Patient understanding of genetic information influences reproductive decision making in retinoblastoma.

BACKGROUND: Retinoblastoma is the most common malignant tumour of the eye in childhood, with nearly all bilateral tumours and around 17% to 18% of unilateral tumours due to an oncogenic mutation in the RB1 gene in the germline. Genetic testing enables accurate risk assessment and optimal clinical management for the affected individual, siblings, and future offspring. MATERIAL AND METHODS: We carried out the first UK-wide audit of understanding of genetic testing in individuals with retinoblastoma. A total of 292 individuals aged 16 to 45 years were included. RESULTS: Patients with bilateral disease were significantly more likely to understand the implications of retinoblastoma for siblings and children. There was a significant association between not knowing the results of genetic testing or not understanding the implications and not having children, particularly in women. Surprisingly, this was also true for individuals treated for unilateral disease with a low risk of retinoblastoma for their offspring. CONCLUSION: We are concerned that individuals may be making life choices based on insufficient information regarding risks of retinoblastoma and reproductive options. We suggest that improvement in transition care is needed to enable individuals to make informed reproductive decisions and to ensure optimal care for children born at risk of retinoblastoma.

Gene expression profiling identifies different sub-types of retinoblastoma.

BACKGROUND: Mutation of the RB1 gene is necessary but not sufficient for the development of retinoblastoma. The nature of events occurring subsequent to RB1 mutation is unclear, as is the retinal cell-of-origin of this tumour. METHODS: Gene expression profiling of 21 retinoblastomas was carried out to identify genetic events that contribute to tumorigenesis and to obtain information about tumour histogenesis. RESULTS: Expression analysis showed a clear separation of retinoblastomas into two groups. Group 1 retinoblastomas express genes associated with a range of different retinal cell types, suggesting derivation from a retinal progenitor cell type. Recurrent chromosomal alterations typical of retinoblastoma, for example, chromosome 1q and 6p gain and 16q loss were also a feature of this group, and clinically they were characterised by an invasive pattern of tumour growth. In contrast, group 2 retinoblastomas were found to retain many characteristics of cone photoreceptor cells and appear to exploit the high metabolic capacity of this cell type in order to promote tumour proliferation. CONCLUSION: Retinoblastoma is a heterogeneous tumour with variable biology and clinical characteristics.

Cataract management in children: a review of the literature and current practice across five large UK centres.

Congenital and childhood cataracts are uncommon but regularly seen in the clinics of most paediatric ophthalmology teams in the UK. They are often associated with profound visual loss and a large proportion have a genetic aetiology, some with significant extra-ocular comorbidities. Optimal diagnosis and treatment typically require close collaboration within multidisciplinary teams. Surgery remains the mainstay of treatment. A variety of surgical techniques, timings of intervention and options for optical correction have been advocated making management seem complex for those seeing affected children infrequently. This paper summarises the proceedings of two recent RCOphth paediatric cataract study days, provides a literature review and describes the current UK 'state of play' in the management of paediatric cataracts.

17 beta-estradiol: inducer of uterine hexokinase.

Administration of estradiol to ovariectomized rats induced new synthesis of uterine hexokinase which was prevented by actinomycin D, 5-fluorouracil, cycloheximide, or ethionine. The estradiol-induced increase in uterine hexokinase activity was detectable as early as 4 hours. The increase in enzyme activity was dependent upon the dose of the hormone. The evidence indicates that the increased hexokinase activity induced by 17beta-estradiol may entail an acceleration of the synthesis of certain RNA species.

Pseudodacryocystitis: paediatric case series of infected atypical ethmoid air cells masquerading as recurrent dacryocystitis.

PurposeTo highlight the clinical and surgical considerations in treating patients with apparent recurrent acute dacryocystitis with a patent lacrimal system.MethodsThree children referred to a tertiary unit as recurrent acute dacryocystitis were reviewed retrospectively. Imaging and subsequent surgical intervention revealed the underlying diagnosis.ResultsAll three cases presented with recurrent abscesses in the region of the lacrimal sac that failed to respond to incision and drainage. The lesions were lower and more lateral to the usual location of a sac abscess and closer to the inferior orbital rim. All three cases were found to have patent lacrimal systems on syringing, and all were found to have infected, low-lying, anteriorly placed aberrant ethmoid air cells on computed tomography and magnetic resonance imaging. These were confirmed on subsequent surgical exploration.ConclusionsInfected low-lying ethmoid air cells can mimic dacryocystitis with recurrent abcesses. In cases where a patent nasolacrimal system is demonstrated and a more inferolateral location of the swelling than would be expected in dacryocystitis is seen, imaging is warranted to ensure the appropriate intervention is undertaken. Anterior ethmoidectomy as opposed to dacryocystorhinostomy is the appropriate treatment in these cases.

Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake.

Leptin is a protein encoded by the ob gene and expressed in adipocytes. A sensitive marker of nutritional status, leptin is known to correlate with fat mass and to respond to changes in caloric intake. Leptin may also be an important mediator of reproductive function, as suggested by the effects of leptin infusions to restore ovulatory function in an animal model of starvation. We hypothesized that leptin levels are decreased in women with hypothalamic amenorrhea and that leptin may be a sensitive marker of overall nutritional status in this population. We, therefore, measured leptin levels and caloric intake in 21 women with hypothalamic amenorrhea (HA) and 30 age-, weight-, and body fat-matched eumenorrheic controls. Age (24 +/- 5 vs. 24 +/- 3 yr), body mass index (20.6 +/- 1.3 vs. 21.1 +/- 1.5 kg/m2), percent ideal body weight (94.9 +/- 5% vs. 96.3 +/- 6.3%), and fat mass (14.2 +/- 3.6 vs. 15.5 +/- 2.9 kg, determined by dual energy x-ray absortiometry) did not differ between the groups. Leptin levels were significantly lower in the HA subjects compared with those in the controls (7.1 +/- 3.0 vs. 10.6 +/- 4.9 micrograms/L; P = 0.005). Total caloric intake (1768 +/- 335 vs. 2215 +/- 571 cal/day; P = 0.003), fat intake (333 +/- 144 vs. 639 +/- 261 cal/day; P < 0.0001), and insulin levels (5.6 +/- 1.2 vs. 7.4 +/- 3.2 microU/mL; P = 0.015) were lower in the women with HA than in the eumenorrheic controls. The difference in leptin levels remained significant after controlling for insulin (P = 0.023). These data are the first to demonstrate hypoleptinemia, independent of fat mass, in women with HA. The hypoleptinemia may reflect inadequate calorie intake, fat intake, and/or other subclinical nutritional disturbances in women with HA. The mechanism and reproductive consequences of low leptin in this large population of women remain unknown.

Detection of low molecular mass GTP-binding proteins in chromaffin granules and other subcellular fractions of chromaffin cells.

A homogenate of purified chromaffin cells was fractionated, after removal of the nuclear fraction, by sucrose density gradient ultracentrifugation. The presence and subcellular localization of low molecular mass GTP-binding proteins was explored by incubation of blots of proteins from different subcellular fractions with [alpha-32P]GTP in the presence of Mg2+. The fractions enriched in intact chromaffin granule markers, i.e. catecholamines, chromogranin A, chromogranin B and cytochrome b-561 were also enriched in labelled GTP-binding proteins. Two major labelled components of 23 and 29 kDa were rapidly detected by autoradiography. Traces of 26 and 27 kDa components were also present. These components were detectable in both plasma and granule membranes. In addition to these components, the cytosolic fraction contained another GTP-binding protein of about 20 kDa. Binding of [alpha-32P]GTP was specific and dependent on Mg2+. By analogy to the findings reported in non-mammalian systems, the observations described here suggest the involvement of low molecular mass GTP-binding proteins in the chromaffin cell secretory process.

Effects of parenteral vanadium administration on pulmonary metabolism of rats.

Daily, intraperitoneal administration of either vanadium pentoxide (VP) or sodium vanadate (NaV) at a dose of 1 mg/kg for 14 days produced no marked change in pulmonary protein, glycogen and phospholipid (PL) levels of adult male rats. Increasing the VP dose to 4 mg/kg decreased lung PL content, while an equivalent NaV dose elevated tissue glycogen. Treatment with either dosage of NaV elevated the activities of pulmonary 6-phosphogluconate dehydrogenase (6PGDH), pyruvate kinase (PK) and glutathione peroxidase (GP), and the higher dose increased lactate dehydrogenase (LDH) and glutathione reductase (GR). The 1 mg/kg VP produced a significant rise in glucose-6-phosphate dehydrogenase (G6PDH) and 6PGDH. while the higher VP dose in general failed to alter enzymic activity. Our data suggest that similar to intratracheal instillation, parenteral administration of vanadium exerts an effect on lung metabolism of rats.

