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Purpose: To describe a series of patients treated for congenital microphthalmia associated with orbital cyst and recommend a management protocol. Methods: This retrospective case series comprised 6 patients (7 eyes) who attended an oculoplastic tertiary medical center from 2001 to 2018. Clinical, treatment, and outcome data were collected from the electronic files. Main outcome measures were preservation of vision and cosmetic appearance. Results: Four patients were diagnosed at birth. Six cysts were located inferiorly and one superiorly. Two patients had a visual potential of light perception or better in the affected eye. In 4 eyes, the cyst was initially retained and the eye was fitted with a custom-made conformer. In 1 eye, the fornices were too shallow for a conformer, warranting fornix reconstruction and cyst excision. Early surgery was required in 1 eye for an expanded cyst and large orbit volume, and in another eye the cyst had overgrown the orbit, causing bone erosion and remodeling. Cosmetic results were good in 3 of the eyes in which the cyst was retained in early childhood, stimulating orbital growth. Conclusions: Congenital microphthalmia with orbital cyst is rare. Management should focus on preserving visual potential, especially in unilateral cyst cases when the other eye is also microphthalmic. Otherwise cosmetic symmetry is the main concern; cyst retention combined with ocular conformers may stimulate socket expansion. The authors found that, in most cases, if treated early, enucleation was avoidable during cyst excision. Early assessment, meticulous follow-up, and individually tailored treatment are warranted. [ J Pediatr Ophthalmol Strabismus . 2022;59(3):192–199.]

Purpose: To characterize a genetic mutation causing Stickler syndrome in a previously undiagnosed family. Methods: Five generations of a single family suspected of having Stickler syndrome were eva...

We aimed to characterise the response of locally advanced basal cell carcinoma (BCC) to systemic treatment with Vismodegib, a Hedgehog pathway inhibitor, by changes in the expression levels of Hedgehog pathway genes. Data were collected prospectively on 12 patients treated systemically for locally advanced BCC. Biopsy samples taken on admission and after treatment cessation were analysed pathologically and with the NanoString nCounter system to quantify the expression of 40 Hedgehog signaling pathway genes. Findings were compared before and after treatment, between complete and partial responders, and with localised BCC samples from 22 patients. Sixteen Hedgehog pathway genes changed significantly from before to after treatment. GAS1 was the only gene with a significantly different expression at baseline between complete responders (6 patients) and partial responders (4 patients) to Vismodegib (P = 0.014). GAS, GLIS2 and PRKACG1 showed different expression before treatment between the locally advanced and localised BCCs. The baseline expression level of GAS1 appears to be predictive of the response of locally advanced BCC to systemic Vismodegib treatment. A change in expression of many Hedgehog pathway genes, albeit expected by the known activity of Vismodegib, may nevertheless serve as an indicator of the response potential of the tumour.

This study evaluated the potential neuroprotective effect of azithromycin (AZ) intraperitoneal injections in male C57Bl/6 (wild type, WT) and female NOD scid gamma (NSG) mice subjected to optic nerve crush (ONC) as a model for optic neuropathy. Histologically, reduced apoptosis and improved retinal ganglion cell (RGC) preservation were noted in the AZ-treated mice as shown by TUNEL staining—in the WT mice more than in the NSG mice. The increased microglial activation following ONC was reduced with the AZ treatment. In the molecular analysis of WT and NSG mice, similar trends were detected regarding apoptosis, as well as stress-related and inflammatory markers examining BCL2-associated X (Bax), heme oxygenase 1 (Ho-1), interleukin 1 beta (Il1β), superoxide dismutase 1 (Sod1), and nuclear factor-kappa B (Nfkb) levels. In the optic nerve, AZ increased the levels of expression of Sod1 and Nfkb only in the WT mice and decreased them in the NSG mice. In the retinas of the WT and NSG mice, the Bax and Ho-1 levels of expression decreased following the AZ treatment, while the Sod1 and Nfkb expression decreased only in the WT mice, and remained stable near the baseline in the NSG mice. Il1β remained at the baseline in WT mice while it decreased towards the baseline in AZ-treated NSG mice. The neuroprotective effects demonstrated by the reduced RGC apoptosis in AZ-treated WT mice retinae, and in the optic nerves as stress-related and inflammatory gene expression increase. This did not occur in the immunodeficient NSG mice. AZ modulated the inflammatory reaction and microglial activation. The lack of an effect in NSG mice supports the assumption that AZ acts by immunomodulation, which is known to play a role in ONC damage. These findings have implications for the development and repurposing of drugs to preserve RGCs after acute optic neuropathies.

