Application of OCT-angiography to characterise the evolution of chorioretinal lesions in acute posterior multifocal placoid pigment epitheliopathy.

PurposeThe aim of this study was to determine a sequence of structural changes in acute posterior multifocal placoid pigment epitheliopathy (APMPPE) using optical coherence tomography-angiography (OCT-A) and comparing with other imaging modalities.Patients and methodsPatients with a new diagnosis of acute-onset APMPPE referred to a regional specialist centre from October 2015 to October 2016 were included. Multimodal imaging employed on all patients from diagnosis included the following: fundus fluorescein angiography, indocyanine green angiography, fundus autofluorescence, spectral domain-OCT (SD-OCT), and OCT-A. All non-invasive imaging processes were repeated during follow-up.ResultsTen eyes of five patients were included in the study, three males and two females, with a mean age of 26.2 years (range: 21-32) and a mean follow-up of 6.4 months (range: 2.6-13.3). All patients presented with bilateral disease and macular involving lesions. OCT-A imaging of the choriocapillaris was supportive of hypoperfusion at the site of APMPPE lesions during the acute phase of this condition with normalisation of choroidal vasculature during follow-up. Multimodal imaging consistently highlighted four sequential phases from presentation to resolution of active disease.ConclusionsMultimodal imaging in patients with APMPPE in acute and long-term follow-up demonstrates a reversible choroidal hypoperfusion supporting the primary inciting pathology as a choriocapillaritis. The evolution shows resolution of the ischaemia through a defined sequence that results in persistent changes at the level of the retinal pigment epithelium and outer retina. OCT-A was able to detect preclinical changes and chart resolution at the level of the choriocapillaris.

Study on the performance of different craniofacial superimposition approaches (I).

As part of the scientific tasks coordinated throughout The 'New Methodologies and Protocols of Forensic Identification by Craniofacial Superimposition (MEPROCS)' project, the current study aims to analyse the performance of a diverse set of CFS methodologies and the corresponding technical approaches when dealing with a common dataset of real-world cases. Thus, a multiple-lab study on craniofacial superimposition has been carried out for the first time. In particular, 26 participants from 17 different institutions in 13 countries were asked to deal with 14 identification scenarios, some of them involving the comparison of multiple candidates and unknown skulls. In total, 60 craniofacial superimposition problems divided in two set of females and males. Each participant follow her/his own methodology and employed her/his particular technological means. For each single case they were asked to report the final identification decision (either positive or negative) along with the rationale supporting the decision and at least one image illustrating the overlay/superimposition outcome. This study is expected to provide important insights to better understand the most convenient characteristics of every method included in this study.

Remote surveillance after colorectal cancer surgery: an effective alternative to standard clinic-based follow-up.

AIM: Most colorectal cancer recurrences are asymptomatic and are detected through routine postoperative clinic surveillance programmes with associated investigations. However, attendance at these clinics has a financial cost and may be associated with an increase in patient anxiety and dissatisfaction. The results of a remote follow-up system developed for selected patients are reported. METHOD: A remote surveillance programme has been in place in our institution for over 9 years. Patients having elective and emergency treatment for colorectal cancer were enrolled. The timeliness of the investigation, detection of local recurrence and distant metastases and overall 5-year survival rates were determined. A cost review and patient satisfaction survey were performed. RESULTS: The programme was suitable for over 900 patients who had received surgery for colorectal cancer between 2004 and 2012, representing some 50% of the total number of patients treated in this period. Of these, 811 (90%) had investigations carried out on time. Five-year survival rates were comparable with national data. Cost-minimization analysis demonstrated a financial saving of 63% and a 75% reduction in clinic appointments. High levels of overall patient satisfaction (97%) were noted with the programme. CONCLUSION: A remote surveillance system after colorectal cancer surgery is a safe and cost-effective alternative to traditional clinic-based follow up and has high patient satisfaction.

Which visual acuity measurements define high-quality care for patients with neovascular age-related macular degeneration treated with ranibizumab?

