Flutamide-induced hepatotoxicity: ethical and scientific issues.

OBJECTIVE: Flutamide (FLU) is a non-steroidal antiandrogen drug approved for the treatment of advanced prostate cancer. While this indication limits the use to male patients, FLU is widely prescribed to women, off-label, for the treatment of polycystic ovary syndrome (POCS) related hirsutism and acne. According to the literature, its assumption is associated with a higher incidence of adverse events in women than in male patients. MATERIALS AND METHODS: A literature search was conducted in main databases targeting unwilling FLU effects in hepatic and reproductive function. References in the selected paper were also considered as an additional source of data. Human- and animal-based studies were separately considered. RESULTS: Twenty-three human-based studies were evaluated: ten were case reports, six were retrospective studies, four were prospective, two were surveillance studies, while the last was an observational study. Nine animal-based studies were also evaluated. CONCLUSIONS: Scientific contributions highlight that FLU is responsible for specific hepatotoxic profiles in the female gender. From the ethical point of view, off-label prescribing of FLU in women is not only substantially unlawful, but also, without major safeguards being granted, a potential source of liability for prescribers.

Malignant peripheral nerve sheath tumour (malignant epithelioid Schwannoma) of the parotid gland.

PROBLEMS/OBJECTIVES: Malignant peripheral nerve sheath tumours are uncommon soft tissue tumours originating from Schwann cells or nerve sheath cells. Malignant epithelioid schwannoma is an aggressive variant of malignant peripheral nerve sheath tumour, and unfortunately is related with a high rate of recurrence and poor prognosis. METHODOLOGY: In this study we present a rare case of malignant epithelioid schwannoma of the parotid gland and we discuss its origin, unusual presentation, and possible treatments options. RESULTS: Patient underwent total parotidectomy without neck dissection. Postoperative radiotherapy and chemotherapy management were not necessary. CONCLUSION: Patients with malignant epithelioid schwannomas typically present with pain and/or rapid enlargement of a pre-existing lesion but the diagnosis of these tumours remains difficult as it is based primarily on clinical suspicion. There is no recognized management for this tumour yet while the prognosis seems to correlate best with the extent of surgical resection (Fig. 4, Ref. 16).

Glycaemic and insulinaemic responses to feeding hay with different non-structural carbohydrate content in control and polysaccharide storage myopathy-affected horses.

The aim of this study was to determine whether the glycaemic/insulinaemic responses to hay with non-structural carbohydrate (NSC, soluble carbohydrate) of 17% (HC), 10% (MC) or 4% (LC) differs in control horses and whether these responses differ between control and horses with polysaccharide storage myopathy (PSSM). Five clinically normal control horses and seven PSSM horses, all unfit and of Quarter Horse breeding (age 9.4 ± 3.4 years, body condition score range: 4.5-6). A crossover design compared the HC and LC hay, with horses randomly assigned to hay type for 5 days, and all horses fed the MC hay during washout, after which the diets were switched. Horses were fed 1.5% BW (as fed) divided into 2 feeding per day, no grain. On morning of the fifth day of each block (seventh day for washout), horses were given 0.5% BW in hay, blood was drawn before and every 30 min for 5 h after feeding, and the rate of intake was measured. Whole blood glucose and plasma insulin were measured. The intake rate was significantly higher for HC. In control horses, the insulin area under the curve (6891.7 ± 3524.2 HC vs. 1185.4 ± 530.2 LC) was significantly higher than LC. Polysaccharide storage myopathy horses had significantly higher glycaemic and insulinaemic responses to HC vs. LC, however; the magnitude of insulin response was lower and glucose response higher in PSSM vs. control horses. Results suggest that insulin responses can differ significantly with the NSC content of hay. Feeding hay with 17% NSC produces elevations in insulin that could be detrimental for PSSM horses.

Differences in the metabolic properties of gluteus medius and superficial digital flexor muscles and the effect of water treadmill training in the horse.