Pseudotumor cerebri syndrome can have a recurrent course. We compared the long-term disease course, recurrences, and final visual outcomes in prepubertal children, adolescents, and adults.In this retrospective observational study, patients were divided into prepubertal children (group A) adolescents (group B), and adults (group C).Sixty-five patients (56 females, nine males) were included, 26.2% in group A, 24.6% in group B, and 49.2% in group C. Age at diagnosis was 8.6 ± 2.0 years, 14.3 ± 1.5 years, and 31.9 ± 9.7 years for the prepubertal children, adolescents, and adults, respectively. Medical treatment duration was similar (2.4 to 3.3 years, P 0.05). Recurrences were observed in 23.5% of prepubertal children, 50% of adolescents, and 28.1% of adults. Recurrences occurred within 1.3 ± 0.6 years from treatment cessation in the prepubertal group compared with 3.8 ± 5.1 years in adolescents and 2.7 ± 2.0 years in adults (P = 0.267). Optic neuropathy was evident in 41% of group A, 31% of group B, and 87.5% of group C (P 0.001). Obesity and cerebrospinal fluid opening pressures were unassociated with either relapsing rates or final visual outcomes in all groups.Pseudotumor cerebri syndrome exhibits a relapsing course in a third of cases. Recurrences tend to occur within one year after treatment cessation in prepubertal children, and within three years in older patients, revealing the importance of longer follow-up, especially in adults. Optic neuropathy was more common in adults along with a tendency for visual decline. Longer treatment times were associated with fewer recurrences.

We describe the ophthalmologic, clinical, and genetic findings in a patient of Yemenite-Jewish origin diagnosed with Alstrom syndrome due to a novel splice-site mutation 10 years after a clinical misdiagnosis of Leber congenital amaurosis.Ophthalmological evaluations included visual acuity, cycloplegic refraction, slit-lamp, and optical coherent tomography. Genetic analyses included whole exome sequencing followed by bioinformatics analysis and segregation analysis. An in vitro splicing assay was used to evaluate the effect of the identified mutation on splicing. Taqman assay was used to determine the need for population screening for the identified mutation.Ophthalmologic findings at age 6 were impaired vision, nystagmus, and hyperopia. At age 16 years, the patient presented with obesity, hypothyroidism, and elevated transaminase levels in addition to reduced vision, wandering nystagmus, disc pallor, and degenerative retinal changes. Targeted genetic analysis of ALMS1 revealed a homozygous transversion, c.11544 + 3AT, suggesting a novel splicing mutation, with elimination of the donor splice site and insertion of 73 nucleotides at the end of exon 16. These changes were validated by Sanger sequencing and co-segregation on family members.Ophthalmologists should be alert to the differential diagnosis of inherited retinal degeneration in young patients who present with impaired vision, especially if systemic symptoms are mild and there is no known family history. In the present case, targeted genetic analysis of a child with a syndromic cone-rod dystrophy yielded a novel splicing mutation in ALMS1 causing Alstrom syndrome.

Background/aim Germline mutations in PTCH1 or SUFU in the sonic hedgehog (SHH) pathway cause Gorlin's syndrome with increased risk of developing SHH-subgroup medulloblastoma. Gorlin's syndrome precludes the use of radiotherapy (a standard component of treatment) due to the development of multiple basal cell carcinomas. Also, current SHH inhibitors are ineffective against SUFU-mutated medulloblastoma, as they inhibit upstream genes. In this study, we aimed to detect differences in the expression of genes and microRNAs between SUFU- and PTCH1-mutated SHH medulloblastomas which may hint at new treatment directions. Patients and methods We sequenced RNA and microRNA from tumors of two patients with germline Gorlin's syndrome - one having PTCH1 mutation and one with SUFU mutation - followed by bioinformatics analysis to detect changes in genes and miRNAs expression in these two tumors. Expression changes were validated using qRT-PCR. Ingenuity pathway analysis was performed in search for targetable pathways. Results Compared to the PTCH1 tumor, the SUFU tumor demonstrated lower expression of miR-301a-3p and miR-181c-5p, matrix metallopeptidase 11 (MMP11) and OTX2, higher expression of miR-7-5p and corresponding lower expression of its targeted gene, connexin 30 (GJB6). We propose mechanisms to explain the phenotypic differences between the two types of tumors, and understand why PTCH1 and SUFU tumors tend to relapse locally (rather than metastatically as in other medulloblastoma subgroups). Conclusion Our results help towards finding new treatable molecular targets for these types of medulloblastomas.

