–10.8); p=0.0001).
Conclusions: Our results suggest that in untreated patients with CHC and serial liver biopsies, fibrosis progression is strongly associated with worsening of steatosis.
PMCID: PMC1774979  PMID: 12524415
hepatitis C; steatosis; fibrosis; liver biopsy
4.  Impact of smoking on histological liver lesions in chronic hepatitis C 
Gut  2003;52(1):126-129.
Aims and methods: To examine the association between smoking and histological liver lesions in chronic hepatitis C, we studied 244 consecutive patients (152 men, 92 women; mean age 45.9 (12.6) years) with histologically proven chronic hepatitis C. Daily tobacco consumption during the six months preceding liver biopsy was recorded as the number of cigarettes smoked daily. Total lifetime tobacco consumption was recorded as the number of cigarette packs smoked per year (packs-years). Liver biopsy specimens were graded for histological activity and fibrosis according to the METAVIR scoring system.
Results: The proportion of patients with moderate (A2) or marked (A3) activity increased gradually from 62.0% in non-smokers to 81.7% in patients who smoked more than 15 cigarettes per day (p<0.009). A similar relationship was observed with total lifetime tobacco consumption: 59.0% of patients who had never smoked had grade A2 or A3 disease activity compared with 84.6% of patients who smoked more than 20 packs per year (p<0.002). Multivariate analysis showed that age over 50 years (odds ratio (OR) 5.4), alcohol intake exceeding 20 g/day (OR 2.75), and tobacco consumption of more than 15 cigarettes/day (OR 3.6) were independently related to the histological activity score. No relationship was found between the severity of fibrosis and either daily tobacco consumption or total lifetime tobacco consumption. Multivariate analysis showed that only age over 50 years (OR 8.8), daily alcohol intake exceeding 30 g/day (OR 3.4), and histological activity score (OR 7.9) were independently related to the fibrosis score.
Conclusion: This study suggests that smoking, independent of alcohol, could aggravate the histological activity of chronic hepatitis C and that patients with chronic hepatitis C virus infection should be advised to reduce or stop smoking.
PMCID: PMC1773517  PMID: 12477773
smoking; hepatitis C virus; hepatitis C infection; liver lesions
5.  Factors associated with Pneumocystis carinii pneumonia in Wegener's granulomatosis. 
Annals of the Rheumatic Diseases  1995;54(12):991-994.
OBJECTIVE--To determine the factors associated with the occurrence of Pneumocystis carinii pneumonia (PCP) in Wegener's granulomatosis (WG). METHODS--We retrospectively compared a group of 12 patients with WG and PCP (PCP group), with 32 WG patients without PCP followed over the same period in the same centres (control group). RESULTS--The mean delay of onset of PCP after the start of the immunosuppressive therapy was 127 (SD 128) days. Before treatment, the clinical and biological features of the two groups were similar, except for the mean lymphocyte count which was lower in the PCP group than in the control group (1060/mm3 v 1426/mm3; p = 0.04). During treatment, both groups were lymphopenic. There was a significant difference between the lowest absolute lymphocyte count in each group (244/mm3 in the PCP group v 738/mm3 in the control group; p = 0.001). During the first three months of treatment, the lymphocyte count was less than 600/mm3 at least once in 10 of the 12 patients in the PCP group and in 11 of the 32 patients in the control group (p < 0.01). The mean cumulative dose of cyclophosphamide was greater in the PCP group than in the control group at the end of both the second (1.55 mg/kg/day v 0.99 mg/kg/day; p = 0.05) and the third (1.67 mg/kg/day v 0.97 mg/kg/day; p = 0.03) months. However, in multivariate analysis, the only two factors independently and significantly associated with the occurrence of PCP were the pretreatment lymphocyte count (p = 0.018) and the lymphocyte count three months after the start of the immunosuppressive treatment (p = 0.014). CONCLUSIONS--The severity of lymphocytopenia before and during immunosuppressive treatment is the factor best associated with PCP in WG.
PMCID: PMC1010066  PMID: 8546533
6.  GEMHEP multicenter quality control study of PCR detection of GB virus C/hepatitis G virus RNA in serum. 
Journal of Clinical Microbiology  1997;35(12):3298-3300.
PCR is, to date, the only available tool for the detection of GB virus C (GBV-C) and hepatitis G virus (HGV) RNAs. Twenty-two French laboratories participated in a quality control study to assess the sensitivity and specificity of their procedures. The panel included 13 positive controls and 7 negative controls. The laboratories used either in-house PCR techniques adapted from the literature or partly standardized commercial tests. Three laboratories performed faultlessly with the entire panel. Most laboratories had excellent specificity (100% in 20 of 22 laboratories). Sensitivity was acceptable (85 to 100%) in 15 centers and insufficient (38 to 77%) in 7. As with nonstandardized in-house PCR, the commercial assays gave discrepant performances in different laboratories. These results suggest that laboratories willing to use PCR for detection of GBV-C/HGV RNA for research or diagnostic purposes should participate in multicenter quality control trials.
