Deregulation of DNA-dependent protein kinase catalytic subunit contributes to human hepatocarcinogenesis development and has a putative prognostic value.

BACKGROUND: The DNA-repair gene DNA-dependent kinase catalytic subunit (DNA-PKcs) favours or inhibits carcinogenesis, depending on the cancer type. Its role in human hepatocellular carcinoma (HCC) is unknown. METHODS: DNA-dependent protein kinase catalytic subunit, H2A histone family member X (H2AFX) and heat shock transcription factor-1 (HSF1) levels were assessed by immunohistochemistry and/or immunoblotting and qRT-PCR in a collection of human HCC. Rates of proliferation, apoptosis, microvessel density and genomic instability were also determined. Heat shock factor-1 cDNA or DNA-PKcs-specific siRNA were used to explore the role of both genes in HCC. Activator protein 1 (AP-1) binding to DNA-PKcs promoter was evaluated by chromatin immunoprecipitation. Kaplan-Meier curves and multivariate Cox model were used to study the impact on clinical outcome. RESULTS: Total and phosphorylated DNA-PKcs and H2AFX were upregulated in HCC. Activated DNA-PKcs positively correlated with HCC proliferation, genomic instability and microvessel density, and negatively with apoptosis and patient's survival. Proliferation decline and massive apoptosis followed DNA-PKcs silencing in HCC cell lines. Total and phosphorylated HSF1 protein, mRNA and activity were upregulated in HCC. Mechanistically, we demonstrated that HSF1 induces DNA-PKcs upregulation through the activation of the MAPK/JNK/AP-1 axis. CONCLUSION: DNA-dependent protein kinase catalytic subunit transduces HSF1 effects in HCC cells, and might represent a novel target and prognostic factor in human HCC.

Pulmonary carcinoma associated with cystic airspaces in two dogs.

Malignant pulmonary neoplasia associated with cystic airspaces is a well-recognised disease entity in humans. Two elderly dogs, previously diagnosed with a solitary emphysematous bulla, presented with non-specific clinical signs. At presentation, pulmonary auscultation was unremarkable. In both cases, thoracic CT demonstrated the transformation of the cystic airspace lesions characterised by a progressive increase of the solid component and reduction of the air component. Cytological evaluation and subsequent surgical excision followed by histopathology confirmed pulmonary carcinoma in both cases. These two cases represent the first demonstration of possible malignant transformation of pulmonary cystic airspace in dogs. Veterinarians should consider neoplastic transformation as a differential diagnosis in cases of cystic airspaces, particularly cases with features including thickening or irregularity of the wall, associated soft-tissue nodules or solid and non-solid tissue intermixed within clusters of multiple cystic airspaces. Ongoing monitoring of cystic airspace lesions through diagnostic imaging is recommended.

Forkhead box M1B is a determinant of rat susceptibility to hepatocarcinogenesis and sustains ERK activity in human HCC.

BACKGROUND AND AIMS: Previous studies indicate unrestrained cell cycle progression in liver lesions from hepatocarcinogenesis-susceptible Fisher 344 (F344) rats and a block of G(1)-S transition in corresponding lesions from resistant Brown Norway (BN) rats. Here, the role of the Forkhead box M1B (FOXM1) gene during hepatocarcinogenesis in both rat models and human hepatocellular carcinoma (HCC) was assessed. METHODS AND RESULTS: Levels of FOXM1 and its targets were determined by immunoprecipitation and real-time PCR analyses in rat and human samples. FOXM1 function was investigated by either FOXM1 silencing or overexpression in human HCC cell lines. Activation of FOXM1 and its targets (Aurora Kinose A, Cdc2, cyclin B1, Nek2) occurred earlier and was most pronounced in liver lesions from F344 than BN rats, leading to the highest number of Cdc2-cyclin B1 complexes (implying the highest G(2)-M transition) in F344 rats. In human HCC, the level of FOXM1 progressively increased from surrounding non-tumorous livers to HCC, reaching the highest levels in tumours with poorer prognosis (as defined by patients' length of survival). Furthermore, expression levels of FOXM1 directly correlated with the proliferation index, genomic instability rate and microvessel density, and inversely with apoptosis. FOXM1 upregulation was due to extracellular signal-regulated kinase (ERK) and glioblastoma-associated oncogene 1 (GLI1) combined activity, and its overexpression resulted in increased proliferation and angiogenesis and reduced apoptosis in human HCC cell lines. Conversely, FOXM1 suppression led to decreased ERK activity, reduced proliferation and angiogenesis, and massive apoptosis of human HCC cell lines. CONCLUSIONS: FOXM1 upregulation is associated with the acquisition of a susceptible phenotype in rats and influences human HCC development and prognosis.