PURPOSE: The purpose of this study is to define which visual acuity (VA) measurements are the best indicators of high-quality care for patients receiving intravitreal ranibizumab for neovascular age-related macular degeneration (nAMD). METHODS: Analysis of prospectively collected data recorded within an electronic medical record system on treatment-naive, first-eligible eyes with nAMD, treated with ranibizumab using an as-needed treatment regimen with a minimum follow-up of 1 year. Data collection included the following: age, gender, laterality, type of nAMD, VA, central 1 mm OCT retinal thickness, number of intravitreal injections, and number of follow-up assessments. RESULTS: Data were available on the first-treated eye from 406 patients with at least 1 year follow-up; of these, 198 had data at 2 years. The mean baseline VA of 54.4 Early Treatment Diabetic Retinopathy Study letters improved to 58.5 letters at 12 months and to 56.8 letters at 24 months. The mean VA changes from baseline to 1 year were +6.5, +7.5, +1.7, and -1.5 letters, respectively, for baseline VA categories of 23-35, 36-55, 56-70, and >70 letters. Change in mean VA from the end of the loading phase to year 1 ranged from -2.9 to +1.4 letters for the different baseline VA categories. The mean number of injections were similar across baseline VA categories ranging from 5.7 to 6.0 injections in year 1 and from 3.3 to 3.8 in year 2. CONCLUSIONS: This large, real-world series demonstrates that mean change in VA is largely a function of selection criteria and baseline VA. The quality of a service is therefore better judged by actual VA outcomes and maintenance of vision after the loading phase.

Implications of dimorphism, population variation, and secular change in estimating population affinity in the Iberian Peninsula.

Morphometric cranial variation among Spanish samples was compared to a 19th century Portuguese sample using both traditional and three-dimensional approaches. The Spanish samples included the regional 19th century Oloriz collection and the local 16-17th century Villanubla and Vallolid sample from northwestern Spain. Results suggest moderate variation among the samples and suggest that varying patterns of regional variation, sexual dimorphism and secular change represent important factors to be considered in the evaluation of population affinity using craniometric approaches.

Review of lateral orbital wall ossifying fibroma.

Significant histological overlap exists between fibro-osseous lesions and diagnosis is made on a clinicopathological basis. Ossifying fibroma is a benign fibro-osseous neoplasm of the jaw and craniofacial complex that has generated a degree of controversy regarding diagnosis and classification, especially with respect to the psammomatoid variant. Orbital lesions mainly arise from the paranasal sinuses affecting the medial or inferior orbital wall. Lateral orbital wall ossifying fibroma is, therefore, a rare condition with only a single previous case report. We present a second case of lateral orbital wall ossifying fibroma and a review of the associated literature.

Nonarteritic anterior ischaemic optic neuropathy in Addison's disease.

PURPOSE: To report three cases of Nonarteritic anterior ischaemic optic neuropathy (NAAION) in patients with Addison's disease. METHODS: We present a retrospective review of patients presenting with NAAION with underlying Addison's disease. RESULTS: Three eyes of two young patients presented with NAAION. Both patients had underlying Addison's disease with episodes of prolonged hypotension. CONCLUSION: To our knowledge, this is the first published report of NAAION associated with Addison's disease. As hypotension may be one of the few situations, in which NAAION may be treatable and the visual loss reversible, it is important to recognize and treat sustained episodes of hypotension in these individuals.

The use of imiquimod in the treatment of periocular tumours.

PURPOSE: To review our experience with 5% topical Imiquimod in the treatment of periocular tumours. METHODS: Imiquimod, an imidazoquinoline, is an immune response modifier which has been shown to have potent anti-viral and anti-tumour activity. We present a retrospective case series of 5 patients who received topical Imiquimod for various eyelid tumours. Two patients were diagnosed with basal cell carcinoma of the eyelid, one patient with actinic keratosis, one with intraepidermal squamous cell carcinoma (Bowen's disease) and one patient had concomitant squamous cell carcinoma and intraepidermal squamous cell carcinoma. RESULTS: All 5 patients, with various eyelid neoplastic/pre-neoplastic pathology, responded well with clinical resolution, to treatment with topical Imiquimod. There were few adverse reactions to periocular use of 5% Imiquimod, with only 1 patient developing a chemical conjunctivitis which resolved on dose reduction. CONCLUSIONS: There is limited experience and published literature on the use of topical 5% Imiquimod in the treatment of periocular tumours. In our experience, it is a safe and effective treatment for periocular lesions, including actinic keratosis, intraepidermal squamous cell carcinoma, basal cell carcinoma and squamous cell carcinoma. To our knowledge, this is the first published description of the successful use of 5% Imiquimod in treating moderately differentiated squamous cell carcinoma of the eyelid.

Lacrimal gland uptake of gallium (67Ga) citrate in patients without ocular pathology.

PURPOSE: To report a series of patients with bilateral lacrimal gland uptake of Gallium (67Ga) Citrate in patients without ocular pathology and to assess the degree to which this can be a normal phenomenon. METHODS: We present an index case of lacrimal gland uptake of Gallium (67Ga) Citrate in a patient without lacrimal pathology and a subsequent retrospective review of all Gallium scans performed at the Bristol Royal Infirmary, UK from 2002 to 2008. Patients who demonstrated Ga67 uptake within the lacrimal glands were identified and case notes from all scans were retrieved and reviewed. The notes were analysed to determine the rationale for the gallium investigation as well as whether there was any preexisting ocular pathology. RESULTS: Retrospective review demonstrated that 21 gallium scans were performed from 2002 to 2008, from which 4 patients demonstrated bilateral lacrimal gland Ga67 uptake with no evidence of past or current lacrimal/ocular pathology. On the basis of our review, we report that bilateral gallium uptake is not a specific finding, occurring in normal individuals with no history or symptoms of ocular or orbital pathology.