REASONS FOR PERFORMING STUDY: Flexor tendon injury may be due to flexor muscle fatigue, contributing to fetlock joint hyperextension and tendon damage. A water treadmill provides resistance training on flexor tendon muscles, which might reduce the risk of tendon injury. OBJECTIVE: To determine the effect of water treadmill training on the properties of the gluteal and superficial digital flexor (SDF) muscles and on cardiocirculatory response to a standardised exercise test. METHODS: Five healthy unfit horses were trained on a water treadmill for 5 days/week for 4 weeks, starting with 5 min/day increasing to 20 min/day. Before and after the water treadmill training, an incremental SET was performed on a land treadmill to determine velocity at a heart rate 200 beats/min (V(200)) and resting gluteal and SDF muscle biopsies were obtained for biochemical analyses. RESULTS: There was no measurable difference in resting concentrations of gluteal or SDF muscle glycogen, lactate, ATP or glucose-6-phosphate (G6P), or activities of citrate synthase (CS), 3-hydroxyacyl CoA dehydrogenase (HAD) and lactate dehydrogenase (LDH) after training and no change in V(200), Lactate, glycogen, G6P and ATP concentrations were 50% lower and type 1 fibres 30% higher in SDF compared to gluteal muscles. CS and HAD activities were similar between SDF and gluteal, while LDH was lower in the SDF muscle. CONCLUSIONS: A more strenuous water treadmill conditioning protocol may be needed to induce a training effect in gluteal and SDF muscle and heart rate response. The low substrate concentrations and oxidative capacity of SDF may predispose this muscle to catastrophic fatigue during maximal exercise.

Polysaccharide storage myopathy phenotype in quarter horse-related breeds is modified by the presence of an RYR1 mutation.

In this study we examined a family of Quarter Horses with Polysaccharide Storage Myopathy (PSSM) with a dominant mutation in the skeletal muscle glycogen synthase (GYS1) gene. A subset of horses within this family had a more severe and occasionally fatal PSSM phenotype. The purpose of this study was to identify a modifying gene(s) for the severe clinical phenotype. A genetic association analysis was used to identify RYR1 as a candidate modifying gene. A rare, known equine RYR1 mutation, associated with malignant hyperthermia (MH), was found to segregate in this GYS1 PSSM family. Retrospective analysis of patient records (n=179) demonstrated that horses with both the GYS1 and RYR1 mutations had a more severe clinical phenotype than horses with the GYS1 mutation alone. A treadmill trial (n=8) showed that serum creatine kinase activity was higher and exercise intolerance greater in horses with both mutations compared to the GYS1 mutation alone.

Intravitreal triamcinolone acetonide as primary treatment for diffuse diabetic macular edema: a prospective noncomparative interventional case series.

PURPOSE: To evaluate the efficacy and safety of one intravitreal injection of 25 mg of triamcinolone acetonide as primary treatment for diffuse diabetic macular edema. METHODS: Intravitreal triamcinolone acetonide injection was performed in 30 eyes with previously untreated diabetic macular edema. The main outcome measures were logMAR visual acuity (VA) and central macular thickness (CMT) at 1, 3, and 6 months. A secondary outcome was intraocular pressure progression. RESULTS: Visual acuity results for 30 eyes that had a follow-up of at least 6 months are presented. Twenty of them were followed up to 10.1+/-2.38 months. Preoperatively, VA was 0.54+/-0.27. At 1, 3, and 6 months follow-up, VA was 0.44+/-0.29 (p=0.001), 0.43+/-0.28 (p=0.001), and 0.45+/-0.29 (p=0.006), respectively. Preoperatively, CMT was 417.3+/-143.5 microm. At 1, 3, and 6 months follow-up, CMT was 277.3 +74.0 microm (p<0.0001), 279.6+/-94.4 microm (p<0.0001), and 297.07+/-114.87 microm (p=0.002), respectively. For the 20 eyes with a follow-up of 10.1+/-2.38 months, VA was 0.5+/-0.25 and 0.50+/-0.32 at baseline and at the last follow-up visit, respectively (p>0.05). Preoperatively, intraocular pressure (IOP) was 15.13+/-1.48 mmHg. IOP was 18.26+/-2.71 mmHg, 20.07+/-4.27 mmHg, and 20.4+/-6.18 mmHg, at 1, 3, and 6 months, respectively (p<0.0001). Four eyes underwent uncomplicated filtrating surgery for intractable glaucoma. CONCLUSIONS: Intravitreal triamcinolone as primary treatment effectively increases VA and reduces CMT due to diffuse diabetic macular edema. Longer follow-up and randomized clinical trial are warranted. Safety results highlight the need to further study the relationship between triamcinolone and intraocular pressure.