Hepatocellular carcinoma as a complex polygenic disease. Interpretive analysis of recent developments on genetic predisposition.

The different frequency of hepatocellular carcinoma (HCC) in humans at risk suggests a polygenic predisposition. However, detection of genetic variants is difficult in genetically heterogeneous human population. Studies on mouse and rat models identified 7 hepatocarcinogenesis susceptibility (Hcs) and 2 resistance (Hcr) loci in mice, and 7 Hcs and 9 Hcr loci in rats, controlling multiplicity and size of neoplastic liver lesions. Six liver neoplastic nodule remodeling (Lnnr) loci control number and volume of re-differentiating lesions in rat. A Hcs locus, with high phenotypic effects, and various epistatic gene-gene interactions were identified in rats, suggesting a genetic model of predisposition to hepatocarcinogenesis with different subset of low-penetrance genes, at play in different subsets of population, and a major locus. This model is in keeping with human HCC epidemiology. Several putative modifier genes in rodents, deregulated in HCC, are located in chromosomal segments syntenic to sites of chromosomal aberrations in humans, suggesting possible location of predisposing loci. Resistance to HCC is associated with lower genomic instability and downregulation of cell cycle key genes in preneoplastic and neoplastic lesions. p16(INK4A) upregulation occurs in susceptible and resistant rat lesions. p16(INK4A)-induced growth restraint was circumvented by Hsp90/Cdc37 chaperons and E2f4 nuclear export by Crm1 in susceptible, but not in resistant rats and human HCCs with better prognosis. Thus, protective mechanisms seem to be modulated by HCC modifiers, and differences in their efficiency influence the susceptibility to hepatocarcinogenesis and probably the prognosis of human HCC.

[Recovery of sickle cell disease ischemic maculopathy after erythropheresis: a clinical case study]. / Maculopathie ischémique drépanocytaire résolutive après échange érythrocytaire.

The authors report a case of a young patient with a recent decrease in unilateral vision. He had homozygote sickle cell disease with multiple general complications. Fundus examination was normal apart from a mild alteration of the macular reflect in the left eye, but fluorescein angiography showed multiple arteriolar macular occlusions, explaining the decrease in vision in the left eye. After erythropheresis, vision acuity improved and fluorescein angiography showed reperfusion. This case suggests that transfusional exchange may improve acute macular ischemia secondary to sickle cell disease.

Increase in D2 dopamine receptors in the substantia nigra after chronic (-)-sulpiride treatment.

Changes in D2 dopamine (DA) receptors in the substantia nigra (SN) and caudate nucleus (CN) homogenates were studied in rats following chronic treatment with the specific D2 receptor antagonist (-)-sulpiride (50 mg/kg s.c. twice daily for 8 days). Sixty hours after (-)-sulpiride withdrawal, the Bmax of [3H]spiroperidol binding (in the presence of 30 Nm ketanserin) was found to be increased by 76% and 38% in the SN and CN, respectively. No changes in the KdS were observed. The findings suggest that chronic (-)-sulpiride results in the upregulation of DA autoreceptors in the SN.

Autoreceptors mediate the inhibition of dopamine synthesis by bromocriptine and lisuride in rats.