As treatment protocols for medulloblastoma (MB) are becoming subgroup-specific, means for reliably distinguishing between its subgroups are a timely need. Currently available methods include immunohistochemical stains, which are subjective and often inconclusive, and molecular techniques—e.g., NanoString, microarrays, or DNA methylation assays—which are time-consuming, expensive and not widely available. Quantitative PCR (qPCR) provides a good alternative for these methods, but the current NanoString panel which includes 22 genes is impractical for qPCR. Here, we applied machine-learning–based classifiers to extract reliable, concise gene sets for distinguishing between the four MB subgroups, and we compared the accuracy of these gene sets to that of the known NanoString 22-gene set. We validated our results using an independent microarray-based dataset of 92 samples of all four subgroups. In addition, we performed a qPCR validation on a cohort of 18 patients diagnosed with SHH, Group 3 and Group 4 MB. We found that the 22-gene set can be reduced to only six genes (IMPG2, NPR3, KHDRBS2, RBM24, WIF1, and EMX2) without compromising accuracy. The identified gene set is sufficiently small to make a qPCR-based MB subgroup classification easily accessible to clinicians, even in developing, poorly equipped countries.

Objective To assess the association between pediatric Idiopathic intracranial hypertension (IIH) and olfactory performance. Methods A cross-sectional comparative study was conducted including 17 patients under 18 years diagnosed with IIH at a tertiary hospital and 17 healthy age- and sex-matched subjects. All participants underwent the semi-objective chemosensory Sniffin’ Sticks test for evaluation of odor threshold (OT), indicative of peripheral olfactory function, and odor identification (OI), reflecting higher cognitive olfactory processing. Scores were compared and referred to the updated normative values. Demographic, clinical, and neuroimaging data were collected from the medical files. The patients with IIH were reassessed for olfactory function and clinical state at the subsequent follow-up, under treatment. Results Compared to controls, the IIH group had a significantly lower mean OT score (6.41 ± 3.43 vs 10.21 ± 2.79, p = 0.001) and higher rate of OT score below the 10th percentile for age and sex according to the normative values (47.1% vs 0%, p = 0.001). There was no significant between-group difference in mean OI scores (9.82 ± 1.63, vs 10.59 ± 1.84, p = 0.290). OT scores were not associated with sex, age, body mass index, neuroimaging abnormalities, or lumbar puncture opening pressure. At the follow-up assessment, the OT scores were improved (9.36 ± 4.17 vs 6.7 ± 3.32, p = 0.027) whereas the OI scores were unchanged (9.88 ± 2.5 vs 9.69 ± 1.58, p = 0.432). Conclusions As reported in adults, children and adolescents with IIH appear to have a selective reversible deficit in olfactory detection threshold, which may imply a reduction in peripheral olfactory perceptual ability. Future studies should examine the predictive value of olfactory function for IIH., Highlights • A selective reversible deficit in olfactory detection threshold is common among children with IIH. • Pediatric IIH does not influence the ability to identify odors presented at supra-threshold levels. • No association was found between the degree of olfactory impairment and sex, age, BMI percentile, LPOP, presence of papilledema, number of reported symptoms or neuroimaging features of IIH.

To report the 10-year experience of two tertiary medical centers with children presenting with proptosis due to an intraorbital space-occupying lesion. Patients were identified by file review. Data were collected on demographics, findings on ophthalmologic and imaging evaluations, etiology, treatment, and outcome. Nineteen children (7 male) were included. Eleven patients had optic nerve glioma, including 9 with substantially decreased visual acuity. Treatment consisted of chemotherapy alone or with radiation, resection or anti-VEGF agents, MEK inhibitor, or observation only (n = 1). Visual and cosmetic outcomes were poor in all cases. Outcome for arteriovenous malformations was good following corticosteroid treatment (n = 1), but catheterization led to persistent proptosis and fluctuating visual acuity (n = 1). Compound capillary hemangioma (n = 1) was treated with laser and systemic beta blockers with satisfactory results. Rhabdomyosarcoma had a good prognosis in one patient treated with resection and radiation but was fatal in another even after chemotherapy. Juvenile xanthogranuloma, frontal bone osteoma, and localized hypertrophic neuropathy of the supraorbital nerve (n = 1 each) were treated by resection with good visual and cosmetic outcomes. Proptosis accompanied by visual loss is an uncommon presentation in children and suggests an orbital tumor. We found that visual outcome was better when the nerve was not involved by tumor. Optic nerve glioma was the most common cause and failed to respond to various treatments. Catheterization for arteriovenous malformation did not prevent proptosis, and final visual acuity fluctuated. Surgery for rhabdomyosarcoma and xanthogranuloma led to remission with preservation of vision in 2 of 3 cases.