Intravitreal triamcinolone acetonide as primary treatment for diffuse diabetic macular edema: A prospective noncomparative interventional case series.

PURPOSE: To evaluate the efficacy and safety of one intravitreal injection of 25 mg of triamcinolone acetonide as primary treatment for diffuse diabetic macular edema. METHODS: Intravitreal triamcinolone acetonide injection was performed in 30 eyes with previously untreated diabetic macular edema. The main outcome measures were logMAR visual acuity (VA) and central macular thickness (CMT) at 1, 3, and 6 months. A secondary outcome was intraocular pressure progression. RESULTS: Visual acuity results for 30 eyes that had a follow-up of at least 6 months are presented. Twenty of them were followed up to 10.1+/-2.38 months. Preoperatively, VA was 0.54+/-0.27. At 1, 3, and 6 months follow-up, VA was 0.44+/-0.29 (p=0.001), 0.43+/-0.28 (p=0.001), and 0.45+/-0.29 (p=0.006), respectively. Preoperatively, CMT was 417.3+/-143.5 micronm. At 1, 3, and 6 months follow-up, CMT was 277.3 +74.0 micronm (p<0.0001), 279.6+/-94.4 micronm (p<0.0001), and 297.07+/-114.87 micronm (p=0.002), respectively. For the 20 eyes with a follow-up of 10.1+/-2.38 months, VA was 0.5+/-0.25 and 0.50+/-0.32 at baseline and at the last follow-up visit, respectively (p>0.05). Preoperatively, intraocular pressure (IOP) was 15.13+/-1.48 mmHg. IOP was 18.26+/-2.71 mmHg, 20.07+/-4.27 mmHg, and 20.4+/-6.18 mmHg, at 1, 3, and 6 months, respectively (p<0.0001). Four eyes underwent uncomplicated filtrating surgery for intractable glaucoma. CONCLUSIONS: Intravitreal triamcinolone as primary treatment effectively increases VA and reduces CMT due to diffuse diabetic macular edema. Longer follow-up and randomized clinical trial are warranted. Safety results highlight the need to further study the relationship between triamcinolone and intraocular pressure. (Eur J Ophthalmol 2006; 16: 129-33).

The pituitary-testicular axis in microgravity: analogies with the aging male syndrome.

Extraterrestrial exploration has gone on for decades before reversible testicular failure was shown to be a consequence of space flight in humans and animals at the end of the XXth century. This phenomenon was initially thought to depend on the psycho-physical stress expected to derive from a decidedly unusual environment, but the lack of consistent data concerning cortisol increase and/or gonadotrophin suppression pointed to the possibility of a primary defect. This was indirectly confirmed by the observation that a continuum of testicular androgen secretion potential exists from microgravity to centrifuge-derived hypergravity. Further experiments using tissue slices and suspended cells confirmed a direct inhibitory effect of microgravity upon testicular androgen production. A parallel deterioration of major physiological parameters, such as bone density, muscle mass/force, red blood cell mass, hydration and cardiopulmonary performance, has been repeatedly described during space missions, which, luckily enough, fully recover within days to weeks after landing, the time lag depending on single organ/system adaptation rates. According to the Authors of the present review, when taking together all reported changes occurring in space, a picture emerges closely resembling the so-called aging male syndrome, which is currently the object of daily screening and clinical care in their endocrine unit, so that microgravity may become a tool for better understanding subtle mechanisms of testicular senescence.

Subfoveal choroidal neovascularization in a patient with pre-existing pseudomacular hole.

