Jean-Paul Saint-André

Sources of variability in histological scoring of chronic viral hepatitis

Inter‐observer agreement on activity and fibrosis scores used in chronic viral hepatitis has only been studied under selected conditions. The aim of this study was to identify the sources of variability due to specimen characteristics and observers. This study included 254 liver specimens and 15 pathologists and used the Metavir score. In 44 specimens scored by 4 academic pathologists, agreement of Metavir score was good overall, but better for fibrosis (κ = 0.59) than for activity (κ = 0.43) and poor for lobular necrosis (κ = 0.15). The mean agreement was better for senior (0.60 ± 0.24) than junior pathologists (0.52 ± 0.30, P < .05). Mean intrabserver agreement was better than inter‐observer agreement (0.77 ± 0.18 vs. 0.58 ± 0.26, P < .01). In 157 specimens scored by 2 expert pathologists (one senior, one junior), agreement of Metavir score was only good but greatly improved after consensus reading (fibrosis: κ = 0.48 and 0.77, activity: κ = 0.44 and 0.70, respectively, before and after consensus). Several causes of disagreement were identified: specimen length, fibrosis class number, observer bias, and putative causes related to Metavir score or specimen. In an intercenter evaluation involving 59 specimens, 1 expert and 10 nonacademic pathologists, agreement was very poor and did not improve over 5 years for activity (κ = 0.22‐0.25) or fibrosis (κ = 0.13‐0.18). In conclusion, the level of experience (specialization, duration, and location of practice) has more influence on agreement than the characteristics of the specimen (length, fibrosis class number, miscellaneous factors). Agreement can be improved by experienced pathologist or consensus reading. (HEPATOLOGY 2005,41:257–264.)

Local and sustained delivery of 5‐fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma

The authors have developed a new method of drug delivery into the brain using implantable biodegradable microspheres. In this study, this method was used to provide localized and sustained delivery of 5‐fluorouracil (5‐FU) after the surgical resection of glioblastoma. This antimetabolite and radiosensitizing drug was selected in an attempt to decrease the rate of local recurrence of the tumor.

Expression of Nerve Growth Factor and Nerve Growth Factor Receptor Genes in Human Tissues and in Prostatic Adenocarcinoma Cell Lines

Abstract: Nerve growth factor (NGF) mRNAs were detected and quantified in a variety of normal and neoplastic human tissues by northern blot hybridization. Human heart contained the highest NGF mRNA levels, whereas lower but comparable levels were found in the placenta, prostate, and kidney. All tissues examined coexpressed the low‐affinity NGF receptor (LNGFR), whereas none of these tissues expressed the high‐affinity NGF receptor encoded by the trk protooncogene. The widespread distribution of the LNGFR suggests that it plays a role in the regulation of normal cell growth. No overexpression of NGF or LNGFR mRNA was detected in neoplastic tissues, whereas LNGFR‐like immunoreactivity was localized outside of tumor cells. Transforming growth factor‐α and protooncogene c‐fos expression in these tissues did not show a systematic correlation with NGF/LNGFR expression. Furthermore, regulation of the human NGF gene was studied in DU145 cells, a prostatic adenocarcinoma cell line that synthesizes significant NGF mRNA levels. Serum induced, whereas dexamethasone inhibited, NGF mRNA synthesis in these cells. Serum induction was preceded by a rapid and transient activation of the c‐fos protooncogene.

C-cell hyperplasia associated with chronic lymphocytic thyroiditis: a retrospective quantitative study of 112 cases.

Since the first description by Wolfe et al of C-cell hyperplasia (CCH) in asymptomatic relatives of patients suffering from a medullary thyroid carcinoma (MTC), several investigators have described CCH associated with a chronic lymphocytic thyroiditis (CLT) not within the context of MTC or multiple endocrine neoplasia (MEN). We report the study of C-cell density in 112 cases of CLT on retrospective surgical material to determine the frequency of the association between CCH and CLT. The cases of CLT were compared with 19 normal thyroid glands obtained at necropsy. C cells, immunoreactive with a polyclonal anti-calcitonin (CT) antibody, were counted at high magnification (X400) and the number of low-power magnification (X100) microscopic fields (LPFs) containing at least 50 C cells per slide was assessed. Image analysis was performed to determine the C-cell density expressed in number of C cells/cm2. C-cell hyperplasia was defined by the following criteria: C-cell density > 40 cells/cm2 and the presence of at least three LPFs containing more than 50 C cells. Twenty percent of the cases of CLT showed a CCH thus defined, and four of them had an elevated serum CT level. Statistical analysis showed no clinical or biological correlation with the presence of CCH. However, the frequency of CCH was higher if a follicular cell carcinoma was associated with CLT. This study confirms a pathological association between CCH and CLT, provides new criteria for the definition of CCH on surgical pathology material, and reports four cases with an elevated serum CT level not within the context of MTC or MEN.