Objective: Inflammation of the meninges is a source of severe morbidity and therefore is an important health concerns worldwide. The conventional clinical microbiology approaches used today to identify pathogens suffer from several drawbacks and frequently provide false results. This research describes a fast method to detect the presence of pathogens using the frequency domain (FD) fluorescence lifetime (FLT) imaging microscopy (FLIM) system. Methods: The study included 43 individuals divided into 4 groups: 9 diagnosed with different types of bacteria; 16 diagnosed with different types of viruses; 5 healthy samples served as a control; and 12 samples were negative to any pathogen, although presenting related symptoms. All samples contained leukocytes that were extracted from the cerebrospinal fluid (CSF) and were subjected to nuclear staining by 4′, 6-diamidino-2-phenylindole (DAPI) and FLT analyses based on phase and amplitude crossing point (CRPO). Results: Using notched boxplots, we found differences in 95% probability between the first three groups through different notch ranges (NR). Pathogen samples presented a longer median FLT (3.28 ns with NR of 3.24–3.32 ns in bacteria and 3.18 ns with NR of 3.16–3.21 ns in viruses) compared to the control median FLT (2.65 ns with NR of 2.63–2.67 ns). Furthermore, we found that the undetected forth group was divided into two types: a relatively normal median FLT (2.72 ns with NR of 2.68–2.76 ns) and a prolonged FLT (3.22 ns with NR of 3.17–3.27 ns). Conclusion: FLT measurements can differentiate between control and pathogen by the CRPO method. Significance: The FD-FLIM system can provide a high throughput diagnostic technique that does not require a physician.

Sivan Gershanov,1 Helen Toledano,2,3 Shalom Michowiz,3,4 Orit Barinfeld,3,5 Albert Pinhasov,1 Nitza Goldenberg-Cohen,5–7 Mali Salmon-Divon1 1Genomic Bioinformatics Laboratory, Department of Molecular Biology, Ariel University, Ariel, Israel; 2Department of Pediatric Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 4Department of Pediatric Neurosurgery, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; 5The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Beilinson Hospital, Petah Tikva, Tel Aviv, Israel; 6Department of Ophthalmology, Bnai Zion Medical Center, Haifa, Israel; 7The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa,Israel Purpose: Medulloblastoma (MB), the most common malignant brain tumor in children, is divided into four tumor subgroups: wingless-type (WNT), sonic hedgehog (SHH), Group 3, and Group 4. ­Ideally, clinical practice and treatment design should be subgroup specific. While WNT and SHH subgroups have well-defined biomarkers, distinguishing Group 3 from Group 4 is not straightforward. MicroRNAs (miRNAs), which regulate posttranscriptional gene expression, are involved in MB tumorigenesis. However, the miRNA–messenger RNA (mRNA) regulatory network in MB is far from being fully understood. Our aims were to investigate miRNA expression regulation in MB subgroups, to assess miRNA target relationships, and to identify miRNAs that can distinguish Group 3 from Group 4. Patients and methods: With these aims, integrated transcriptome mRNA and miRNA expression analysis was performed on primary tumor samples collected from 18 children with MB, using miRNA sequencing (miRNA-seq), RNA sequencing (RNA-seq), and quantitative PCR. Results: Of all the expressed miRNAs, 19 appeared to be significantly differentially expressed (DE) between Group 4 and non-Group 4 subgroups (false discovery rate [FDR]

Background/AimsBenign positional vertical opsoclonus in infants, also described as paroxysmal tonic downgaze, is an unsettling phenomenon that leads to extensive work-up, although benign course has been reported in sporadic cases. We describe long-term follow-up of a series of infants with the phenomenon.MethodsThis retrospective cohort included all infants diagnosed with rapid downgaze eye movement in 2012–2015 and followed until 2016. The databases of two medical centres were retrospectively reviewed. Benign positional vertical opsoclonus was diagnosed based on clinical findings of experienced neuro-ophthalmologists. Data were collected on demographics, symptoms and signs, neuro-ophthalmological and neurological evaluations, and outcome. Imaging studies were reviewed. Main outcome measures were long-term outcome and findings of the thorough investigation.ResultsThe cohort included six infants. All infants were born at term. Age at presentation was several days to 12 weeks. Episodes lasted a few seconds and varied in frequency from ConclusionsOur identification of six patients in only 3 years suggests benign positional vertical opsoclonus may be more prevalent than previously described. In our experience, it affects otherwise healthy infants and resolves spontaneously. In view of the good long-term outcome, a comprehensive clinical investigation may not be necessary.