The administration of bromocriptine and lisuride to rats caused a decrease in striatal dopamine (DA) synthesis, as measured by 3,4-dihydroxy-phenylalanine (DOPA) accumulation after decarboxylase inhibition. DOPA formation was inhibited by a maximum of about 60% of control values by bromocriptine and lisuride, 5.0 and 0.3 mg/kg, respectively. Both compounds showed very similar time-courses for the effect and failed to modify DOPA accumulation during the first 30 min. Pretreatment with (-)-sulpiride (50 mg/kg i.p.), a specific D2-receptor blocker, completely prevented the inhibitory effect of bromocriptine and lisuride on DOPA accumulation. Finally, both compounds significantly reversed the gamma-butyrolactone (GBL) (700 mg/kg i.p.)-induced DOPA accumulation at doses (0.25 and 0.015 mg/kg, respectively) that were inactive in normal rats. The data suggest that bromocriptine and lisuride act as agonists on D2-presynaptic autoreceptors which have different sensitivity to the agonist according to the basal firing rate of DA neurons.

Ocular toxoplasmosis in human immunodeficiency virus-infected patients.

The files of 45 human immunodeficiency virus-infected patients with ocular toxoplasmosis were reviewed, with a median follow-up of eight months. The condition was unilateral in 37 of the 45 patients (82%) and was bilateral in eight (18%). Inflammation of the anterior chamber and the vitreous was present in 32 of 53 eyes (60%) and 38 of 53 eyes (72%), respectively. Cytomegalovirus retinitis developed during the follow-up period in nine patients (20%). Cerebral toxoplasmosis was concurrently diagnosed with the ocular toxoplasmosis in 13 patients (29%). The efficacy of the combination of pyrimethamine and sulfadiazine or clindamycin was assessed in 42 patients for the induction therapy and in 38 patients for the maintenance therapy. Induction therapy was always effective within a median period of six weeks. During maintenance treatment, the 24-month relapse rates were 0.20 and 0.18 for the 50-mg/day and 25-mg/day dosage of pyrimethamine, respectively. The overall 12-month survival rate was 0.72. Our results suggested that ocular toxoplasmosis has a better ocular prognosis than cytomegalovirus retinitis, but that it requires appropriate treatment because life-threatening cerebral involvement is often associated.

[Health indicators in urban areas. Variations in function of social coherence of the geographic areas used]. / Indicadores de salud en el medio urbano. Variaciones en función de la coherencia social de las áreas geográficas utilizadas.

The detection of health inequalities in the urban environment and their magnitude depends to a great extent on the internal social coherence of the geographical division used. Using an existing social map of Alicante which divides the city into Basic Units for Social Intervention (BUSI), we have compared the distribution of an indicator with wellknown relationship with the socio-economic level such as Low Birth Weight, using both the BUSI and the municipal districts as analysis units. The data of the newborn were obtained from the records of the Hospital of Alicante corresponding to the years 1985, 1986 and 1987, analysing the 177 Low Birth Weights of the 7,728 born within the period. Using the BUSI we found a dose-response relationship between the socio-economic level and the LBW frequency with a range varying from 86.3 to 123.2. Using the municipal districts, the range varied from 62.5 to 159.6. We conclude that, although the geographical divisions with internal social coherence are better to detect health inequalities, municipal districts can be an analysis unit of easy access and useful for describing inequalities in the cities.

[Therapeutic strategy in delayed postoperative endophtalmitis: a report on 15 cases]. / Stratégie thérapeutique dans les endophtalmies chroniques survenues après chirurgie de la cataracte.