IL-26 Is Overexpressed in Rheumatoid Arthritis and Induces Proinflammatory Cytokine Production and Th17 Cell Generation

Human interleukin-26 induces Th17 cells, is over-expressed in rheumatoid arthritis, and is thus a promising therapeutic target in chronic inflammatory disease.

Seasonal and regional dynamics of M. ulcerans transmission in environmental context: deciphering the role of water bugs as hosts and vectors.

Background Buruli ulcer, the third mycobacterial disease after tuberculosis and leprosy, is caused by the environmental mycobacterium M. ulcerans. Various modes of transmission have been suspected for this disease, with no general consensus acceptance for any of them up to now. Since laboratory models demonstrated the ability of water bugs to transmit M. ulcerans, a particular attention is focused on the transmission of the bacilli by water bugs as hosts and vectors. However, it is only through detailed knowledge of the biodiversity and ecology of water bugs that the importance of this mode of transmission can be fully assessed. It is the objective of the work here to decipher the role of water bugs in M. ulcerans ecology and transmission, based on large-scale field studies. Methodology/Principal Findings The distribution of M. ulcerans-hosting water bugs was monitored on previously unprecedented time and space scales: a total of 7,407 water bugs, belonging to large number of different families, were collected over one year, in Buruli ulcer endemic and non endemic areas in central Cameroon. This study demonstrated the presence of M. ulcerans in insect saliva. In addition, the field results provided a full picture of the ecology of transmission in terms of biodiversity and detailed specification of seasonal and regional dynamics, with large temporal heterogeneity in the insect tissue colonization rate and detection of M. ulcerans only in water bug tissues collected in Buruli ulcer endemic areas. Conclusion/Significance The large-scale detection of bacilli in saliva of biting water bugs gives enhanced weight to their role in M. ulcerans transmission. On practical grounds, beyond the ecological interest, the results concerning seasonal and regional dynamics can provide an efficient tool in the hands of sanitary authorities to monitor environmental risks associated with Buruli ulcer.

Stenotic intimal thickening of the external lliac artery in competition cyclists

Twenty-three cases of an arterial disease that affects competition cyclists are reported. Patients complained of intermittent acute claudication appearing on one lower limb only at the time of a maximal strain while cycling. Doppler hemodynamic investigation on an ergometric bicycle revealed a collapse of the ankle systolic pressure. Arteriography showed a sinuous lengthening and moderate stenosis of the external iliac artery. Pathologic examination of the artery disclosed a stenotic intimal thickening due to moderately cellular loose connective tissue with a variable distribution of collagen and elastic fibers. The cells in the affected zone were readily labeled with anti-actin and anti-myosin antibodies, and electron microscopy revealed features of synthetic smooth muscle cells. The lesion observed differs from intimal fibrodysplasia and from artherosclerosis. Abnormal local hemodynamic conditions may lead to this type of lesion. Thus, stenotic intimal thickening of the external iliac artery appears to be a new arterial disease defined by clinical, arteriographic, and pathologic features.

The virulence variability of different Acinetobacter baumannii strains in experimental pneumonia.

OBJECTIVES Our objective was to compare the virulence of 5 strains of Acinetobacter baumannii by using a mouse model of pneumonia. METHODS Six-week old female C3H/HeN mice were used. The pneumonia was inducted by intra-tracheal inoculation of 5.10(6) bacteria. Spontaneous outcome was evaluated by mortality, mice weight variations, and a clinical score. Bacterial counts in lungs, spleen and blood, and inflammatory response in lungs (dosages of tumor necrosis factor-alpha and macrophage inflammatory protein-2) were also measured. Lastly, a histological examination of lungs was performed for 3 strains, giving a histological score. RESULTS Global mortality varied from 13% to 79% (P<10(-4)). Bacterial counts in lungs within the 4 days following inoculation varied significantly according to different strains. The evolution curves of bacterial counts were also different. There was a significant correlation between the clinical score and mortality (P<0.05) but not between bacterial counts in lungs and mortality. The increase of pro-inflammatory mediator production in lungs and the histological score also varied according to strains. CONCLUSIONS These results demonstrate the variability of the virulence between strains, and suggest that bacterial proliferation is not the only virulence factor responsible for the pathogenesis in A. baumannii pneumonia.

