Intraocular optical quality of phakic intraocular lenses: comparison of angle-supported, iris-fixated, and posterior chamber lenses.

PURPOSE: To evaluate internal aberrometric profiles following phakic intraocular lens (PIOL) implantation. DESIGN: Retrospective and consecutive case series. METHODS: One hundred and five eyes of 65 patients were included. The optical aberrations were measured with the Topcon KR-1W aberrometer. Comparisons of internal aberrations for different models were made. Comparisons at 4 and 6 mm were made also within the same model for all the lenses. Comparisons regarding the implantation site were also performed: angle-supported (AS) anterior chamber (AC) (n = 47), iris-fixated (IF) (n = 27), and posterior chamber (PC) (n = 31). RESULTS: Root mean square (RMS) of internal optical higher-order aberrations (HOAs) changed significantly to higher values from 4-6 mm aperture diameter in each PIOL, as should be expected. However, this significant change was not detected in spherical aberration for Kelman Duet (P = .753) and in trefoil for Acrysoft (P = .059). Kelman lens showed significantly lower values of spherical aberration compared to Acrysoft at 4 mm (P = .022) and at 6 mm (P = .042). Acrysoft showed the lowest values at central zone for trefoil (P = .043) and tetrafoil (P = .002) in AC group. In the IF group, Artisan and Artiflex showed similar results for all internal aberrations. In the comparison between Visian Implantable Collamer Lens (ICL; STAAR Surgical Co, Monrovia, California, USA) and phakic refractive lens (PRL), both for posterior chamber, significantly lower values of coma were observed for ICL (P = .033). IF lenses showed clinical evidence, but not significant, of better centering capability than AS lenses (P = .096). CONCLUSIONS: The study of intraocular aberrations is an adequate method to identify the clinical optical behavior and could help the surgeon to identify the most frequent problems related with each model.

Laser-assisted in situ keratomileusis in high mixed astigmatism with optimized, fast-repetition and cyclotorsion control excimer laser.

PURPOSE: To evaluate the visual refractive and aberrometric outcomes of laser-assisted in situ keratomileusis (LASIK) surgery for the correction of high mixed astigmatism using a new-generation excimer laser and optimized aspherical profiles. DESIGN: Retrospective interventional case series. METHODS: Fifty-two eyes of 36 patients (21-53 years) with primary mixed astigmatism over 3.0 diopters (D) were included. All cases underwent LASIK surgery using the sixth-generation excimer laser Amaris with cyclotorsion control and a femtosecond platform for flap creation. Visual, refractive, corneal topographic, and aberrometric outcomes were evaluated during a 3-month follow-up. Refractive astigmatic changes were analyzed by Alpins method. RESULTS: A significant reduction of refractive sphere and cylinder was observed 3 months postoperatively (P = .001), with an associated improvement of uncorrected distance visual acuity (P = .001). Best-corrected distance visual acuity (CDVA) remained unchanged in 31 eyes (59.6%), while 3 eyes (5.76%) lost 2 lines of CDVA. Fourteen eyes (26.9%) had spherical equivalent (SE) within ±0.5 D of emmetropia and 34 (65.3%) had SE within ±1.0 D of emmetropia. No significant difference was observed when comparing surgically induced and target astigmatism. A significant induction of higher-order aberration attributable to increase of spherical aberration was found (P = .003). Seven eyes (13.4%) required retreatment. CONCLUSIONS: LASIK for primary high mixed astigmatism using optimized aspherical profiles and a fast-repetition-rate excimer laser with cyclotorsion control is a safe, effective, and predictable procedure. Induction of higher-order aberrations is still present in the correction of the refraction error of the magnitude included in this study.

Analysis of IL-10, IL-4 and TNF-alpha polymorphisms in drug-induced liver injury (DILI) and its outcome.