PURPOSE: To report the treatment strategies and visual acuity outcomes of chronic postoperative endophthalmitis. MATERIAL: and methods: The authors reviewed the records of 15 patients presenting 3 or more weeks after cataract surgery with intraocular inflammation and treated at Bicêtre Hospital from 1992 to 1998. Group I included 6 consecutive patients treated with vitrectomy and intravitreal antibiotic injection (vancomycin and cefazolin). Group II included 9 consecutive patients treated with intravitreal antibiotic injection (vancomycin and ceftazidime) and irrigation of the capsular bag (vancomycin). The minimum follow-up period was 1 year. RESULTS: In group I, 2 patients had recurrent inflammation. In these patients, the capsular bag and the intraocular implant were removed. In 1 patient there was culture-proven Corynebacterium and in 1 patient a Staphylococcus epidermidis was found. Final visual acuity was 20/40 or better in 5 patients and 20/100 in 1 patient. Visual acuity improved in all cases. In group II no recurrence was seen in the 12-20 months of follow-up. In 2 patients there was proven Staphylococcus epidermidis and in one patient Propionibacterium acnes was found. Final visual acuity was 20/40 or more in 3 patients, 20/100 or more in 4 patients and less than 20/200 in 2 patients. Visual acuity improved in 8 cases. CONCLUSIONS: Intravitreal antibiotic injection with vitrectomy and intravitreal antibiotic injection with antibiotic irrigation of the capsular bag are both effective in the treatment of delayed chronic postoperative endophthalmitis; however, with the second approach, there is minimal surgical trauma and the intraocular implant is retained.

[Characteristics of uveitis presenting de novo in the elderly]. / Caractéristiques des uvéites de novo chez les patients de plus de 60 ans.

INTRODUCTION: This study aimed to describe the clinical characteristics of uveitis presenting de novo in the elderly. The study design was a description of a retrospectively identified case series. PATIENTS: The records of 193 patients with uveitis referred to Bicêtre Hospital's department of ophthalmology between January 1995 and January 2000 were reviewed. Among these patients, the records of 57 patients with uveitis de novo beginning after age 60 were analyzed. RESULTS: Idiopathic uveitis accounted for the majority of cases. Whereas herpes viruses were the most frequent specific diagnosis, presumed sarcoidosis and birdshot choroidopathy were also identified as diagnostic entities of uveitis presenting for the first time in the elderly. Only three cases of masquerade syndrome were identified, two cases of intraocular lymphoma, and one metastasis of a visceral melanoma. CONCLUSION: Masquerade syndromes are not the leading cause of uveitis in the elderly. Idiopathic uveitis and herpes viruses are the most common etiology found.

[Total anterior opacification on the anterior surface of hydrophilic acrylic implanted lens]. / Opacification antérieure totale en avant d'un implant acrylique hydrophile.

We report a case of cloudiness occurring on the anterior surface of a hydrophilic acrylic foldable intraocular lens 1 year following implantation. This was not a case of phimosis of the capsulorhexis; the dondiness seemed secondary to fibroepithelial proliferation. Successful reopening was obtained with YAG laser. No recurrence was observed during the six months of follow-up.

[Current status of retinal detachment in AIDS patients]. / Aspect actuel des décollements de la rétine chez les patients atteints de SIDA.

Cytomegalovirus retinitis is the most common opportunistic ocular infection in patients with AIDS affecting 30 to 40% of the patients. It usually occurs in patients in the terminal stage of the disease presenting with low CD4+ count (<50/mm(3)). Retinal detachment (RD) is a frequent complication of this disease, with an incidence varying from 18% to 29%. Risk factors for development of rhegmatogenous RD in patients with CMV retinitis were peripheral involvement greater than 25%, the presence of active retinitis, greater patient age and lower CD4+ cell counts. Multiple or single holes, as well as micro holes, were observed in areas of retinal necrosis leading to complex retinal detachments. Strong vitreoretinal adherences in these young patients, associated with chronic inflammation, were important elements in the pathophysiology of retinal detachment in AIDS patients. For localized RD, demarcating laser photocoagulation may delayed or avoided vitreoretinal surgery. For RD with macula off, good anatomical results have been obtained by repairing CMV retinitis-related retinal detachments using primary vitrectomy and instillation of silicone oil. Despite good anatomical results, poor long term functional results are related to optic atrophy. Since the introduction of highly active antiretroviral therapy (HAART), retinal detachment incidence has nevertheless dramatically decreased. Under HAART, CMV retinitis remains quiescent for long periods of time with a reduction of retinal detachment incidence of approximately 77%. For some patients on HAART, retinal reattachment can be obtained using vitrectomy, posterior hyaloid removal, and intraocular tamponade with SF-6 gas.

[Familial amyloid polyneuropathy type I complicated by chronic glaucoma: 3 cases]. / Amyloses familiales avec polyneuropathie de type I compliquées de glaucome chronique.A propos de trois cas.

