Cutis laxa,exocrine pancreatic insufficiency and altered cellular metabolomics as additional symptoms in a new patient with ATP6AP1-CDG

Congenital disorders of glycosylation (CDG) are genetic defects in the glycoconjugate biosynthesis. > 100 types of CDG are known, most of them cause multi-organ diseases. Here we describe a boy whose leading symptoms comprise cutis laxa, pancreatic insufficiency and hepatosplenomegaly. Whole exome sequencing identified the novel hemizygous mutation c.542 T > G (p.L181R) in the X-linked ATP6AP1, an accessory protein of the mammalian vacuolar H⁺-ATPase, which led to a general N-glycosylation deficiency. Studies of serum N-glycans revealed reduction of complex sialylated and appearance of truncated diantennary structures. Proliferation of the patient's fibroblasts was significantly reduced and doubling time prolonged. Additionally, there were alterations in the fibroblasts' amino acid levels and the acylcarnitine composition. Especially, short-chain species were reduced, whereas several medium- to long-chain acylcarnitines (C14-OH to C18) were elevated. Investigation of the main lipid classes revealed that total cholesterol was significantly enriched in the patient's fibroblasts at the expense of phophatidylcholine and phosphatidylethanolamine. Within the minor lipid species, hexosylceramide was reduced, while its immediate precursor ceramide was increased. Since catalase activity and ACOX3 expression in peroxisomes were reduced, we assume an ATP6AP1-dependent impact on the β-oxidation of fatty acids. These results help to understand the complex clinical characteristics of this new patient.     

Central corneal thickness in adult Chinese. Association with ocular and general parameters. The Beijing Eye Study

Background To evaluate the distribution of central corneal thickness and its associations in the adult Chinese population. Methods The Beijing Eye Study 2006 is a population-based study including 3,251 (73.3%) subjects (aged 45+ years) out of 4,439 subjects who participated in the survey in 2001 and who returned for re-examination. Central corneal thickness (CCT) measurements were performed by slit lamp-based optical coherence tomography. Results Central corneal thickness measurement data were available for 3,100 (95.4%) subjects. Mean CCT was 556.2±33.1 μm (median: 553 μm; range: 429–688 μm). In multiple regression analysis, CCT was significantly associated with optic disc area (P = 0.043), urban region (P < 0.001; odds ratio (OR): 4.77; 95% confidence interval (CI): 2.37, 7.17), male gender (P < 0.001; OR: 5.64; 95%CI: 2.57, 8.71), and intraocular pressure measurements (P < 0.001). It was not significantly associated with body weight (P = 0.54) and body height (P = 0.66), age (P = 0.17), and refractive error (P = 0.43). Intraocular pressure (measured by pneumotonometry) increased for each μm central corneal thickness increase by 0.03 mmHg. Conclusions In the adult Chinese population, CCT was significantly associated optic disc area, urban region, and male gender. Intraocular pneumotonometric pressure measurements increased for each μm increase in central corneal thickness by 0.03 mmHg. CCT was not associated with age and refractive error. Supported by Beijing Natural Science Foundation No 7071003, Beijing, China.     

Structure of intracorneal femtosecond laser pulse effects in conical incision profiles

PURPOSE: As the applicative potential of femtosecond lasers is to be extended from LASIK-flap creation into intrastromal ablation uses, the interdependency of influencing factors has to be understood. We therefore evaluated the relationship between focus depth, energy level, spatial distribution and morphology of fs-Laser pulse effects at a given repetition rate in corneal tissue. METHODS: The experimental study included five porcine corneae obtained from slaughterhouse pigs. Using a prototype of a femtosecond laser (FEMTEC; 20/10 Perfect Vision AG, Heidelberg, Germany), a conical circular cut was performed in posterior-anterior direction through the entire corneal profile. The laser energy applied ranged from 4.0 to 8.5 muJ. Histological sections (n = 337) of a thickness of 7 mum were obtained, stained with hematoxylin/eosin, and morphometrically evaluated. RESULTS: The intrastromal femtosecond laser effects were aligned throughout the corneal stroma in a line that followed the dissection line programmed for the laser. The lesions were mostly of roughly elliptic shape with a fine dense lining at the inner wall, without evidence of a collateral damage beyond the disruption cavity. The mean maximal diameter of the intrastromal laser effects was 34.2 +/- 18.6 mum (range: 9-120 mum), and the mean maximal lesion diameter was 60.8 +/- 42.6 mum. In multivariate analysis, the lesion type (single shot cavity, partly confluent lesions, and fully confluent lesions) was significantly associated with the laser energy applied (P = 0.027) and the lesion diameter (P = 0.01). CONCLUSIONS: At higher laser energies, the intrastromal laser lesions were larger and more confluent, suggesting that, with the prototype of femtosecond laser used, a higher laser energy may lead to more confluent intrastromal laser effects. It may facilitate the complete cutting of the corneal tissue with the laser. Neither discernable debris nor stainable collateral damage were detected, suggesting a purely mechanical action of the laser.     