BACKGROUND/AIMS: The aim of this study was to assess whether genetic polymorphism of three important candidate cytokine genes, IL-10 (-1082G/A, -819C/T, and -592C/A), IL-4 (-590C/T) and TNF-alpha (-308G/A), play a role in the susceptibility to developing drug-induced liver injury (DILI), and in determining its phenotypic expression and severity. METHODS: Cytokine genotyping was analysed using TaqMan 5' allelic discrimination assay in 140 DILI patients (mean age 51 y, range 13-82, with equal sex distribution) included in the Spanish Registry and 268 healthy controls. RESULTS: Genotypes, haplotypes and allele frequencies were similar for both cases and controls. The low IL-10 producing haplotype was more prevalent in DILI patients with the absence of peripheral blood eosinophilia (Pc=0.004, OR=5.29, 95% CI: 2.04-13.67), revealing significantly lower median eosinophil counts (0.19 x 10(9)L; P<0.0002) compared to the intermediate (0.24 x 10(9)L) and high (0.40 x 10(9)L) IL-10 haplotypes. All cases with serious DILI outcome carried low or intermediate IL-10 producing haplotype and had normal or low eosinophil counts. CONCLUSIONS: IL-10, IL-4 and TNF-alpha genetic polymorphisms were not related to the risk of developing DILI. Low IL-10 producing haplotype is associated with low eosinophil count, absence of eosinophilia and may be associated with worse clinical outcome from DILI.

Genetic and molecular factors in drug-induced liver injury: a review.

The diagnosis of drug-induced liver injury (DILI) is challenging and based on complex diagnostic criteria. DILI falls into two main categories i) intrinsic "dose-dependent" Type A reactions ii) "idiosyncratic" or Type B reactions (which are usually not predictable). Idiosyncratic reactions can be immunoallergic (hypersensitivity), or metabolic, although overlap between categories can occur. The aim of this review is to summarise the general view of underlying mechanisms in DILI and to highlight individual risk factors for developing hepatotoxicity. Polymorphisms of bioactivation/toxification pathways through CYP450 enzymes (Phase I), detoxification reactions (Phase II) and excretion/transport (Phase III) are explored together with immunological factors that might determine DILI. The importance of establishing a multidisciplinary and multi-centric network to promote the understanding and research in hepatotoxicity is underlined. Challenges such as genetic analyses for association studies and whole genome studies, pharmacogenetic testing and future approaches to study DILI are considered. Knowledge regarding these operational mechanisms could provide further insight for the prospective identification of susceptible patients at risk of developing drug-induced hepatotoxicity.

Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry.

A chronic adverse reaction may occur in some instances of drug-induced liver injury (DILI), even despite drug cessation. In our study, we obtained records from a Spanish registry and evaluated cases of DILI with biochemical evidence of long-term damage. Chronic outcome was defined as a persistent biochemical abnormality of hepatocellular pattern of damage more than 3 months after drug withdrawal or more than 6 months after cholestatic/mixed damage. Data on 28 patients with a chronic clinical evolution (mean follow-up 20 months) between November 1995 and October 2005 were retrieved (18 female; overall mean age 55 yr) and accounted for 5.7% of total idiosyncratic DILI cases (n = 493) submitted to the registry. The main drug classes were cardiovascular and central nervous system (28.5% and 25%, respectively), which, in contrast, represented only 9.8% and 13%, respectively, of all DILI cases. The most frequent causative drugs were amoxicillin-clavulanate (4 of 69 cases), bentazepam (3 of 7 cases), atorvastatin (2 of 7 cases), and captopril (2 of 5 cases). Patients with cholestatic/mixed injury (18 of 194 cases [9%]) were more prone to chronicity than patients with hepatocellular injury (10 of 240 cases; P < .031). In the case of chronic hepatocellular injury, 3 patients progressed to cirrhosis and 2 to chronic hepatitis. In the cholestatic/mixed group, liver biopsy indicated cirrhosis in 1 patient and ductal lesions in 3 patients. In conclusion, cholestatic/mixed type of damage is more prone to become chronic while, in the hepatocellular pattern, the severity is greater. Cardiovascular and central nervous system drugs are the main groups leading to chronic liver damage.

Determinants of the clinical expression of amoxicillin-clavulanate hepatotoxicity: a prospective series from Spain.

