Clinical disorders affecting mesopic vision

Vision in the mesopic range is affected by a number of inherited and acquired clinical disorders. We review these conditions and summarize the historical background, describing the clinical characteristics alongside the genetic basis and molecular biological mechanisms giving rise to rod and cone dysfunction relevant to twilight vision. The current diagnostic gold standards for each disease are discussed and curative and symptomatic treatment strategies are summarized

Is EGFR expression altered following postoperative chemotherapy for colorectal adenocarcinoma?

BACKGROUND: There is immunohistochemical evidence to suggest that expression of epidermal growth factor receptor (EGFR) in primary colorectal adenocarcinoma predicts its expression in recurrent disease. This study investigates whether postoperative chemotherapy affects the degree of concordance between EGFR statuses of the two tumors. METHODS: Thirty-three patients were identified from the files of Sunnybrook Health Sciences Center from July 1994 to June 2005. All patients had resection of their primary tumors and their distant recurrences. Eighteen patients received postoperative chemotherapy, 3 of which also received postoperative radiation therapy. Representative primary and recurrent tumor sections were stained using mouse anti-EGFR antibodies and only membranous staining of malignant cells was recorded. Results were reported as negative (no staining), 1+ (positivity in <50% of cells) or 2+ (positivity in >50% of cells). RESULTS: EGFR immunostaining in the 15 patients, who received no postoperative chemotherapy, was decreased in 3 recurrences, remained the same in 10 and increased in 2. In the group of 18 patients who received postoperative chemotherapy, EGFR immunostaining was decreased in 6 recurrences, remained the same in 9 and increased in 3 (p = 0.6598). In patients who received postoperative chemotherapy, the odds ratio for a recurrence to show lower levels of EGFR immunostaining compared to its originally resected primary was 4.75 (CI = 0.94 – 26.73). CONCLUSION: These preliminary data suggest that recurrences following postoperative chemotherapy are likely to have lower levels of EGFR expression compared to cases who receive no chemotherapy. Although the difference of immunostaining profiles between the two groups was not statistically significant, this observation might impact the management of these patients by targeted biologic therapies and its practical implications need further validation in larger series

Ca2+-induced changes in energy metabolism and viability of melanoma cells

Cancer cells are characterized by a high rate of glycolysis, which is their primary energy source. We show here that a rise in intracellular-free calcium ion (Ca2+), induced by Ca2+-ionophore A23187, exerted a deleterious effect on glycolysis and viability of B16 melanoma cells. Ca2+-ionophore caused a dose-dependent detachment of phosphofructokinase (EC 2.7.1.11), one of the key enzymes of glycolysis, from cytoskeleton. It also induced a decrease in the levels of glucose 1,6-bisphosphate and fructose 1,6-bisphosphate, the two stimulatory signal molecules of glycolysis. All these changes occurred at lower concentrations of the drug than those required to induce a reduction in viability of melanoma cells. We also found that low concentrations of Ca2+-ionophore induced an increase in adenosine 5′-triphosphate (ATP), which most probably resulted from the increase in mitochondrial-bound hexokinase, which reflects a defence mechanism. This mechanism can no longer operate at high concentrations of the Ca2+-ionophore, which causes a decrease in mitochondrial and cytosolic hexokinase, leading to a drastic fall in ATP and melanoma cell death. The present results suggest that drugs which are capable of inducing accumulation of intracellular-free Ca2+ in melanoma cells would cause a reduction in energy-producing systems, leading to melanoma cell death. © 1999 Cancer Research Campaig

National Case-Control Study of Kaposi\u27s Sarcoma and Pneumocystis Carinii Pneumonia in Homosexual Men: Part 1. Epidemiologic Results