Spontaneous foreign body extrusion following perforating eye injury.

A structured approach to the management of a perforating ballistic eye injury is illustrated in this case, where initial treatment was limited to simple corneal wound closure and antibiotic prophylaxis. A pellet had passed completely through the globe but the retina remained attached, and it was decided to manage the case conservatively. Two retained foreign bodies were extruded spontaneously some months after the injury when suture removal and delayed cataract surgery led to a virtually perfect visual outcome. The patient has had no further complications at least three years after initial injury. The management of this civilian case illustrates some basic concepts in treating ballistic eye injuries that may be applicable in a military setting.

Antirelapse Efficacy of Various Primaquine Regimens for Plasmodium vivax.

Background. Efficacy of standard dose of primaquine (PQ) as antirelapse for P. vivax has decreased. We aimed to assess efficacy of different PQ regimens. Methods. It was an open label, randomized, controlled, parallel group, assessor blind study comparing antirelapse efficacy of 3 PQ regimens (B = 15 mg/day × 14 days, C = 30 mg/day × 7 days, and D = 30 mg/day × 14 days) with no PQ group (A) in P. vivax patients. Paired primary and recurrence samples were subjected to 3 methods: (i) month of recurrence and genotyping, (ii) by PCR-RFLP, and (iii) PCR sequencing, to differentiate relapse and reinfection. The rates of recurrence relapse and reinfection were compared. Methods were compared for concordance between them. Results. The recurrence rate was 16.39%, 8.07%, 10.07%, and 6.62% in groups A, B, C, and D, respectively (P = 0.004). The relapse rate was 6.89%, 1.55%, 4%, and 3.85% as per the month of recurrence; 8.2%, 2%, 4.58%, and 3.68% (P = 0.007) as per PCR-RFLP; and 2.73%, 1.47%, 1.55%, and 1.53% as per PCR sequencing for groups A, B, C, and D, respectively. The concordance between methods was low, 45%. Conclusion. The higher recurrence rate in no PQ as compared to PQ groups documents PQ antirelapse activity. Regimens tested were safe. However, probable resistance to PQ warrants continuous monitoring and low concordance and limitations in the methods warrant caution in interpreting.

Temporary cosmetic painted prostheses in anophthalmic surgery: an alternative to early postoperative clear conformers.

PURPOSE: To evaluate the use and safety of temporary, cosmetic, painted prostheses as an alternative to clear conformers immediately post removal of eye or socket surgery in children and adults. PATIENTS AND METHODS: A 2-year, two-centre, retrospective audit of 54 patients undergoing enucleation, evisceration, secondary implant or socket reconstruction receiving a temporary painted prosthesis as an alternative to clear conformers immediately post surgery. Patient questionnaire and review of clinical notes was conducted for all patients. RESULTS: We reviewed 54 consecutive patients (22 females, 32 males, mean age 18.6 years, range 6 days to 82 years) who received cosmetic painted prostheses from January 2009 to December 2010. Procedures included: evisceration with primary implant (5), enucleation with primary implant (37), secondary implant (9), dermis fat graft (2) and fornix reconstruction with buccal graft (1). Complications included: pyogenic granuloma (2), mucous discharge (2) and exposure (2). All adults found their prosthesis comfortable, and no problems were reported by the parents of the children included in this study. In all, 46 patients (88% of respondents) returned to normal activities within 2 weeks. The temporary prosthesis fell out at least once in 25% of cases. In all, 90% of respondents expressed a definite preference towards the painted shell over a clear shell. CONCLUSION: Temporary cosmetic painted prostheses placed immediately after removal of the eye or socket surgery are well tolerated and preferred to standard clear shells. Painted prostheses, matched to the contralateral iris are a valuable option in anophthalmic surgery as an alternative to traditional clear conformers.

Sub-Tenon's local anaesthesia for the treatment of retinopathy of prematurity with diode laser.