Diffusion reflectance spectroscopy measurements targeted with gold nanoparticles (GNPs) can identify residual cutaneous squamous cell carcinoma (SCC) in excision borders. Human SCC specimens were stained with hematoxylin and eosin to identify tumor borders, and reflected onto an unstained deparaffinized section. Diffusion reflection of three sites (normal and SCC) were measured before and after GNPs targeting. Hyperspectral imaging showed a mean of 2.5 sites with tumor per specimen and 1.2 tumor-free (p &lt, 0.05, t-test). GNPs were detected in 25/30 tumor sites (sensitivity 83.3%, false-negative rate 16.6%) and 12/30 non-tumor sites (specificity 60%, false-positive rate 40%). This study verifies the use of nanotechnology in identifying SCC tumor margins. Diffusion reflection scanning has high sensitivity for detecting the residual tumor.

Purpose: To test the frequency of single-nucleotide polymorphisms in the IL-10, IL23R-IL12RB2 genes in patients with Behcet's uveitis. Methods: Blood samples were collected from 89 Israeli and Turkish patients, and from healthy control subjects of different origins. Genomic DNA was extracted from peripheral blood leukocytes and genotyped. Results: The risk allele, A, in rs1800871, of IL-10 gene was highly prevalent in Behcet's uveitis and healthy control samples alike; highest among the Turkish groups. Prevalence of G allele, in rs1495965, in the IL23R-IL12RB2 gene was high in Behcet's uveitis patients, and among healthy Turkish and Israelis of Middle Eastern origin, while lower among the other Israeli control group (77.9%, 78.9%, 27.8%, respectively, P < 0.001). Conclusion: Our findings highlight the differences between populations and may account for the increased prevalence of the disease among Turkish and Israelis of Middle Eastern origin. Further studies are required to map other healthy and affected populations.

Contains fulltext : 218165.pdf (Publisher’s version ) (Closed access) Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of Israeli IRD patients. To date, we recruited 2,420 families including 3,413 individuals with IRDs. On the basis of our estimation, these patients represent approximately 40% of Israeli IRD patients. To the best of our knowledge, this is, by far, the largest reported IRD cohort, and one of the first studies addressing the genetic analysis of IRD patients on a nationwide scale. The most common inheritance pattern in our cohort is autosomal recessive (60% of families). The most common retinal phenotype is retinitis pigmentosa (43%), followed by Stargardt disease and cone/cone-rod dystrophy. We identified the cause of disease in 56% of the families. Overall, 605 distinct mutations were identified, of which 12% represent prevalent founder mutations. The most frequently mutated genes were ABCA4, USH2A, FAM161A, CNGA3, and EYS. The results of this study have important implications for molecular diagnosis, genetic screening, and counseling, as well as for the development of new therapeutic strategies for retinal diseases.

BACKGROUND The need for an extensive evaluation for neuroblastoma in children with Horner syndrome is controversial. METHODS A retrospective study design was used. The cohort included 47 children with anisocoria who were diagnosed with Horner syndrome and 135 children with neuroblastoma evaluated at a pediatric medical center between 2007 and 2015. To detect neuroblastoma, patients with Horner syndrome underwent brain and cervical MRI, abdominal ultrasound, and/or measurement of urinary vanillylmandelic acid (VMA). The neuroblastoma group was evaluated for signs/symptoms of Horner syndrome at the time of diagnosis. RESULTS Seven patients with Horner syndrome were lost to follow-up, and the findings of the remaining 40 were categorized according to the age of the patient. Horner syndrome most frequently was idiopathic (58%), and in only 1 patient did the discovery of neuroblastoma precede the appearance of Horner syndrome. In the 21 patients aged 1-18 years, Horner syndrome was acquired in 15 patients and congenital in 6. The most common etiology was trauma (62%). Imaging was performed in 14 patients and VMA testing in 13. Neuroblastoma was diagnosed in 5 patients; in none was it related to Horner syndrome. In the 135 patients with neuroblastoma, most of the tumors were diagnosed at Stage 4 (60%) or Stage 3 (30%) with 53% originating in the abdomen. In one patient (0.74%) with signs/symptoms of Horner syndrome at diagnosis of neuroblastoma, the tumor had been identified prenatally and the diagnosis confirmed by imaging postnatally. CONCLUSIONS The absence of occult neuroblastoma in children with Horner syndrome and of signs/symptoms of Horner syndrome in the children diagnosed with neuroblastoma suggests that Horner syndrome might not be as frequent a cause of neuroblastoma as previously thought. We recommend that full investigation for neuroblastoma be reserved for suspicious cases associated with additional systemic signs or symptoms.