To identify risk factors for the occurrence of Kaposi\u27s sarcoma and Pneumocystis carinii pneumonia in homosexual men, we conducted a case-control study in New York City, San Francisco, Los Angeles, and Atlanta. Fifty patients (cases) (39 with Kaposi\u27s sarcoma, 8 with pneumocystis pneumonia, and 3 with both) and 120 matched homosexual male controls (from sexually transmitted disease clinics and private medical practices) participated in the study. The variable most strongly associated with illness was a larger number of male sex partners per year (median, 61 for patients; 27 and 25 for clinic and private practice controls, respectively). Compared with controls, cases were also more likely to have been exposed to feces during sex, have had syphilis and non-B hepatitis, have been treated for enteric parasites, and have used various illicit substances. Certain aspects of a lifestyle shared by a subgroup of the male homosexual population are associated with an increased risk of Kaposi\u27s sarcoma and pneumocystis pneumonia

AAV-mediated photoreceptor transduction of the pig cone-enriched retina

Recent success in clinical trials supports the use of adeno-associated viral (AAV) vectors for gene therapy of retinal diseases caused by defects in the retinal pigment epithelium (RPE). In contrast, evidence of the efficacy of AAV-mediated gene transfer to retinal photoreceptors, the major site of inherited retinal diseases, is less robust. In addition, although AAV-mediated RPE transduction appears efficient, independently of the serotype used and species treated, AAV-mediated photoreceptor gene transfer has not been systematically investigated thus so far in large animal models, which also may allow identifying relevant species-specific differences in AAV-mediated retinal transduction. In the present study, we used the porcine retina, which has a high cone/rod ratio. This feature allows to properly evaluate both cone and rod photoreceptors transduction and compare the transduction characteristics of AAV2/5 and 2/8, the two most efficient AAV vector serotypes for photoreceptor targeting. Here we show that AAV2/5 and 2/8 transduces both RPE and photoreceptors. AAV2/8 infects and transduces photoreceptor more efficiently than AAV2/5, similarly to what we have observed in the murine retina. The use of the photoreceptor-specific rhodopsin promoter restricts transgene expression to porcine rods and cones, and results in photoreceptor transduction levels similar to those obtained with the ubiquitous promoters tested. Finally, immunological, toxicological and biodistribution studies support the safety of AAV subretinal administration to the large porcine retina. The data presented here on AAV-mediated transduction of the cone-enriched porcine retina may affect the development of gene-based therapies for rare and common severe photoreceptor diseases

High- and Low-Affinity Epidermal Growth Factor Receptor-Ligand Interactions Activate Distinct Signaling Pathways

Signaling mediated by the Epidermal Growth Factor Receptor (EGFR) is crucial in normal development, and aberrant EGFR signaling has been implicated in a wide variety of cancers. Here we find that the high- and low-affinity interactions between EGFR and its ligands activate different signaling pathways. While high-affinity ligand binding is sufficient for activation of most canonical signaling pathways, low-affinity binding is required for the activation of the Signal transducers and activators of transcription (Stats) and Phospholipase C-gamma 1 (PLCγ1). As the Stat proteins are involved in many cellular responses including proliferation, migration and apoptosis, these results assign a function to low-affinity interactions that has been omitted from computational models of EGFR signaling. The existence of receptors with distinct signaling properties provides a way for EGFR to respond to different concentrations of the same ligand in qualitatively different ways

A Mutation in Myo15 Leads to Usher-Like Symptoms in LEW/Ztm-ci2 Rats

The LEW/Ztm-ci2 rat is an animal model for syndromal deafness that arose from a spontaneous mutation. Homozygous animals show locomotor abnormalities like lateralized circling behavior. Additionally, an impaired vision can be observed in some animals through behavioral studies. Syndromal deafness as well as retinal degeneration are features of the Usher syndrome in humans. In the present study, the mutation was identified as a base substitution (T->C) in exon 56 of Myo15, leading to an amino acid exchange from leucine (Leu) to proline (Pro) within the carboxy-terminal MyTH4 domain in the proteins' tail region. Myo15 mRNA was expressed in the retina as demonstrated for the first time with the help of in-situ hybridization and PCR. To characterize the visual phenotype, rats were examined by scotopic and photopic electroretinography and, additionally, histological analyses of the retinas were conducted. The complete loss of sight was detected along with a severe degeneration of photoreceptor cells. Interestingly, the manifestation of the disease does not solely depend on the mutation, but also on environmental factors. Since the LEW/Ztm-ci2 rat features the entire range of symptoms of the human Usher syndrome we think that this strain is an appropriate model for this disease. Our findings display that mutations in binding domains of myosin XV do not only cause non-syndromic hearing loss but can also lead to syndromic disorders including retinal dysfunction

JACIE accreditation for blood and marrow transplantation: past, present and future directions of an international model for healthcare quality improvement.

Blood and marrow transplantation (BMT) is a complex and evolving medical speciality that makes substantial demands on healthcare resources. To meet a professional responsibility to both patients and public health services, the European Society for Blood and Marrow Transplantation (EBMT) initiated and developed the Joint Accreditation Committee of the International Society for Cellular Therapy and EBMT-better known by the acronym, JACIE. Since its inception, JACIE has performed over 530 voluntary accreditation inspections (62% first time; 38% reaccreditation) in 25 countries, representing 40% of transplant centres in Europe. As well as widespread professional acceptance, JACIE has become incorporated into the regulatory framework for delivery of BMT and other haematopoietic cellular therapies in several countries. In recent years, JACIE has been validated using the EBMT registry as an effective means of quality improvement with a substantial positive impact on survival outcomes. Future directions include development of Europe-wide risk-adjusted outcome benchmarking through the EBMT registry and further extension beyond Europe, including goals to faciliate access for BMT programmes in in low- and middle-income economies (LMIEs) via a 'first-step' process

Diabetes mellitus in dogs attending UK primary-care practices: frequency, risk factors and survival

Background: Diabetes mellitus (DM) is an important endocrine disorder of dogs. The objectives of this study were to estimate prevalence and incidence of DM in dogs, and to explore risk factors for DM and the survival of DM cases in primary-care clinics in the UK. Results: A case-control study nested in the cohort of dogs (n = 480,469) aged ≥3 years presenting at 430 VetCompass clinics was used to identify risk factors for DM, using multivariable logistic regression. Overall 409 new and 863 pre-existing DM cases (total 1272) were identified in 2016, giving an apparent annual prevalence of 0.26% (95% confidence interval (CI): 0.25–0.28%), and an annual incidence risk of 0.09% (95%CI: 0.08–0.09%) in dogs aged ≥3 years. Factors associated with increased odds for DM diagnosis were all age categories > 8 years, female entire dogs (odds ratio (OR): 3.03, 95% CI 1.69–5.44, p < 0.001) and male neutered dogs (OR: 1.99, 95% CI 1.18–3.34, p = 0.010) compared to male entire dogs, Border Terriers (OR: 3.37, 95% CI 1.04–10.98, p = 0.043) and West Highland White Terriers (WHWT) (OR: 2.88, 95% CI 1.49–5.56, p = 0.002) compared to crossbreeds. Dogs that had received previous glucocorticoid treatment (OR: 2.19, 95% CI 1.02–4.70, p = 0.044) and those with concurrent conditions (documented obese, pancreatitis, hyperadrenocorticism) also had increased odds for DM diagnosis. Cox regression modelling was used to evaluate factors associated with survival in the 409 incident DM cases in 2016. Increased hazard of death following diagnosis of DM was shown in dogs that were ≥ 10 years age, Cocker Spaniels (HR: 2.06, 95% CI 1.06–4.01, p = 0.034) compared to crossbreeds, had a blood glucose (BG) level at diagnosis > 40 mmol/L (HR: 2.73, 95% CI 1.35–5.55, p = 0.005) compared to < 20 mmol/L at diagnosis, or had received previous glucocorticoid treatment (HR: 1.86, 95% CI 1.21–2.86, p = 0.005). Dogs at reduced hazard of death included neutered dogs (HR: 0.58, 95% CI 0.42–0.79, p = 0.001), Border Collies (HR: 0.39, 95% CI 0.17–0.87, p = 0.022) and those starting insulin treatment (HR: 0.08 95% CI 0.05–0.12, p < 0.001). Conclusions: Certain breeds and concurrent health conditions are associated with an increased risk of DM. In addition to certain signalment factors, a high BG level at diagnosis and prior glucocorticoid treatment were adversely associated with survival of dogs with DM. Keywords: Diabetes mellitus, Risk factors, Survival, Case-control study, Benchmarking, VetCompas