Evaluation of a new cataract surgery referral pathway.

AIMS: To compare the quality of referrals and listing rates of direct optometric referrals vs traditional GP referrals for cataract surgery. METHODS: A retrospective cohort of 124 patients referred for cataract surgery was identified (62 via optometric pathway and 62 via GP pathway). The quality of the referral was assessed by establishing if it contained adequate information relating to the College of Optometrists' referral framework document. Age, sex, drug history, listing rate, operative rate, and visual acuity (best corrected) at referral and at the postoperative visit were recorded and compared between the two referral pathways using the Fisher's exact test. RESULTS: Optometric referrals, relative to GP referrals, were more likely to include information relating to objective visual loss (100 vs 87%, P=0.0061) and to counsel the patient (97 vs 18%, P=0.0001). GP referrals, relative to optometric referrals, were more likely to comment on personal circumstances (32 vs 3%, P=0.0001), past medical history (95 vs 68%, P=0.0001), and drug history (94 vs 69%, P=0.0009). Operative rates were higher for the optometric direct referrals relative to GP referrals (87 vs 69%, P=0.0284). There was no difference in the visual acuity before or after surgery between the pathways. CONCLUSIONS: Optometric direct cataract referrals provide better information on objectively measured vision and better delivery of preoperative counselling. Traditional GP referrals contain better medical history, drug information, and details of personal circumstances. Rates of surgery were slightly higher with optometric referrals.

Thyroid function in patients with proteinuria.

BACKGROUND: Patients with proteinuria may suffer from substantial losses of functional proteins such as hormones and hormone-binding proteins. A limited number of studies have reported urinary losses of thyroid hormones and thyroxin-binding globulin. Overt hypothyroidism attributable to these urinary losses has been described. However, the impact of proteinuria on thyroid function parameters has not been studied in a large patient cohort. METHODS: We evaluated thyroid function parameters in patients with proteinurea who are negative to thyroxine peroxidase antibodies (TPOAbs). Values of free thyroxin and thyroid-stimulating hormone (TSH) were compared with data from age- and gender-matched controls derived from the Nijmegen Biomedical Study, a population-based survey conducted in our hospital. RESULTS: We evaluated 159 patients. There were 111 males and 48 females. Median (IQR) age was 52 (40 to 62) years, serum creatinine concentration 99 (82 to 134) micromol/l, serum albumin concentration 29 (22 to 35) g/l, and proteinuria 6.6 (3.1 to 10.9) g/10 mmol creatinine. Median TSH was significantly higher in the patients than the controls (1.81 mU/l vs 1.34 mU/l, p.<0.001); however, overt hypothyroidism was observed in only one patient. CONCLUSION: Patients with proteinuria have higher TSH levels, consistent with urinary loss of thyroid hormones. However, these urinary losses do not result in overt, clinically relevant, hypothyroidism. The role of subclinical hypothyroidism in these patients needs further evaluation.

Association of increased phosphatidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas.

OBJECT: Glioblastoma multiforme is the most malignant of the primary brain tumors and aggressively infiltrates surrounding brain tissue, resulting in distant foci within the central nervous system, thereby rendering this tumor surgically incurable. The recent findings that both phosphatidylinositol 3-kinase (PI 3-K) and the phosphatase and tensin homolog (PTEN) regulate tumor cell invasiveness have led the authors to surmise that these lipid signaling molecules might play a role in regulating matrix metalloproteinases (MMPs), which are essential for tumor cell invasion. METHODS: Using the C6 glioma cell line, which does not express measurable amounts of PTEN protein and in which in vitro invasiveness is MMP dependent, the authors determined that in vitro glioma cell invasiveness was significantly reduced when cells were preincubated overnight with LY294002 or wortmannin, two specific inhibitors of PI 3-K signaling. Next, using gelatin zymography, it was noted that these compounds significantly inhibited MMP-2 and MMP-9 activities. Moreover, the decrease in MMP activity correlated with the decrease in PI 3-K activity, as assessed by Akt phosphorylation. Finally, using semiquantitative reverse transcriptase-polymerase chain reaction, the authors demonstrated that LY294002 decreased messenger (m)RNA levels for both MMPs. Thus, these in vitro data indicate that PI 3-K signaling modulates gelatinase activity at the level of mRNA. Using immunostaining of phosphorylated Akt (p-Akt) as a measure of PI 3-K activity, the authors next assessed rat brains implanted with C6 cells. Compared with surrounding brain, there was marked p-Akt staining in C6 glioma cells and in neurons immediately adjacent to the tumor, but not in normal brain. The p-Akt staining in tumors was especially intense in perivascular areas. Using double-labeling techniques, colocalization of p-Akt with MMP-2 and MMP-9 was also noted in perivascular tumor areas. CONCLUSIONS: The increase in p-Akt staining within these PTEN-deficient gliomas is consistent with what would be predicted from unchecked PI 3-K signaling. Furthermore, the immunohistochemically detected colocalization of p-Akt and MMP-2 and MMP-9 supports the authors' in vitro studies and the proposed linkage between PI 3-K signaling and MMP activity in gliomas.

Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid.

One of the endogenous transformation products of tetrahydrocannabinol (THC) is THC-11-oic acid, and ajulemic acid (AJA; dimethylheptyl-THC-11-oic acid) is a side-chain synthetic analog of THC-11-oic acid. In preclinical studies, AJA has been found to be a potent anti-inflammatory agent without psychoactive properties. Based on recent reports suggesting antitumor effects of cannabinoids (CBs), we assessed the potential of AJA as an antitumor agent. AJA proved to be approximately one-half as potent as THC in inhibiting tumor growth in vitro against a variety of neoplastic cell lines. However, its in vitro effects lasted longer. The antitumor effect was stereospecific, suggesting receptor mediation. Unlike THC, however, whose effect was blocked by both CB(1) and CB(2) receptor antagonists, the effect of AJA was inhibited by only the CB(2) antagonist. Additionally, incubation of C6 glioma cells with AJA resulted in the formation of lipid droplets, the number of which increased over time; this effect was noted to a much greater extent after AJA than after THC and was not seen in WI-38 cells, a human normal fibroblast cell line. Analysis of incorporation of radiolabeled fatty acids revealed a marked accumulation of triglycerides in AJA-treated cells at concentrations that produced tumor growth inhibition. Finally, AJA, administered p.o. to nude mice at a dosage several orders of magnitude below that which produces toxicity, inhibited the growth of subcutaneously implanted U87 human glioma cells modestly but significantly. We conclude that AJA acts to produce significant antitumor activity and effects its actions primarily via CB(2) receptors. Its very favorable toxicity profile, including lack of psychoactivity, makes it suitable for chronic usage. Further studies are warranted to determine its optimal role as an antitumor agent.

PTEN: a newly identified regulator of neuronal differentiation.

Even though phosphorylation of phosphatidylinositols by phosphoinositide 3-kinase has an important and pervasive role in the nervous system, little is known about the phosphatases that reverse this reaction. Recently, such a phosphatase, PTEN, was cloned as a tumor suppressor for gliomas. We now know that PTEN is a tumor suppressor for many tumor types and is a phosphatidylinositol phosphatase specific for the 3-position of the inositol ring. PTEN is expressed in most, if not all, neurons and is localized in the nucleus and cytoplasm. PTEN is not evident in neural processes or synapses. PTEN is induced during neuronal differentiation and is required for survival of differentiating neuronal cells. In summary, PTEN is a regulatory molecule with multiple functions at multiple subcellular sites. Further studies are required to determine which downstream pathways are regulated by PTEN, by which mechanisms PTEN activity is regulated, which stimuli regulate PTEN activity, and why a molecule that inhibits several survival pathways is induced during neurogenesis.

The Ras-ERK pathway is required for the induction of neuronal nitric oxide synthase in differentiating PC12 cells.

We have studied the role of MAP kinase pathways in neuronal nitric oxide synthase (nNOS) induction during the differentiation of PC12 cells. In nerve growth factor (NGF)-treated PC12 cells, we find nNOS induced at RNA and protein levels, resulting in increased NOS activity. We note that neither nNOS mRNA, nNOS protein nor NOS activity is induced by NGF treatment in cells that have been infected with a dominant negative Ras adenovirus. We have also used drugs that block MAP kinase pathways and assessed their ability to inhibit nNOS induction. Even though U0126 and PD98059 are both MEK inhibitors, we find that U0126, but not PD98059, blocks induction of nNOS protein and NOS activity in NGF-treated PC12 cells. Also, the p38 kinase inhibitor, SB203580, does not block nNOS induction in our clone of PC12 cells. Since the JNK pathway is not activated in NGF-treated PC12 cells, we conclude that the Ras-ERK pathway and not the p38 or JNK pathway is required for nNOS induction in NGF-treated PC12 cells. We find that U0126 is much more effective than PD98059 in blocking the Ras-ERK pathway, thereby explaining the discrepancy in nNOS inhibition. We conclude that the Ras-ERK pathway is required for nNOS induction.