Purpose To determine whether Toll-like receptor 4 knockout protects mice from corneal neovascularization following chemical injury compared to wild-type (WT) mice. Methods A chemical burn (75% silver nitrate, 25% potassium nitrate) was created under anesthesia in the central right cornea of 32 WT and 31 Toll-like receptor 4 knockout mice. Corneal neovascularization was evaluated at 3, 4, 6, 8, 10, and 35 days after injury using digital photography, fluorescein angiography, gelatin perfusion with fluorescence vascular imaging, immunofluorescence staining, and molecular analysis. Results There was no significant between-group difference in relative corneal burn area at 10 days after injury (39.0 ± 2.4% vs. 38.8 ± 9.8%, respectively). Neovascularization was detected in all corneas in vivo and perfusion was detected by fluorescence vascular imaging, reaching maximum area on day 10. The relative area of neovascularization was significantly smaller in the knockout than the WT mice on days 6 (33.3 ± 4.2% vs. 46.8 ± 7.4%, respectively, p = 0.005) and 8 (36.6 ± 1.1% vs. 52.2 ± 6.4%, respectively, p = 0.027), although neovascularization was intensive in both groups. In line with the immunostaining findings of angiogenesis and inflammatory infiltration of damaged corneas, molecular analysis (performed on day 3) revealed elevated expression levels of angiogenesis-related genes (vascular endothelial growth factor, VEGFR2, VEGFR1) and inflammation-related genes (CD45 and TGFβ1) in the WT mice. The knockout mice had higher TNF-α expression than the WT mice. Conclusion In a mouse corneal chemical burn model, lack of Toll-like receptor 4 expression did not completely inhibit angiogenesis, but did have a relative effect to reduce neovascularization as compared to the WT.

A critical challenge arising during a surgical procedure for tumor removal is the determination of tumor margins. Gold nanorods (GNRs) conjugated to epidermal growth factor receptors (EGFR) (GNRs-EGFR) have long been used in the detection of cancerous cells as the expression of EGFR dramatically increases once the tissue becomes cancerous. Optical techniques for the identification of these GNRs-EGFR in tumor are intensively developed based on the unique scattering and absorption properties of the GNRs. In this study, we investigate the distribution of the GNRs in tissue sections presenting squamous cell carcinoma (SCC) to evaluate the SCC margins. Air scanning electron microscopy (airSEM), a novel, high resolution microscopy is used, enabling to localize and actually visualize nanoparticles on the tissue. The airSEM pictures presented a gradient of GNRs from the tumor to normal epithelium, spread in an area of 1 mm, suggesting tumor margins of 1 mm. Diffusion reflection (DR) measurements, performed in a resolution of 1 mm, of human oral SCC have shown a clear difference between the DR profiles of the healthy epithelium and the tumor itself.

To evaluate the effect of bevacizumab and sildenafil on stroke parameters in a mouse model, middle cerebral artery occlusion was induced in male C57Bl/6 mice using an intra-arterial filament method. The filament was removed after 60 minutes, and the mice were immediately given a single intraperitoneal injection of saline, bevacizumab, or sildenafil. An additional group of mice (n=7) received bevacizumab 6 h after MCAO induction. The mice were euthanized 24 hours later and evaluated for infarct area and brain edema using triphenyltetrazolium chloride staining and ImageJ. In the saline-treated mice (n=16), total stroke volume was19.20±6.38 mm3, mean penumbra area was4.5±2.03 mm3, and hemispheric asymmetry was 106.5%. Corresponding values in the bevacizumab group (n=19) were17.79±5.80 mm3,7.3±3.5 mm3, and 108.6%; in the delayed (6 h) bevacizumab injected mice (n=7) they were9.80±8.00 mm3,2.4±2.0 mm3, and 98.2%; and in the sildenafil group (n=16) they were18.42±5.41 mm3,5.7±2.02 mm3, and 109.9%. The bevacizumab group had a significantly larger mean penumbra area when given immediately and smaller total stroke area in both groups than the saline- (p=0.03) and sildenafil-treated (p=0.003) groups. Only delayed bevacizumab group had reduced edema. Bevacizumab, injected immediately or delayed after injury, exerts a neuroprotective/salvage effect, whereas immediate treatment with sildenafil does not. Inflammation may play a role in the neuroprotective effect.