PURPOSE: To report concomitant use of fluorescein angiography (FA) and optical coherence tomography (OCT) in a case of pre-existing pseudomacular hole (PMH) and macular choroidal neovascularization (CNV) treated with photodynamic therapy (PDT). METHODS: Case report. RESULTS: A 63-year-old man who received laser treatment for branch retinal vein occlusion in 1993 developed an asymptomatic macular epiretinal membrane 2 years later. In 2001, the patient complained of metamorphopsia. Biomicroscopy showed a PMH, confirmed by OCT. One year later, metamorphopsia suddenly increased and visual acuity dropped from 20/20 to 20/70. FA and OCT revealed subfoveal occult CNV PDT was successfully performed. FA and OCT were essential diagnostic tools during the follow-up. CONCLUSIONS: The case presented stresses the importance of different tools for accurate diagnosis and proper follow-up of macular diseases.

Silent occult choroidal vascular abnormalities.

PURPOSE: To describe clinically occult choroidal vascular abnormalities that can be revealed by indocyanine green (ICG) angiography. METHODS: Out of approximately 2,700 patients who underwent ICG angiography, a lesion was incidentally observed in eight eyes of eight patients. In five patients, the ICG study included a second examination taken during artificially induced intraocular hypertension. Examinations were repeated in six patients over a follow-up period ranging from 4 months to 3 years. RESULTS: On ICG angiogram, the choroidal vasculopathy appeared as a round-oval hyperfluorescent area 2-4 disk diameters in size that was located at the temporal vascular arcades in six eyes, at the inferomacular region in one eye, and above the optic disk in one eye. The lesions were not identifiable with funduscopic, fluorescein angiographic, or ultrasonographic examination. The lesions filled at the same time as the choroidal arteries and lost fluorescence in mid-late phase of the ICG angiogram. The ICG series taken during induced intraocular hypertension showed the hyperfluorescent areas originated from choroidal arterial abnormalities giving rise to confluent hyperfluorescent patches. Draining vessels connecting the choroidal vasculopathy with a vortex vein were evidenced in three eyes. A sector of apparent choroidal hypoperfusion downstream from the lesion was present in three eyes. During the follow-up period, the lesions remained occult and with an unchanged ICG angiographic pattern in all patients. CONCLUSION: Some silent occult choroidal vascular abnormalities may be incidentally revealed by ICG angiography. These must be distinguished from ICG imaging of concomitant chorioretinal disorders.

The deletion polymorphism of the angiotensin I-converting enzyme gene is associated with target organ damage in essential hypertension.

The activity of the renin-angiotensin-aldosterone system is thought to play a significant role in the development of target organ damage in essential hypertension. An insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has recently been associated with increased risk for left ventricular hypertrophy and coronary heart disease in the general population. The D allele is associated with higher levels of circulating ACE and therefore may predispose to cardiovascular damage. The study presented here was performed to investigate the association between the ACE genotype, microalbuminuria, retinopathy, and left ventricular hypertrophy in 106 patients with essential hypertension. ACE gene polymorphism was determined by polymerase chain reaction technique. Microalbuminuria was evaluated as albumin-to-creatinine ratio (A/C) in three nonconsecutive first morning urine samples (negative urine culture) after a 4-wk washout period. Microalbuminuria was defined as A/C between 2.38 to 19 (men) and 2.96 to 20 (women). Hypertensive retinopathy was evaluated by direct funduscopic examination (keith-Wagener-Barker classification) and left ventricular hypertrophy by M-B mode echocardiography. The distribution of the DD, ID, and II genotypes was 27, 50, and 23%, respectively. The prevalence of microalbuminuria, retinopathy, and left ventricular hypertrophy was 19, 74, and 72% respectively. There were no differences among the three genotypes for age, known duration of disease, body mass index, blood pressure, serum glucose, uric acid, and lipid profile. DD and ID genotypes were significantly associated with the presence of microalbuminuria (odds ratio, 8.51; 95% confidence interval, 1.07 to 67.85; P = 0.019), retinopathy (odds ratio, 5.19; 95% confidence interval, 1.71 to 15.75; P = 0.005) and left ventricular hypertrophy (odds ratio, 5.22; 95% confidence interval, 1.52 to 17.94; P = 0.016). Furthermore, patients with DD and ID genotypes showed higher levels of A/C (3.6 +/- 0.9, DD; 2.6 +/- 0.7, ID; 0.9 +/- 0.2 mg/mmol, II; P = 0.0015 by analysis of variance) and increased left ventricular mass index (152 +/- 4.7, DD + ID versus 133 +/- 5.7 g/m2, II; P = 0.01) compared with II patients. The D allele was significantly more frequent in patients with microalbuminuria (odds ratio, 2.59; 95% confidence interval, 1.24 to 5.41; P = 0.013) and in those with retinopathy (odds ratio, 2.44; 95% confidence interval, 1.21 to 4.90; P = 0.015). Multiple regression analyses performed among the entire cohort of patients demonstrated that ACE genotype significantly and independently influences the presence of retinopathy, left ventricular hypertrophy, and microalbuminuria. In conclusion, the D allele of the ACE gene is associated with microalbuminuria as well as with retinopathy and left ventricular hypertrophy, and seems to be an independent risk factor for target organ damage in essential hypertension.