PURPOSE: We report 3 cases of familial amyloid polyneuropathy type I (FAP) with amyloid infiltration of the vitreum and glaucoma. PATIENTS AND METHODS: We reviewed the records of three patients, 2 females and one male, aged 41, 47 and 83 years respectively. The 3 patients had familial amyloid polyneuropathy type I with vitreous infiltration and open angle glaucoma. The two women underwent a liver graft four years earlier. Vitrectomy allowed confirmation of the diagnosis in the 83-year-old patient. Two patients underwent trabeculectomy, histological analysis of the iris and the trabeculum was obtained for one patient. RESULTS: The tree patients presented a polyneuropathy, vitreous infiltration and open angle glaucoma. Results of light microscopy of the iris and the trabeculum showed amyloid deposits in the iris and the trabecular meshworks. CONCLUSION: Familial amyloid polyneuropathy is a hereditary disease which may have a wide range of ocular manifestations. Glaucoma is among the most serious complications of familial amyloid polyneuropathy.

[Circumstances of choroid and ciliary body melanoma detection]. / Circonstances de découvertes des mélanomes de la choroïde et du corps ciliaire.

PURPOSE: To report and analyze the circumstances of uveal melanoma detection. METHODS: The records of 143 consecutive patients diagnosed in the Ophthalmology Department of Gustave Roussy Institute between September 1994 and September 2001 were analyzed. The study included 66 females and 77 males, aged from 21 to 91 years (mean, 62.75 years). RESULTS: The first symptom was decreased visual acuity in 37% of cases. In 34.9%, there was no functional sign and a systematic fundus exam provided the diagnosis. Of the 143 patients, 18.8% presented alteration of the visual field or scotoma, 9.9% complained of phosphenes, 9% complained of metamorphopsia, and 6.5% complained of floaters. In 5.5% of cases, there was documented tumor growth. In 2%, the presence of extrascleral exteriorization was the first sign. At the time of diagnosis, anterior tumors tended to be significantly larger than posterior tumors (p<0.007). Smaller lesions were significantly associated with a systematic detection of the tumor (p<0.005). Liver metastasis occurred more frequently with ciliary body melanomas (p<0.001), which were more frequently the largest lesions. CONCLUSION: These results emphasize the importance of early detection of uveal melanoma. We recommended frequent fundus examination after pupil dilatation.

[Hemangioma of the choroid with extra-scleral extension]. / Hémangiome de la choroïde avec extension extra-sclérale.

We report a case of atypical circumscribed choroidal hemangioma with retinal detachment in a 41-year-old man referred with the diagnosis of Harada disease. B. Scan ultrasonography showed an hyperechogenic area extended through the sclera. Careful examination of the fundus showed a small peripapillary orange mass and an inferior retinal detachment. Surgical exploration revealed an extrascleral hemangioma. Proton beam irradiation was followed by retinal reattachment within three months. No recurrence has been observed 18 months after treatment.

[Bilateral diffuse uveal melanocytic proliferation associated with systemic carcinoma: two case reports]. / Prolifération bilatérale mélanocytaire uvéale diffuse associée à un carcinome systémique: à propos de deux cas.

Diffuse uveal melanocytic proliferation is a rare paraneoplastic syndrome resulting in rapid bilateral visual loss in patients with systemic carcinoma, caused by proliferation of benign melanocytes within the choroid and the ciliary body. More often visual impairment is due to retinal detachment and cataract. The authors report two cases of presumed diffuse uveal melanocytic proliferation. The first patient was a 74-year-old man with a history of colic carcinoma and hemangioendothelioma of the liver who presented with bilateral multiple nevi of the choroid and extrascleral melanic nodule. The second patient was a 59-year-old woman who presented bilateral multiple nevi of the choroid and a history of carcinoma of the thyroid treated by thyroidectomy 2 years before. There was no evidence of systemic melanoma in either patient. Our two patients showed slow progression with no visual impairment and a longer survival than those described in the literature.