PMCID: PMC230166  PMID: 9399538
7.  Effect of alpha interferon (IFN-alpha) on 2'-5' oligoadenylate synthetase activity in peripheral blood mononuclear cells of patients with chronic hepatitis C: relationship to the antiviral effect of IFN-alpha. 
Alpha interferon (IFN-alpha) is, to date, the only treatment with proven efficacy in patients with chronic hepatitis C. However, less than 15% of the patients have a sustained response to IFN-alpha. Interferon acts through the induction of various cellular enzymes. Among them, the 2'-5' oligoadenylate synthetase (2-5OAS) is (at least in part) responsible for a direct antiviral effect of IFN-alpha. The aim of this study was to determine whether basal and IFN-alpha-induced in vivo and in vitro 2-5OAS activities measured in peripheral blood mononuclear cells predict biochemical and virological responses to IFN-alpha in patients with chronic hepatitis C. 2-5OAS activity in peripheral blood mononuclear cells and the antiviral effect of IFN-alpha were studied in 36 patients with chronic hepatitis C (27 men and 9 women; mean age, 44.7 years). Basal in vivo 2-5OAS activity (mean +/- standard error of the mean) was 4.41 +/- 0.69 nmol/10(6) cells. It was significantly induced at month 3 of IFN-alpha therapy (18.07 +/- 2.74 nmol/10(6) cells; P = 0.0001). No significant differences were found in basal in vivo 2-5OAS activities, in IFN-alpha-induced/basal in vitro 2-5OAS activity ratios, in IFN-alpha-induced in vivo 2-5OAS activities, and in IFN-alpha-induced/basal in vivo 2-5OAS activity ratios between the patients with and without a biochemical response (normal alanine aminotransferase activity in serum) or a virological response (normal alanine aminotransferase activity in serum and negative hepatitis C virus RNA detection) at any step of the study. At month 3 of therapy, p69, which is considered to be the active isoform of 2-5OAS, was induced, as demonstrated by Western blot (immunoblot) analysis in 50% of the patients, and induction of the p100 isoform was observed in 70% of the patients. No significant relationship with the response to IFN-alpha therapy was observed. Our results suggest that a deficiency of the IFN-alpha-dependent 2-5OAS system, which could be genetically determined, is unlikely to be responsible for the failure to achieve biochemical and virological responses to IFN-alpha therapy in patients with chronic hepatitis C.
PMCID: PMC163109  PMID: 8834873
8.  Influence of hepatitis C virus (HCV) genotypes on HCV recombinant immunoblot assay patterns. 
Journal of Clinical Microbiology  1995;33(5):1357-1359.
Ninety-six patients with chronic hepatitis C were studied. A second-generation recombinant immunoblot assay detected anti-NS4 antibodies significantly more often in patients infected by hepatitis C virus genotype 1 than in patients infected by other types. By a third-generation recombinant immunoblot assay, the prevalences of the four antibodies measured did not differ according to the hepatitis C virus genotype.
PMCID: PMC228164  PMID: 7542272
9.  Maintenance of intragastric pH > 4 with famotidine in duodenal ulcer patients: factors influencing drug requirements. 
Gut  1994;35(6):750-754.
The gastrojet, a closed loop pH feedback infusion pump capable of maintaining intragastric pH at a target value by infusing H2 blockers at variable rates, was used to assess factors influencing the quantity of famotidine required to maintain intragastric pH above 4 for 24 hours in 34 fed patients with duodenal ulcers. The following factors were considered: sex, age, duration of the disease, previous bleeding, previous poor response to H2 blockers (ulcer unhealed at six weeks, or recurrence within three months during maintenance treatment), activity of the ulcer disease, smoking habits, cirrhosis. The patients had taken no antisecretory drugs for the 15 days before the study. Two standardised meals were given during the study period (from 1000 to 1000). Fifty ml of famotidine (4 mg/ml) was loaded into infusion bags and the pump was programmed to deliver the drug intravenously at 11 rates varying from 0 to 40 microliters/min. The target pH was 4. Mean famotidine use was 111 mg (range 33 to 200), the 23 hour median pH was 5.3, and the mean time during which pH was above 4 was 75.4%. There was a negative correlation (p < 0.001) between famotidine delivery and the inhibition of gastric acidity. Statistical analysis showed that only cirrhosis significantly influenced drug delivery, median pH, and the time during which pH was above 4. Mean drug delivery in the cirrhotic and non-cirrhotic patients was 135 v 97 mg (p < 0.04), 23 hour median pH was 4.7 v 5.6 (p < 0.01), and the mean time at pH > 4 was 65.9 v 81.6% (p < 0.01). There were large interindividual variations in famotidine requirements, but not only cirrhosis was predictive of dose requirement. These results suggest that the appropriate amount of famotidine to treat duodenal ulcer in cirrhotic patients is probably higher than the usually recommended dose.
PMCID: PMC1374871  PMID: 8020798
10.  Significance of highly positive c22-3 "indeterminate" second-generation hepatitis C virus (HCV) recombinant immunoblot assay (RIBA) and resolution by third-generation HCV RIBA. 