Pre-injection fluorescence in indocyanine green angiography.

PURPOSE: To verify whether infrared pre-injection fluorescence can be observed in patients undergoing indocyanine green (ICG) angiography. METHODS: Infrared fundus photographs were taken before dye injection for 450 consecutive patients undergoing ICG angiography for different chorioretinal disorders. The authors used a high-resolution videoangiography system with the standard ICG filters inserted (overlap, < 0.5%) and the highest flash intensity. RESULTS: Pre-injection fluorescence was detected in 184 patients (40.8%). It was a strong fluorescence in 75 patients (40.7%) and a faint fluorescence in 109 (59.2%). When fluorescence was strong, it simulated vascular filling on the ICG angiogram. Pre-injection fluorescence resulted from the following lesions: (1) old grayish subretinal hemorrhages (35 patients); (2) lipofuscin-like deposits (65 patients); (3) pigmented choroidal neovascular membranes (72 patients); and (4) serous retinal detachments lasting from several months or years (12 patients). Highly reflecting white lesions were not fluorescent. CONCLUSION: Pre-injection fluorescence of chorioretinal lesions is frequently detectable in patients with diseases requiring ICG examination. A pre-injection photograph may help to avoid misinterpretation of the angiograms. The authors' findings may be interpreted as pseudofluorescence or autofluorescence. Pigments contained in pathologic structures of the ocular fundus may be the source of autofluorescence emissions in the near-infrared range.

Indocyanine green angiography of circumscribed choroidal hemangiomas.

BACKGROUND: Indocyanine green (ICG) angiography performed with the modern high resolution digital system already has improved our knowledge of several chorioretinal disorders. It could provide new information on circumscribed choroidal hemangiomas. METHODS: Twelve consecutive patients with circumscribed choroidal hemangioma underwent both fluorescein angiography and ICG angiography with a digital high resolution system. In each patient, two ICG angiograms were taken - with normal and with artificially increased intraocular pressure. The latter method allowed analysis of the vascular connections of the tumor with the adjacent choroid during the induced slowdown of blood flow. RESULTS: With ICG, the authors obtained a clear delineation of the choroidal hemangiomas. In all cases, the lesion was better defined on the ICG than on the fluorescein angiogram. Nutrient and draining vessels of the tumors were identified. Nutrient vessels were represented by short posterior ciliary arteries in five eyes with severe exudative syndrome, and by ramifications of choroidal arteries in the other cases. Further special ICG findings were apparent choroidal ischemia downstream from the tumor (9 eyes), and clearing of the dye with a "washout" phenomenon. CONCLUSION: Indocyanine green angiography can be helpful in the clinical evaluation of circumscribed choroidal hemangiomas. The blood supply to these tumors is provided directly by short posterior ciliary arteries or by ramifications of choroidal arteries. An adjacent compromised choroidal perfusion may be present.

Indocyanine green angiographic findings in central serous chorioretinopathy.