Intravitreal bevacizumab for myopic choroidal neovascularization.

BACKGROUND AND OBJECTIVE: To evaluate the effect of intravitreal bevacizumab on visual acuity in patients with myopic choroidal neovascularization. PATIENTS AND METHODS: The retrospective case series study included 13 patients with myopic choroidal neovascularization who received three intravitreal injections of 1.5 mg of bevacizumab. RESULTS: At 1, 3, and 6 months after the first injection, mean visual acuity improved significantly from 0.63 +/- 0.41 logarithm of the minimum angle of resolution units (LogMAR) to 0.39 +/- 0.22 (P< .001), 0.47 +/- 0.49 (P= .002), and 0.52 +/- 0.49 LogMAR (P = 0.009), respectively. The increase in visual acuity was correlated with a significant decrease in central retinal thickness (P = .003) as measured by optical coherence tomography. Mean intraocular pressure did not change significantly (P> .05) during follow-up. CONCLUSION: Intravitreal injections of bevacizumab may be a therapeutic option for exudative myopic macular degeneration.     

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03.

BACKGROUND: Gefitinib is active in patients with pretreated non-small-cell lung cancer (NSCLC). We evaluated the activity and toxicity of gefitinib first-line treatment in advanced NSCLC followed by chemotherapy at disease progression. PATIENTS AND METHODS: In all, 63 patients with chemotherapy-naive stage IIIB/IV NSCLC received gefitinib 250 mg/day. At disease progression, gefitinib was replaced by cisplatin 80 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1, 8 for up to six 3-week cycles. Primary end point was the disease stabilization rate (DSR) after 12 weeks of gefitinib. RESULTS: After 12 weeks of gefitinib, the DSR was 24% and the response rate (RR) was 8%. Median time to progression (TtP) was 2.5 months and median overall survival (OS) 11.5 months. Never smokers (n = 9) had a DSR of 56% and a median OS of 20.2 months; patients with epidermal growth factor receptor (EGFR) mutation (n = 4) had a DSR of 75% and the median OS was not reached after the follow-up of 21.6 months. In all, 41 patients received chemotherapy with an overall RR of 34%, DSR of 71% and median TtP of 6.7 months. CONCLUSIONS: First-line gefitinib monotherapy led to a DSR of 24% at 12 weeks in an unselected patients population. Never smokers and patients with EGFR mutations tend to have a better outcome; hence, further trials in selected patients are warranted.     

Infrared spectroscopic examination of aqueous humor.

OBJECTIVE: The aim of this study was to report on a new technique for examining aqueous humor. PARTICIPANTS: Aqueous humor samples obtained from 198 patients (cataract: n=66 eyes; age-related macular degeneration [AMD]: n=66; diabetic macular edema: n=66) were in vitro examined by mid infrared spectroscopy. After training and validating the technique, 66 samples were taken for the final independent prediction. RESULTS: In computerized analysis of the spectrometric data, 22 (100%) cataract eyes were diagnosed as the cataract group, 17 (77%) diabetic macular edema eyes were diagnosed as the diabetic macular edema group, and 14 (64%) eyes with AMD were diagnosed as the AMD group. Mid infrared spectrometry could statistically significantly (P=0.004) differentiate between the 3 study groups. CONCLUSIONS: Mid infrared spectroscopic examination of aqueous humor may be able to differentiate eyes with cataract, AMD, or diabetic macular edema.     

Promoter hypermethylation of the <Emphasis Type="Italic">SFRP2</Emphasis> gene is a high-frequent alteration and tumor-specific epigenetic marker in human breast cancer

Background  

We have previously reported that expression of the Wnt antagonist genes SFRP1 and SFRP5 is frequently silenced by promoter hypermethylation in breast cancer. SFRP2 is a further Wnt inhibitor whose expression was recently found being downregulated in various malignancies. Here we investigated whether SFRP2 is also implicated in human breast cancer, and if so whether SFRP2 promoter methylation might serve as a potential tumor biomarker.