Journal of Clinical Microbiology  1994;32(5):1357-1359.
Second-generation recombinant immunoblot assay (RIBA) is widely used for the validation of anti-hepatitis C virus (HCV) antibody detection. The aims of this work were (i) to determine, in terms of liver disease and HCV replication, the significance of a peculiar "indeterminate" second-generation RIBA pattern characterized by the presence of high titers of antibodies directed to c22-3, a protein bearing core epitopes and (ii) to determine whether a more advanced version of the same strip assay, namely a third-generation RIBA, may solve the problem of such indeterminate patterns. Sixty patients for which c22-3 indeterminate second-generation RIBAs were highly positive were studied. Forty-two of them (70%) were immunocompromised. Serum transaminases were increased in 46 cases (77%), and HCV RNA was detected by PCR in 50 cases (83%). Third-generation RIBA remained highly positive c22 indeterminate for 9 patients (15%) but was positive for 51 (85%), mostly because of increased sensitivity for the detection of both anti-c100 and anti-c33c antibodies. These results suggest that third-generation RIBA may achieve resolution of most of these cases but that highly positive c22 indeterminate third-generation RIBA may persist when used with some patients with very low titers of anti-HCV nonstructural protein antibodies.
PMCID: PMC263701  PMID: 7519631
11.  Anti-HCV seroprevalence in pregnant women in France. 
Gut  1993;34(2 Suppl):S55-S56.
In a study designed to assess the prevalence of antibodies to hepatitis C virus (HCV) in pregnant women, anti-HCV positivity in French pregnant women was twice as high as that found in French blood donors. Positive ELISA 2 results were confirmed by positive RIBA 2 in most subjects, and seven of nine RIBA 2 positive patients also tested positive for HCV-RNA by PCR. High rates of anti-HCV positivity were seen among immigrant pregnant women, partly because of false positive results with ELISA 2. RIBA 2 results suggested that the prevalence of HCV infection was not any higher in immigrant compared with French pregnant women.
PMCID: PMC1374008  PMID: 7686117
12.  Atrial natriuretic factor in chronic obstructive lung disease with pulmonary hypertension. Physiological correlates and response to peptide infusion. 
Journal of Clinical Investigation  1989;83(3):986-993.
To investigate the physiological role of atrial natriuretic factor (ANF) in patients with hypoxic pulmonary hypertension secondary to chronic obstructive lung disease (COLD), we infused synthetic alpha-human ANF in seven such patients, and investigated the physiological correlates to circulating peptide levels in 24 patients with COLD. ANF infusion, at incremental rates of 0.01, 0.03, and 0.1 micrograms/kg.min, increased basal plasma immunoreactive (ir) ANF (136 +/- 38 pg/ml) by 3-, 10-, and 26-fold, respectively, and reduced pulmonary artery pressure (from 33 +/- 3 to 25 +/- 2 mmHg, P less than 0.001) and systemic arterial pressure (from 88 +/- 4 to 79 +/- 4 mmHg, P less than 0.001) in a dose-related fashion. Cardiac index increased by 13.5% (P less than 0.01) while heart rate was unchanged. Cardiac filling pressures decreased at 0.1 micrograms/kg.min ANF. Pulmonary and systemic vascular resistance fell by 37% (P less than 0.001) and 19% (P less than 0.001), respectively. Arterial oxygenation was impaired during ANF infusion, suggesting partial reversal of hypoxic pulmonary vasoconstriction. Plasma renin activity remained unchanged but aldosterone fell by 44% (P less than 0.01). The levels of plasma irANF in 24 patients correlated directly with the degree of hemoconcentration (r = 0.67, P less than 0.001), respiratory acidosis (r = -0.65, P less than 0.001), and pulmonary hypertension (r = 0.52, P less than 0.01). The results suggest that ANF may serve as a potent pulmonary vasodilator involved in the circulatory homeostasis of patients with COLD.
PMCID: PMC303775  PMID: 2522105
14.  Computer-aided selection of diagnostic tests in jaundiced patients. 
Gut  1985;26(9):961-967.
A model has been developed for ordering diagnostic tests in jaundiced patients. The system proceeds in two steps: (i) diagnostic hypotheses are calculated for each patient from the results of physical examination and routine biological investigations; (ii) given these hypotheses, the most efficient test (out of 22) for reaching the final diagnosis is selected using four criteria: diagnostic value, risk, financial cost, and time in obtaining the result. This model was tested in 62 patients. In 43 of them (69%), the selected test was sufficient for reaching a diagnostic accuracy of 100%. In this group of patients, a mean of 3.7 (range 1-6) tests per patient was ordered by physicians. In the 19 remaining patients, the selected test was not sufficient for the final diagnosis, thus requiring a multiple choice process. It is suggested that such a system could help physicians to improve the care of patients by more efficient ordering of diagnostic tests.
PMCID: PMC1432841  PMID: 3896962

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