Characterizing different pathological states in the cellular level with a high throughput diagnostic tool is one of the main interests today. In previously works, we demonstrated how the frequency domain (FD) fluorescence lifetime imaging microscopy (FLIM) technique could be utilized to implement that in variety of examples. Among them was to classify between different chromosomal abnormalities in patients with b-cell chronic lymphocytic leukemia (B-CLL) and between metastatic cells and inflammation cells in the cerebral spinal fluid of patients with Medulloblastoma. This research describes the use of FD-FLIM system to differentiate between patients diagnosed without any disease (controls) that showed a normal median FLT (2.65±0.11ns) and patients diagnosed with inflammation (viruses and bacteria) that showed a prolong median FLT and a larger distribution (3.18±0.44ns in viruses and 3.28±0.45ns). The study group of this research included 43 samples divided into 4 groups: 9 samples diagnosed with different types of bacteria, 16 samples diagnosed with different types of viruses, 12 samples diagnosed with no any bacteria or virus and 5 samples diagnosed without any disease that served as controls. Furthermore, we studied a group of patients without detection of inflammation that were sick. We found that this group was divided into two groups; one group had the same median FLT as the controls, and the other group had the same median FLT as the inflammatory patients. As a result, we believe the FD-FLIM system can suggest a faster and more accurate diagnostic technique than the methods used today. The correlations of the FLT distribution pattern with the different groups are presented.

Aim This study aims to describe our experience of unique pediatric neurological cases and associated difficulty in differentiating posterior reversible encephalopathy syndrome (PRES) from hypoxic–ischemic insult (HII), and acute toxic leukoencephalopathy (ATL). Methods The study included three children with a clinical picture suggestive of PRES, HII, and ATL of different etiologies who were diagnosed and treated at a tertiary pediatric medical center in 2011 to 2014. Results All patients presented with blindness following seizures with asphyxia/aspiration in a syndromatic child, too-rapid lipid infusion in a child with acute lymphoblastic leukemia, and repeated vomiting in a child with cerebral palsy, hydrocephalus, and malfunction of ventriculoperitoneal shunt. All patients had cortical blindness and high-signal foci in the cortical and subcortical regions on magnetic resonance imaging. All children improved. Conclusions Familiarity with the clinical and radiological characteristics of neurological conditions leading to reversible cortical blindness is essential for diagnosis and management. Distinguishing PRES from HII and ATL can be challenging. Our cases most likely combined these etiologies, with the first patient diagnosed with PRES with HII, the second with PRES with ATL, and the third with focal HII. Given the diversity of the findings and the unclear prognostic significance, studies of the pathophysiology of PRES are warranted.

Falls from heights are the most common traumatic event associated with emergency department visits in children. This study investigated the incidence and clinical course of cranial neuropathies caused by falls from heights in children. The computerized records of a tertiary pediatric medical center were searched for all patients admitted to the emergency department in 2004–2014 with a head injury caused by falling from a height. Those with cranial neuropathies involving optic and eye-motility disturbances were identified, and their clinical, imaging, and outcome data were evaluated. Of the estimated 61,968 patients who presented to the emergency department during the study period because of a fall, 18,758 (30.3 %) had head trauma. Only 12 (seven boys, five girls, average age 6.7 years) had a visual disturbance. Eight were diagnosed with traumatic optic neuropathy, one after a 6-month delay, including two with accompanying cranial nerve (CN) III injuries. Five patients had anisocoria or an abnormal pupillary response to light at presentation, one patient had CN VI paralysis and temporary vision loss, and one patient had an isolated CN III injury diagnosed on follow-up. Visual improvement varied among the patients. Cranial neuropathies due to falls from heights are rare in children and are associated with high visual morbidity. Vision or ocular motility impairment, especially monocular vision loss, may be missed during acute intake to the emergency department, and a high index of suspicion is needed. Assessment of the pupillary response to light is essential.

