Mutations in the human LKB1/STK11 gene

The human LKB gene (official HUGO symbol, STK11) encodes a serine/threonine protein kinase that is defective in patients with Peutz-Jeghers syndrome (PJS). PJS is an autosomal dominantly inherited syndrome characterized by hamartomatous polyposis of the gastrointestinal tract and mucocutaneous pigmentation. To date, 145 different germline LKB1 mutations have been reported. The majority of the mutations lead to a truncated protein product. One mutational hotspot has been observed. A 1-bp deletion and a 1-bp insertion at the mononucleotide repeat (C6 repeat, c.837-c.842) between the codons 279-281 have been found in six and seven unrelated PJS families, respectively. However, these mutations account only for approximately 7% of all mutations identified in the PJS families (13/193). A review of the literature provides a total of 40 different somatic LKB1 mutations in 41 sporadic tumors and seven cancer cell lines. Mutations occur particularly in lung and colorectal cancer. Most of the somatic LKB1 mutations result in truncation of the protein. A mutational hotspot seems to be a C6 repeat accounting for 12.5% of all somatic mutations (6/48). These results are concordant with the germline mutation spectrum. However, the proportion of the missense mutations seems to be higher among the somatic mutations (45%) than among the germline mutations (21%), and only seven of the mutations are exactly the same in both of the mutation types.     

p53Mutations and Presence of HPV DNA Do Not Correlate with Radiosensitivity of Gynecological Cancer Cell Lines

Objective.The correlation betweenp53tumor suppressor gene mutations and the presence of high-risk human papillomavirus (HPV) DNA with thein vitroradiosensitivity of gynecological malignancies was studied in 26 cell lines derived from gynecological cancers of 23 patients.Methods.Comparison of the intrinsic radiosensitivity was performed with mean inactivation dose (D?) determined with the 96-well plate clonogenic assay.p53mutations were investigated with polymerase chain reaction and single-strand conformation polymorphism (PCR–SSCP) analysis and direct DNA sequencing, and the presence of HPV DNA was studied with PCR using HPV consensus primers.Results. p53mutations were found in 6 of 10 vulvar squamous cell carcinoma (SCC) lines. Nine vulvar and 1 vaginal SCC cell lines were HPV DNA negative and 1 vulvar cell line was HPV 16 positive. All 4 cervical SCC lines were HPV positive and possessed the wild-typep53.Three cell lines expressed HPV 16 and 1 HPV 68. Among 10 endometrial cancer cell lines, 2 cell lines with mutantp53and 1 HPV 16 positive cell line were found. No correlation could be demonstrated between inactivation of thep53gene and radiosensitivityin vitro;the cell lines were evaluated as one group or according to their anatomical origin or histology.Conclusion.Our results indicate that inactivation of thep53gene through mutation or binding with HPV DNA does not increase the resistance of gynecological malignancies to ionizing radiationin vitro.     

Clustering of Metabolic Risk Factors Is Associated with High-Normal Levels of Liver Enzymes Among 6- to 8-Year-Old Children: The PANIC Study

Abstract Background: We studied the associations of clustering of metabolic risk factors with plasma levels of alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) in healthy prepubertal children. Methods: The subjects were a representative population sample of 492 children 6-8 years of age. We assessed body fat percentage (dual-energy X-ray absorptiometry), body mass index, waist circumference, systolic and diastolic blood pressure, glucose, insulin, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, ALT, GGT, and high-sensitivity C-reactive protein (hsCRP) and calculated a continuous metabolic syndrome score variable. We also used factor analysis to examine whether high-normal liver enzymes are a feature of metabolic syndrome among children. Results: Children with overweight or obesity, defined by International Obesity Task Force (IOTF) criteria, had a 2.1-times higher risk of having ALT and a 4.5-times higher risk of having GGT in the highest fifth of its distribution than normal weight children. Children in the highest sex-specific third of metabolic syndrome score, body fat percentage, waist circumference, and insulin had a two to three times higher risk of being in the highest fifth of ALT and GGT. Moreover, children in the highest third of glucose and hsCRP had a 2.5-fold risk of being in the highest fifth of GGT. First-order factor analysis yielded three factors; the first included insulin, glucose, and triglycerides; the second waist circumference, insulin, GGT, and hsCRP; and the third HDL-C, triglycerides, waist circumference, and insulin. Second-order factor analysis yielded a single metabolic syndrome factor, explaining 64.1% of the variance. Conclusions: Clustering of metabolic risk factors, particularly excess body fat, is associated with high-normal levels of ALT and GGT in prepubertal children. High-normal levels of liver enzymes, especially GGT, and systemic low-grade inflammation could be considered features of metabolic syndrome among children. Subtle changes in liver function may play an important role in the pathogenesis of metabolic syndrome beginning in childhood.     