PURPOSE: To evaluate the safety and efficacy of sub-Tenon's local anaesthesia (LA) for laser treatment of threshold retinopathy of prematurity (ROP). METHODS: A cohort of 18 eyes of 10 neonates with threshold ROP was treated with diode laser peripheral retinal ablation over 14 treatment sessions using oral sedation and sub-Tenon's anaesthesia. Treatment was performed in a neonatal unit. The heart and respiratory rate, trans-cutaneous oxygen saturation, and physical activity were continuously monitored for signs of neonatal distress. Cardio-respiratory stability during and after the procedure was scored for each eye treated using a Cardio-respiratory index described previously. RESULTS: In all cases, the planned dose of laser was delivered. One out of 18 eyes developed stage 4b tractional retinal detachment over a follow-up of at least 6 months for all babies. Systemic complications during treatment included transient bradycardia and apnoea requiring stimulation in two babies and excessive head mobility in three babies. Treatment duration varied between 20 and 80 min. Ocular complications were conjunctival haemorrhage and chemosis. The mean cardio-respiratory index was 1.13, which compared favourably with the standard published. CONCLUSIONS: Sub-Tenon's LA with oral sedation appears to be a safe and effective alternative to general anaesthesia for laser treatment of ROP, with the potential for lower morbidity.

Feasibility of day-case vitreoretinal surgery.

PURPOSE: The indications for vitreoretinal (VR) surgery are increasing as equipment and techniques available improve. In order to decrease demand on limited health resources, day-case surgery would be beneficial in many cases. This study combines a retrospective and prospective arm to examine the feasibility and safety of routine day-case VR surgery. METHODS: One hundred consecutive patients (50 retrospective and 50 prospective) undergoing VR surgery within the Royal Berkshire NHS trust were included. The retrospective arm aimed to identify the frequency and type of acute ophthalmic or medical intervention during postop overnight stay and the results were used to alter management in the prospective group. The prospective group consisted of patients undergoing a mixture of overnight stay and day-case surgery. All patients in the prospective group had routine subtenon marcaine anaesthesia together with prophylactic pre-operative intravenous acetazolamide. Patients deemed fit postoperatively were offered overnight ward discharge, with obligatory next-day review. RESULTS: In the retrospective arm, 56% required oral nonsteroidal analgesia on the day of surgery and one patient required narcotic analgesia. Twenty-two per cent patients required intraocular pressure (IOP) control on the day of surgery and one patient required medical intervention in the form of urinary catheterisation. Nineteen patients required intervention on next-day review. In the prospective arm, 86% preferred day case and were suitable, 6% were suitable for day-case but preferred overnight stay and 8% were deemed not fit for discharge. No patient required narcotic analgesics. No patient discharged returned as a casualty overnight. Only one patient required topical beta-blocker for the control of IOP on next-day review. CONCLUSIONS: These data suggest that many patients who are hospitalised overnight for VR surgery could be safely treated as day cases. Such a shift in the pattern of care for VR surgery could provide a significant improvement in health-care efficiency and minimise patient inconvenience.

Effect of Mammalian Tissues on Mutagenicity of Several N-Nitroso Compounds 1.

Supernatant fractions from different organs of rat and beef origin were tested for their effect on the mutagenic activity of N-methyl-N'-nitro-N-Nitrosoguanidine (MNNG), using Salmonella typhimurium tester strain (TA 1535). At equal protein concentrations their effects were quite different. Both beef and rat liver supernatant fluids (1.7 - 3.4 mg of protein per plate) completely inhibited the mutagenic action of MNNG (5 µg per 0.1 ml of cell culture) while that of the heart showed partial inactivation. Under similar conditions, beef kidney and rat seminal vesicle fractions had no effect on MNNG-induced mutagenesis. The antimutagenic property of the liver supernatant fluid was unaffected by mild heat treatment (70°C for 30 min) but completely destroyed by boiling for 10 min. Liver supernatant fluids also had a lethal effect on the tester strain. The antibacterial agent was separated from the antimutagenic property by dialysis. The dialyzate fraction had no lethal effect, but still remained active in inhibiting mutagenesis. To test whether the action of liver supernatatnt fluid was specific for MNNG alone, several other carcinogens belonging to the N-nitroso groups, methyl methane sulfonate (MMS), ethyl methane sulfonate (EMS) and l-nitrosopyrrolidine (NO-Pyr), were tested. Among various tissue fractions tested only the liver supernatant fluids drastically reduced the mutagenic activity of MMS (500 µg/plate), EMS (104 µg/plate) and NO-Pyr (104 µM/plate).