Background This study aims to investigate the role of the inflammatory response following optic nerve crush (ONC) in knockout mice for the toll-like receptor-4 gene (TLR4−/−) compared to wild-type (WT) mice. Methods ONC was induced in TLR4−/− and C57BL6 WT mice. Histological sections of the retina and optic nerve were analysed on days 1, 3 or 21 after injury. Molecular analysis with real-time quantitative polymerase chain reaction was used to study the expression of CD45, tumour necrosis-alpha (TNF-α) and glial fibrillary acidic protein, as well as retinal ganglion cell (RGC) markers THY-1 and Brn3b. Results There was a 25.5% and 38% loss in the RGC layer of the ONC-injured eyes of the TLR4−/− and the WT mice, respectively (with 27% and 9% of the remaining cells positive for Brn3a, respectively). Mean levels of Thy-1 and Brn3b were higher in the TLR4−/− mice. CD45 and Iba1 staining revealed infiltration of inflammatory cells into the injured nerve and retina in both groups. Molecular analysis of the optic nerve on day 1 showed increased TNF-α expression and reduced CD45 and GFAP expression; on day 3, CD45 reverted to baseline but GFAP remained low; on day 21, all 3 markers were at baseline in the TLR4−/− group and decreased in the WT group. Conclusion Inflammation plays a major role in the response to ONC injury. Reduced levels of inflammation are associated with improved RGC preservation. The increase in TNF-α and reduction in CD45 in both TLR4−/− and WT mice may indicate the presence of an alternative pathway for induction of RGC death.

Background: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Complete resection is impossible. Overexpression of epidermal growth factor receptor (EGFR) by the tumor has been associated with the level of malignancy and possibly with prognosis. Monoclonal antibodies may be used to identify tumor borders. The aim of the present study was to investigate the value of immunostaining with anti-EGFR antibodies conjugated to gold nanoparticles (GNPs) for detecting tumor infiltration into adjacent tissue. Methods: Fresh GBM samples were collected intraoperatively from 14 patients treated at a tertiary medical center in 2014-2015, in accordance with the guidelines of the local and national ethic committees. Demographic, clinical, and outcome data of the patients were recorded. Analysis for EGFR overexpression by polysomy or amplification was determined by calculating the ratio of expression between pairs of the following genes: EGFR, GPER, and RNaseP. Tumor sample with known overexpression of EGFR underwent immunostaining with GNPconjugated anti-EGFR antibodies followed by light-scattering spectroscopy and electron microscopy. The findings were compared with routine hematoxylin and eosin staining. Results: On molecular analysis, EFGR overexpression was identified in 10/14 GBM samples (71%). Amplification was detected in 50% and polysomy in 27%, and one sample showed both. Patients whose samples were characterized by an overexpression of EGFR died within 3-10 months, whereas 2 of the patients with normal EGFR expression were still alive 9 and

Purpose To investigate the potential neuroprotective effect of sildenafil on the ocular circulation in mice with/without optic nerve crush (ONC). Methods Male adult mice (n = 63) were treated with intravitreal (IVT) sildenafil 24 μg/3 μL, intraperitoneal (IP) sildenafil 24 μg/300 μL, or IP saline immediately before right ONC induction (ONC group). A second group (n = 123) received the same treatments without ONC induction (naive group). Evaluations included fluorescein angiography (naive group; day 0), molecular studies (days 1 and 3), and retinal and optic nerve histology (day 21). Results Maximal retinal vessel dilatation and increased choroidal effusion were detected within 30 minutes of sildenafil injection. In the ONC group, moderate retinal ganglion cell (RGC) loss was noted at 21 days. However, molecular studies showed increased stress induced gene expression (IP superoxide dismutase [SOD]-1: 3.1-fold; heme oxygenase [HO]-1: 5.8-fold; IVT SOD-1: 1.47-fold), proapoptotic gene expression (IP BAX/B-cell lymphoma [BCL]-2 10.8-/2.3-fold), and glial gene expression (IP glial fibrillary acidic protein [GFAP]: 2.8- and myelin basic protein [MBP]: 2.5-fold). In the naive group, IVT sildenafil was not associated with RGC loss or optic nerve stroke on histology, although in two samples, molecular parameters were compatible with stroke, showing increased gene expression of HO-1 (3.8-fold) and BCL-2 (2.5-fold). In the IP sildenafil subgroup, optic neuropathy was observed in 6/120 optic nerves, including 3 cyan fluorescence protein (CFP)-Thy-1 mice. Levels of antiapoptosis and anti-ischemia genes were decreased (