Protection against Mycobacterium ulcerans lesion development by exposure to aquatic insect saliva

Background Buruli ulcer is a severe human skin disease caused by Mycobacterium ulcerans. This disease is primarily diagnosed in West Africa with increasing incidence. Antimycobacterial drug therapy is relatively effective during the preulcerative stage of the disease, but surgical excision of lesions with skin grafting is often the ultimate treatment. The mode of transmission of this Mycobacterium species remains a matter of debate, and relevant interventions to prevent this disease lack (i) the proper understanding of the M. ulcerans life history traits in its natural aquatic ecosystem and (ii) immune signatures that could be correlates of protection. We previously set up a laboratory ecosystem with predatory aquatic insects of the family Naucoridae and laboratory mice and showed that (i) M. ulcerans-carrying aquatic insects can transmit the mycobacterium through bites and (ii) that their salivary glands are the only tissues hosting replicative M. ulcerans. Further investigation in natural settings revealed that 5%–10% of these aquatic insects captured in endemic areas have M. ulcerans–loaded salivary glands. In search of novel epidemiological features we noticed that individuals working close to aquatic environments inhabited by insect predators were less prone to developing Buruli ulcers than their relatives. Thus we set out to investigate whether those individuals might display any immune signatures of exposure to M. ulcerans-free insect predator bites, and whether those could correlate with protection. Methods and Findings We took a two-pronged approach in this study, first investigating whether the insect bites are protective in a mouse model, and subsequently looking for possibly protective immune signatures in humans. We found that, in contrast to control BALB/c mice, BALB/c mice exposed to Naucoris aquatic insect bites or sensitized to Naucoris salivary gland homogenates (SGHs) displayed no lesion at the site of inoculation of M. ulcerans coated with Naucoris SGH components. Then using human serum samples collected in a Buruli ulcer–endemic area (in the Republic of Benin, West Africa), we assayed sera collected from either ulcer-free individuals or patients with Buruli ulcers for the titre of IgGs that bind to insect predator SGH, focusing on those molecules otherwise shown to be retained by M. ulcerans colonies. IgG titres were lower in the Buruli ulcer patient group than in the ulcer-free group. Conclusions These data will help structure future investigations in Buruli ulcer–endemic areas, providing a rationale for research into human immune signatures of exposure to predatory aquatic insects, with special attention to those insect saliva molecules that bind to M. ulcerans.

Medullary thyroid microcarcinoma: A clinicopathologic retrospective study of 38 patients with no prior familial disease

Thirty-eight patients (25 women, 13 men; mean age, 57.8 [32 to 91]) showing one or more medullary thyroid microcarcinomas (ie, < 1 cm), with no prior MEN II or medullary thyroid carcinoma history in their family, were reviewed. Follow-up was available for 29 patients (mean, 53.6 months [1 to 147]). 21 patients (72.4%) are alive and free of disease, four patients (13.8%) died during follow-up without disease, 2 patients are alive with disease (local recurrence and persistent hypercalcitoninemia) after 80 and 99 months, respectively, and 2 patients died of disease after 24 and 46 months. Most tumors were incidental pathological findings (19 of 38) or were discovered by systematic blood calcitonin measurement for a nodular thyroid disease (15 of 38). Only the four patients who had an unfavorable outcome were symptomatic cases (palpable micro-MTC, diarrhea, cervical lymph node metastasis and pulmonary metastatic disease). The two patients with metastatic disease at diagnosis died during follow-up. In univariate analysis, a symptomatic medullary thyroid carcinoma was a strong predictor of an unfavourable outcome (p < .00008), as were the preoperative calcitonin level (P = .007) and an elevated postoperative calcitonin level (P = .004). Among 30 histopathological criteria, only the presence of amyloid correlated with an unfavorable outcome (P = .018).