Abnormal pupillary activity in a brainstem-dead patient.

The pupils in brainstem-dead patients are classically fixed and dilated. We present a case of a brainstem-dead patient whose pupils displayed persistent asynchronous pupillary constriction and dilatation independent of external physical stimuli. Central causes for the phenomenon were excluded leaving an unexplained peripheral cause as the most likely explanation. Early recognition of this phenomenon prevents delay in the diagnosis of brainstem death, lessening to some extent the distress for the family, and facilitating earlier organ donation and allowing the better use of resources.

Modification by phenobarbital of chlorphentermine-induced changes in lung morphology and drug-metabolizing enzymes in newborn rats.

Treatment of newborn rat pups with 60 mg/kg.d chlorphentermine for 7 d produced on accumulation of alveolar foam cells accompanied by an increase in relative pulmonary tissue weight. In contrast, administration of 20 mg/kg.d for 1 wk did not markedly alter lung ultrastructure or weight in newborns. Both doses of chlorphentermine elevated the activity of pulmonary aminopyrine N-demethylase but not that of aniline hydroxylase. The increase in relative liver weight was associated with stimulation of the activities of aniline hydroxylase and aminopyrine N-demethylase in newborns administered either chlorphentermine dose. Phenobarbital treatment produced an increase in relative liver weight accompanied by elevated activities of pulmonary aminopyrine N-demethylase and hepatic aniline hydroxylase and aminopyrine N-demethylase. Simultaneous barbiturate and chlorphentermine administration produced stimulation in liver enzymes to the same extent as phenobarbital alone. In contrast, phenobarbital potentiated the chlorphentermine-induced rise in pulmonary aminopyrine N-demethylase. In the case of 60 mg/kg chlorphentermine and barbiturate, the observed potentiation of lung enzyme activity was associated with a reduction in the number of alveolar foam cells. The results suggest that chlorphentermine and phenobarbital stimulate drug-metabolizing enzyme in lung and liver of newborn rats and that phenobarbital may provide protection against phospholipidosis through stimulation of pulmonary, drug-metabolizing enzymes.

Metabolic control mechanisms in mammalian systems. Involvement of adenosine 3':5'-cyclic monophosphate in androgen action.

1. The ability of exogenously administered cyclic AMP (adenosine 3':5'-monophosphate) to exert andromimetic action on certain carbohydrate-metabolizing enzymes was investigated in the rat prostate gland and seminal vesicles. 2. Cyclic AMP, when injected concurrently with theophylline, produced marked increases in hexokinase, phosphofructokinase, glyceraldehyde phosphate dehydrogenase, pyruvate kinase, and two hexose monophosphate-shunt enzymes, as well as alpha-glycerophosphate dehydrogenase activity in accessory sexual tissues of castrated rats. The 6-N,2'-O-dibutyryl analogue of cyclic AMP caused increases of enzyme activity that were greater than those induced by the parent compound. 3. Time-course studies demonstrated that, whereas significant increases in the activities of most enzymes occurred within 4h after the injection of cyclic AMP, maximal increases were attained at 16-24h. 4. Increase in the activity of the various prostatic and vesicular enzymes was dependent on the dose of cyclic AMP; in most instances, 2.5mg of the cyclic nucleotide/rat was sufficient to elicit a statistically significant response. 5. Administration of cyclic AMP and theophylline also produced stimulation of enzyme activities in secondary sexual tissues of immature rats. 6. Cyclic AMP and theophylline did not affect significantly any of the enzymes studied in hepatic tissue. 7. Stimulation of various carbohydrate-metabolizing enzymes in the prostate gland and seminal vesicles by cyclic AMP was independent of adrenal function. 8. Concurrent treatment with actinomycin or cycloheximide prevented the cyclic AMP- and theophylline-induced increases in enzyme activities in both castrated and adrenalectomized-castrated animals. 9. Administration of a single dose of testosterone propionate (5.0mg/100g) to castrated rats caused a significant increase in cyclic AMP concentration in both accessory sexual tissues. 10. In addition, treatment with theophylline potentiated the effects of a submaximal dose of testosterone (1.0mg/100g) on all those prostatic and seminal-vesicular enzymes that are increased by exogenous cyclic AMP. 11. The evidence indicates that cyclic AMP may be involved in triggering the known metabolic actions of androgens on secondary sexual tissues of the rat.