Amoxicillin-clavulanate (AC) hepatotoxicity has been reported to exhibit a higher predominance of cholestatic types of damage, especially in males. However, the determinants of its clinical expression are unknown. This study prospectively evaluated the profile of AC hepatotoxicity. Data on all cases of hepatotoxicity reported to the Spanish Registry attributed to AC and assessed as definite or probable on the Council for International Organizations of Medical Sciences (CIOMS) scale were collated and compared to published case series. Hepatotoxicity related to amoxicillin-clavulanate was identified in 69 patients (36 males; mean age 56 years) representing 14% of all cases of hepatotoxicity submitted to the Registry. There was an overall sex distribution and the predominant pattern of lesion was hepatocellular (36%) which occurred at a shorter duration of treatment (P < .03). Mean time lapse between therapy initiation and jaundice onset was 16 days. Late onset of symptoms following end of treatment occurred in half the cases. Multiple logistic regression analysis identified advancing age as the factor associated with the development of cholestatic/mixed type of injury (odds ratio for an age interval for 1 year: 1.045 [95% CI = 1.013-1.078; P = .005). An unfavorable outcome was seen in 7% of patients. In conclusion, age is the most important determinant in the biochemical expression of AC hepatotoxicity; younger age is associated with cytolytic damage and shorter treatment duration, whereas cholestatic/mixed type of damage is related to older age and prolonged AC therapy.

Prolonged cholestasis after raloxifene and fenofibrate interaction: A case report.

Assigning causality in drug-induced liver injury is challenging particularly when more than one drug could be responsible. We report a woman on long-term therapy with raloxifen who developed acute cholestasis shortly after starting fenofibrate. The picture evolved into chronic cholestasis. We hypothesized that an interaction at the metabolic level could have triggered the presentation of hepatotoxicity after a very short time of exposure to fenofibrate in this patient. The findings of an overexpression of vascular endothelial growth factor in the liver biopsy suggest that angiogenesis might play a role in the persistence of toxic cholestasis.

Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy.

PURPOSE: Radiotherapy has reduced local recurrence of rectal cancers, but the result is not satisfactory. Further biologic factors are needed to identify patients for more effective radiotherapy. Our aims were to investigate the relationship of cyclooxygenase-2 (Cox-2) expression to radiotherapy, and clinicopathologic/biologic variables in rectal cancers with or without radiotherapy. METHODS AND MATERIALS: Cox-2 expression was immunohistochemically examined in distal normal mucosa (n = 28), in adjacent normal mucosa (n = 107), in primary cancer (n = 138), lymph node metastasis (n = 30), and biopsy (n = 85). The patients participated in a rectal cancer trial of preoperative radiotherapy. RESULTS: Cox-2 expression was increased in primary tumor compared with normal mucosa (p < 0.0001), but there was no significant change between primary tumor and metastasis. Cox-2 positivity was or tended to be related to more p53 and Ki-67 expression, and less apoptosis (p < or = 0.05). In Cox-2-negative cases of either biopsy (p = 0.01) or surgical samples (p = 0.02), radiotherapy was related to less frequency of local recurrence, but this was not the case in Cox-2-positive cases. CONCLUSION: Cox-2 expression seemed to be an early event involved in rectal cancer development. Radiotherapy might reduce a rate of local recurrence in the patients with Cox-2 weakly stained tumors, but not in those with Cox-2 strongly stained tumors.

Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.

BACKGROUND & AIMS: Progress in the understanding of susceptibility factors to drug-induced liver injury (DILI) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases. METHODS: A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form. The liver damage was characterized according to hepatocellular, cholestatic, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed. RESULTS: Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DILI. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (P < .0001), and had the worst outcome (Cox regression, P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had jaundice at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (P < .04). Factors associated with the development of fulminant hepatic failure were female sex (OR = 25; 95% CI: 4.1-151; P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6-37; P < .009), and higher baseline plasma bilirubin value (OR = 1.15; 95% CI: 1.09-1.22; P < .0001). CONCLUSIONS: Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI.