Targeting NOX2 via p47/phox-p22/phox Inhibition with Novel Triproline Mimetics.

On the basis of the knowledge that the proline-rich hot spot PPPRPP region of P(151)PSNPPPRPP(160), an oligopeptide derived from the cytosolic portion of p22phox (p22), binds to the single functional bis-SH3 domain of the regulatory protein p47phox (p47), we designed a mimetic of the tripeptide PPP based on NMR and X-ray crystallographic data for the p22(151-161) peptide PPSNPPPRPPA with a peptide construct. Incorporation of the synthetic pseudo-triproline mimetic Pro-Pro-Cyp in a molecule derived from molecular modeling studies led to only a 7-fold diminution in activity in a surface plasmon resonance assay relative to the same molecule containing the natural Pro-Pro-Pro tripeptide. The alternative sequence corresponding to a Pro-Cyp-Pro insertion was inactive. This is a first example of the use of a triproline mimetic to interfere with the formation of the p47-p22 complex, which is critical for the activation of NOX, leading to the production of reactive oxygen species as superoxide anions.

Keratitis Caused by Candida parapsilosis and Subsequent Corynebacterium macginleyi Infection: Case Report and Short Review.

Keratitis due to Candida parapsilosis or Corynebacterium macginleyi is uncommon. We present a patient with several risk factors who suffered two subsequent corneal infections caused by these pathogens and healed with topical conservative therapy. The important factor was the early detection of infection. Fluconazole solution administered topically as eye drops combined with regular debridement proved in this case a successful alternative to systemic antifungal treatment. With a perceived recurrence of the keratitis, one must take into account the involvement of other pathogens present. The previous use of an antifungal solution other than a conventional eye drop could be an additional risk factor for a second bacterial infection, but the benefits should still rule in favor of such a treatment.

Further Evidence for the Utility of Electrophysiological Methods for the Detection of Subclinical Stage Retinal and Optic Nerve Involvement in Diabetes.

OBJECTIVE: To assess the utility of visual electrophysiological methods, visual evoked potentials (VEPs) and pattern electroretinograms (PERGs) were recorded for the detection of subclinical optic nerve and retinal involvement in patients with diabetes mellitus. SUBJECTS AND METHODS: The data of 63 patients (126 eyes) with no vascular retinopathy or optic neuropathy were retrospectively analyzed. The patients were divided into polyneuropathic/nonpolyneuropathic groups to differentiate between early and late subclinical stages. The recorded parameters were compared with local reference values. RESULTS: 116 eyes (92%) had VEP and 76 (60%) had PERG abnormalities. The most frequent alteration was latency delay, but waveform and amplitude irregularities were also observed. The simultaneous use of the two methods allowed us to differentiate abnormal VEPs of purely optic nerve origin from those reflecting retinal involvement. CONCLUSIONS: We suggest that regular electrophysiological screening should receive more attention in the ophthalmological care of diabetic patients.

Lyme disease associated neuroretinitis - Case report.

We describe a rare case of Lyme disease complicated by unilateral neuroretinitis in the right eye. We report a case of a 27-year-old woman with blurred vision on her right eye. Because of the suspicion of optic neuritis (multiplex sclerosis) neurological examination was ordered. Surprisingly, computer tomography of the brain revealed incomplete empty sella, which generally results not monocular, but bilateral optic nerve swelling. Opthalmological examination (ophthalmoscopy and optical coherence tomography) indicated not only monocular optic nerve, but retinal oedema next to the temporal part of the right optic disk. Visual evoked potentials (VEP) demonstrated no P100 latency delay and mild differences between the amplitudes of the responses of the left and right eye. Optical coherence tomography (OCT) demonstrated the swelling of the optic nerve head and oedematous retina at the temporal part of the disk. Suspicion of an inflammatory cause of visual disturbance blood tests was ordered. Doxycycline treatment was ordered till the result of the blood test arrived. The Western blot and ELISA test were positive for Borrelia burgdorferi sensu lato. Following one week corticosteroide and ceftriaxone treatments, the patient displayed a clinical improvement. Unilateral neuroretinitis with optic disk swelling due to neuroborreliosis is a rare complication and in many cases it is difficult to distinguish between inflammatory and ischemic lesions. Further difficulty in the diagnosis can occur when intracranial alterations such as empty sella is demonstrated by CT examination.

Description of five dirofilariasis cases in South Hungary and review epidemiology of this disease for the country.

BACKGROUND: Dirofilariasis is an emerging zoonosis (supported by climate change) in Central Europe. Human infections are usually caused by Dirofilaria repens and Dirofilaria immitis with mediation of mosquito vectors. Aims of this publication were to report our dirofilariasis cases, and to summarize Hungarian epidemiological data by reviewing literature. METHODS AND RESULTS: We present five (four ophthalomological, one subcutaneous) cases observed within a 2-year period in Southern Hungary. Ages of infected patients were between 31 and 74 years. First case during pregnancy is also reported. There was no travel history in the anamnesis of patients which could explain acquisition of the infection. Moving, intact worms eliminated by surgical interventions were identified on the basis of morphological features as D. repens. Since the first report of human case, 115 further episodes (in addition to ours) were diagnosed in Hungary. Mean age of the patients was 47 years. Reviewing national reports, the ratio of subcutaneous infections was higher than that of the ocular ones (66 and 45, respectively). Evaluation of the territorial distribution of human episodes revealed that most infections occurred in patients living in the Danube-Tisza interfluvial region and eastern part of the country. However, sporadic cases were also found in western counties during 2014. CONCLUSION: Most of the Hungarian dirofilariasis cases were autochthonous infections. Occurrence in the western counties may suggest the spreading of this emerging zoonosis to these areas. Comprehensive monitoring and data analysis are desirable, therefore reporting the epidemiologic data in the case of human infections should be made mandatory.

Interocular amplitude and latency differences of pattern ERG and pattern VEP parameters.

PURPOSE: To determine the normal interocular differences in amplitudes and peak times of the pattern electroretinograms (PERGs) and pattern visual evoked potentials (PVEPs) and to investigate whether the PERG and PVEP parameters correspond in lateral dominance or whether the eye-side distributions of the functional parameters are similar. METHODS: The PERGs and PVEPs were recorded in healthy subjects (N = 77) according to the standards of the International Society for Clinical Electrophysiology of Vision, with the modification of the check size of the PERG to 0.5 degrees. This allows stimulation of the macular ganglion cells and their corresponding visual pathways in healthy subjects. RESULTS: Comparison of the averaged higher and lower response amplitudes and the shorter and longer response peak times showed significant differences (p < 0.001) in both the PERG and the PVEP parameters (median [5 to 95%]): the P50 (1.92% [0 to 5.48%]) and N95 (2.06% [0 to 13.95%]) peak times and the P50 (11.82% [1.32 to 29.93%) and N95 (9.45% [1.17 to 30.38%]) amplitudes of the PERGs and the P100 (1.04% [0 to 4.15%]) and N135 (1.96% [0 to 12.36%]) peak times and the P100 (9.86% [1.26 to 29.76%]) and N135 (11.19% [1.18 to 29.99%]) amplitudes of the PVEPs. No significant correlation was found concerning the eye dominance of the PERG and PVEP parameters. CONCLUSIONS: Our results reveal a significant interocular difference on PERG and PVEP recording, but this could not be ascribed to the anatomy of the retina and related visual pathways. If the difference between the eyes is not taken into account, misinterpretation may occur in a pathological process.

S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab.

Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749-62. ©2013 AACR.

[Combined use of pattern electroretinography and pattern visual evoked potentials in neuroophthalmological practice]. / A mintaváltás-ingerléssel kiváltott elektroretinogram és a látókérgi kiváltott válasz együttes használata a neurooftalmológiai gyakorlatban.

OBJECTIVE: To survey the role of pattern electroretinography (PERG) and pattern visual evoked potentials (VEPs) in the process of clinical evaluation of neuro-ophthalmological cases. The study is illustrated with the electrophysiological findings of 231 patients sent to our laboratory in 2005 because of the suspicion of damage in the optic pathway. METHODS: The RETIport program of the ROLAND equipment (Wiesbaden-Germany) was used to record PERGs and VEPs. The recordings were done according to the recommendations of the International Society for Clinical Electrophysiology of Vision. RESULTS: The combined application of PERG and VEP provided useful data on the retino-cortical conduction time and hence demyelinisation. The comparison of the N35/P50 and P50/N90 amplitudes of the PERG recordings greatly promoted the diagnostic procedure. CONCLUSIONS: The combined application of PERG and VEP methods is recommended in the assessment of optic nerve function of neuro-ophthalmological patients.

A boy or a girl? A Hungarian survey regarding gender selection.

BACKGROUND: Infertile Hungarian couples were surveyed with regard to their opinion of preconception gender selection by the separation of X- and Y-bearing sperm populations. METHODS: Self-completion of a questionnaire. Group 1: subjects presenting for infertility examination; Group 2: presenting for homologous intrauterine insemination. RESULTS: As concerns the gender of the firstborn, 13.8% of those in Group 1 preferred a boy and 10.3% a girl, while 75.9% had no preference. The male preference was higher in Group 2: 33.3% preferred a boy and 7.4% a girl while 59.3% had no preference (chi 2, p < 0.05). In the event of a wish for more offspring, 91% in Group 1 and 94% in Group 2 did not have a wish for only one particular gender. In Group 2, 30.8% were willing to pay the extra costs for a gender selection procedure as compared with only 10.8% of the couples in Group 1 (chi 2, p < 0.05). If the National Health Fund fully covered the costs, 53.4% in Group 1 and 38.5% in Group 2 would request the procedure for nonmedical reasons, while 94.6% and 97.4% of them, respectively would so for medical reasons. CONCLUSIONS: Our findings revealed a trend to preference for firstborn males, although couples wishing more than one offspring prefer equal numbers of male and female children. The utilization of preconception gender selection, therefore, would not seem to appreciably affect the natural male/female ratio. Genetic indications exert significant effects on the decision regarding sex selection procedures.

Magnesium-orotate supplementation for idiopathic infertile male patients: a randomized, placebo-controlled clinical pilot study.

A randomized, placebo-controlled clinical pilot study was performed in order to examine the effect of magnesium-orotate in male idiopathic infertility. Ten males were treated daily for 90 consecutive days with 3000 mg magnesium-orotate (Magnerot) tablets (Group M). As a control, ten other males were treated in the same way with placebo (Group P). Conventional microscopic sperm characteristics (sperm concentration, motility ratio, total number of motile sperm cells, normal morphology ratio), plus total and ionized magnesium levels in seminal plasma and blood serum were evaluated both prior to treatment and on day 90, at the conclusion of the study. No significant changes in sperm characteristics, blood ionized or total Mg, or ejaculate total Mg levels were detected. However, ejaculate ionized Mg levels increased in Group M from 0.18 +/- 0.05 to 0.30 +/- 0.05 (mmol/l; mean +/- SD, p < 0.05). Within the observation period of 3 months, one pregnancy occurred in the partner of a male from Group M. In conclusion, magnesium-orotate treatment at a dose of 3000 mg/day leads neither to a significant improvement of sperm variables nor does it increase the pregnancy rates of female partners of treated males as compared to those of controls. Thus, magnesium-orotate treatment was not shown to be effective therapy for idiopathic male infertility.