The purpose of this study is to better characterise, on the basis of a large number of cases and follow-up evaluations, choroidal abnormalities recently observed with indocyanine green (ICG) angiography in central serous chorioretinopathy (CSC). Digital ICG videoangiography was performed in 145 patients with active or inactive, acute or chronic CSC. Forty-eight patients were re-examined in a follow-up period of 6-22 months (mean 10 months). Areas of choroidal leakage attributable to hyperpermeability of the choriocapillaris were found in 98.6% of patients in association with active or resolved pigment epithelial leaks and pigment epithelial detachments. Diffusion of ICG into the choroid was characterised by rapid centrifugal spreading of the dye with a wash-out pattern which was particularly evident in areas corresponding to pigment epithelial detachments. In patients with a long-standing disease, when choroidal hyperfluorescence faded, hypofluorescent spots became increasingly evident revealing pigment epithelial alterations not shown by fluorescein angiography. Areas of choroidal leakage remained unchanged in each patient during the follow-up period, even when subretinal exudation resolved either spontaneously or after photocoagulation. In 5 eyes we observed the appearance of leakage points on pre-existing areas of choroidal leakage. Zonal hyperpermeability of the choriocapillaris characterises all the evolutional stages of CSC and seems to be the primary alteration of this disease. When it corresponds to pigment epithelial detachments choriocapillaris hypermeability is probably associated with local hyperperfusion.

Central serous chorioretinopathy and indocyanine green angiography.

BACKGROUND: Because of limitations in imaging through the retinal pigment epithelium (RPE), fluorescein angiography has not been able to characterize the choroidal abnormalities that are thought to be causative factors in central serous chorioretinopathy (CSC). METHODS: Digital indocyanine green (ICG) videoangiography and fluorescein angiography were performed in 34 consecutive patients with various forms of CSC to investigate choroidal abnormalities. RESULTS: The ICG videoangiographic studies revealed choroidal staining in association with active, spontaneously resolved, and previously photocoagulated pigment epithelial leaks documented with fluorescein angiography. In the space of a few minutes, the dye progressively spread outward from the region of choroidal staining. CONCLUSION: Localized hyperpermeability of the choriocapillaris, probably associated with segmental choroidal hyperperfusion, may be a causative factor of characteristic RPE and neurosensory retinal exudative changes in CSC.

Measurement variability in digital analysis of optic discs.

The optic disc of nine patients with typical glaucomatous disc damage and ten normal controls has been studied by means of the Optic Disc Analysis program of the Topcon Image-net System. Vertical, horizontal and average cup/disc ratio (VC/D, HC/D, AC/D), disc, cup, rim area (DA, CA, RA), cup volume (CV) have been evaluated and the coefficient of variation (COV) of multiple measurements was calculated. For intra-observer intra-image variability assessment, sterovideographs of each disc were taken once and analyzed 10 times (COV range: 1.39-12.08%). Intra-observer interimage variability was evaluated on eight stereovideographs of each disc taken at one minute intervals (COV range: 1.63-96%). Inter-observer intra-image measurements were taken on each disc by 5 different observer (COV range: 1.28-27.08%).

[New occult choroidal vessels in age-related macular degeneration]. / Néovaisseaux choroïdiens occultes au cours de la dégénérescence maculaire liée à l'âge.

We studied the clinical characteristics and the natural course of occult choroidal new vessels (CNV) in 78 eyes with age-related macular degeneration (AMD). Cases were included in 2 groups characterized respectively by ill-defined subretinal ooze (group 1) and serous detachment of the retinal pigment epithelium (RPE) with adjacent areas of mottled pigmentation (group 2). Both these forms of occult CNV showed to have a slower evolution compared to the classic CNV occurring in AMD, but they also led to disciform scar and severe visual loss. Occult CNV of group 2, contrary to those of group 1, were often multifocal and extrafoveal. They had a greater tendency to hemorrhages and a faster and less gradual progression to fibrovascular scarring and visual loss. Fluorescein angiography showed choroidal filling delay in the macular region of 47% of eyes of group 1. A perfusion defect of the macular choroid could be the basis of the low perfusion pressure and the consequent low activity of CNV with the angiographic pattern of ill-defined ooze.