[Uveitis with hypopyon in patients with acquired immunodeficiency syndrome, treated with Rifabutin]. / Uvéite à hypopion chez des patients présentant un syndrome d'immunodéficience acquise et traités par Rifabutine.

BACKGROUND: Iridocyclitis has been identified as a dosage-dependent side effect in patients with the acquired immunodeficiency syndrome who are treated for Mycobacterium avium complex infections with systemic Rifabutin. We reviewed cases of acute hypopyon uveitis occurring in patients with AIDS to establish whether there was an association or not. METHODS: All patients were referred by an infection disease specialty service for complete ophthamological evaluation and ancillary laboratory. Six patients with AIDS, aged from 29 to 65 years, presented with acute unilateral hypopion. RESULTS: At the time of presentation, all six patients were receiving treatment for MAC infection with Rifabutin (dosage range, 300-600 mg/d) and four received Fluconazol. Results of microbiological investigations were negative. Hypopyon developed in the second eye of two patients. Hypopion resolved rapidly with intensive antibiotherapy without corticosteroids. CONCLUSION: Concomitant use of Rifabutin and Fluconazol may precipitate hypopyon uveitis. The cause of the uveitis is less certain, but the possible role of a microbiological agent cannot be ruled out.

[Toxoplasmic chorioretinitis complicated by retinal detachment]. / Choriorétinites toxoplasmiques compliquées de décollement de rétine.

PURPOSE: To describe and analyse relationship between chorioretinal toxoplasmosis and retinal detachment. PATIENTS AND METHODS: Seven immunocompetent patients examined and treated between November 1992 and March 1996, with ocular toxoplasmic retinochoroiditis and retinal detachment. RESULTS: Of the 7 patients examined, 5 had active retinochoroiditis and 2 had typical inactive scars. Of the patients with active focus 3 had giant retinal tears, one had a posterior retinal tear and one had a retinal tear located at the edge of an atrophic scar. Of the patients with inactive lesions, one had tractional retinal detachment and the other presented with a complete retinal detachment, multiples tears and PVR. Five patients were treated by corticosteroid without antitoxoplasmic drug before they were referred. The seven patients underwent endo-ocular surgery with silicon oil or long actic gas tamponade. Three patients developed PVR and redetachment of the retina and two patients underwent further surgery. Good anatomical result was obtained in 6 patients. CONCLUSION: Retinal detachment associated with toxoplasmic retinochoroiditis is rare. However it represents a serious complication. Steroid administrated to salvage vision may then worsen the clinical course, these may be justified to reduce hypersensitivity to toxoplasma antigen, but they should be combined with an antimicrobial agent.

[Rupture of the hemato-ocular barrier, studied by fluorophotometry, in uveal melanoma patients. Preliminary results]. / Etude de la rupture de la barrière hémato-oculaire par fluorophotométrie du vitré chez des patients porteurs d'un mélanome de l'uvée. Résultats préliminaires.

PURPOSE: To evaluate the use of intravenous vitreous fluorophotometry in assessment of the blood-aqueous barrier in eyes with uveal melanoma. METHOD: Vitreous fluorophotometry was performed before treatment in 14 patients with uveal melanoma. Both eyes of patients were examined, and fifteen control healthy patients were examined between November 1996 and December 1996 at the department of ophthalmology of Bicêtre hospital. RESULTS: Tumors with height > 6 mm and serous retinal detachments were accompanied by marked alterations of the blood-aqueous barrier, vitreous fluorophotometry showed diffusion of dye in posterior, mid and anterior vitreous: 2.99 ng/ml in the posterior vitreous and 5.20 ng/ml in the anterior vitreous. The posterior vitreous fluorescence at 60 minutes in the control eyes was 1.43 ng/ml and 1.30 ng/ml in the anterior vitreous. Diffusion of dye was present in the posterior vitreous in patients with tumor height less than 6 mm: 2.38 ng/ml (1.43 ng/ml in control eyes) at 60 minutes. CONCLUSIONS: Fluorophotometry provides a method for the assessment of the blood-aqueous ocular barrier in eyes with choroidal melanoma.