Cyclophotocoagulation with the transscleral contact red 670‐nm diode laser in the treatment of glaucoma

Purpose: To retrospectively evaluate the results of cyclophotocoagulation (CPC) with the transscleral contact red 670‐nm diode laser in treating glaucoma. Methods: Cyclophotocoagulation was performed in 60 eyes of 60 patients with a mean age of 74 ± 11 years (range 49–90 years). The treatment was delivered via a fibre‐optic probe. The power per application was 430 mW. Exposure time was 10 seconds. Results: The mean overall follow‐up time after the initial CPC was 26 ± 20 months (range 3–75 months). Preoperative intraocular pressure (IOP) was 27 ± 11 mmHg (n = 60). After one or more CPC treatments, mean IOP decreased to 20 ± 7 mmHg (n = 51) at 1 month, 19 ± 5 mmHg (n = 45) at 3 months, 18 ± 5 mmHg (n = 29) at 6 months, 19 ± 7 mmHg (n = 22) at 1 year, 18 ± 7 mmHg (n = 16) at 2 years, 14 ± 4 mmHg (n = 8) at 3 years, and 18 ± 6 mmHg (n = 60) at the last follow‐up. An IOP of 8–21 mmHg or a > 30% decrease in IOP was obtained in 33 of 41 eyes (80%) with baseline IOP > 21 mmHg at the last follow‐up. Hypotonia (IOP < 8 mmHg) did not develop in any of the eyes studied. Conclusions: Cyclophotocoagulation with the red 670‐nm diode laser is an effective and well tolerated means of treating glaucoma.     

Serum insulin and leptin levels in valproate-associated obesity

PURPOSE: Weight gain is an important adverse effect of valproate (VPA) therapy, and it is associated with hyperinsulinemia and hyperandrogenism in women with epilepsy. Leptin is considered a signaling factor regulating body weight and energy metabolism. In human subjects, obesity is in general associated with elevated serum leptin levels, suggesting decreased sensitivity to leptin. The present study aimed at evaluating the role of insulin and leptin in VPA-related obesity. METHODS: Body mass index (BMI) was calculated, and serum insulin and leptin levels were measured in 81 patients with epilepsy taking VPA and in 51 healthy control subjects. RESULTS: Forty (49%) of the patients taking VPA and 25 (49%) of the control subjects were obese. The mean insulin levels were higher in VPA-treated patients than in the control subjects despite similar BMI values, when all subjects were included in the comparison. Both obese male and female patients taking VPA had higher serum insulin levels than the respective control subjects with similar BMI values. Serum insulin levels also were higher in lean male and lean female patients compared with the lean control subjects of same sex. Serum leptin levels did not differ between the VPA-treated patients and the control subjects. CONCLUSIONS: Both obese and lean patients taking VPA for epilepsy have hyperinsulinemia, suggesting development of insulin resistance. This may be one of the factors leading to weight gain during VPA treatment. However, the results of the present study do not suggest an independent role for leptin in the pathogenesis of VPA-related obesity.     

Comparison of topical 0.7% dexamethasone–cyclodextrin with 0.1% dexamethasone sodium phosphate for postcataract inflammation

Background To compare 0.7% dexamethasone–cyclodextrin aqueous eye drop solution applied once daily with 0.1% dexamethasone sodium phosphate eye drops applied three times a day for the control of postoperative inflammation after cataract surgery.Methods Twenty cataract patients who underwent phacoemulsification and intraocular lens implantation were randomly divided into two postoperative treatment groups. Postoperative medication in group I included 0.1% dexamethasone sodium phosphate eye drops three times daily and in group II 0.7% dexamethasone–cyclodextrin eye drop solution once daily. Testing of visual acuity, biomicroscopic examination, applanation tonometry and laser flare cell meter (LFCM) examination were carried out before operation and days 1, 3, 7 and 21 after surgery.Results Preoperative and postoperative visual acuity, aqueous flare and cells in biomicroscopic examination, and the mean intraocular pressure did not show any statistically significant differences between the treatment groups. LFCM examination showed that the mean postoperative photon count values (P=0.032) and the median cell count values on the 1st (P=0.014), 3rd (P=0.031), 7th (P=0.034), and 21st (P=0.0097) postoperative days in group I were more elevated than in group II.Conclusions 0.7% dexamethasone–cyclodextrin eye drops applied once daily is a more effective postoperative anti-inflammatory medication than 0.1% dexamethasone sodium phosphate applied three times a day. In both groups, 3 weeks after the operation the mean visual acuity was normal and intraocular pressure significantly lower than before operation. The use of 0.7% dexamethasone–cyclodextrin eye drops may be useful especially in elderly people who cannot apply themselves the eye drops onto the eye.     

Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study

High levels of cytokines are risk factors for type 2 diabetes. Therefore, we investigated whether the promoter polymorphisms of the tumor necrosis factor-alpha (TNF-alpha; G-308A) and interleukin 6 (IL-6; C-174G) genes predict the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. Altogether, 490 overweight subjects with IGT whose DNA was available were randomly divided into one of the two treatment assignments: the control group and the intensive, individualized diet and exercise intervention group. The -308A allele of the TNF-alpha gene was associated with an approximate twofold higher risk for type 2 diabetes compared with the G-308G genotype (odds ratio 1.80, 95% CI 1.05-3.09; P = 0.034). Subjects with both the A allele of the TNF-alpha gene and the C-174C genotype of the IL-6 gene had a 2.2-fold (CI 1.02-4.85, P = 0.045) higher risk of developing type 2 diabetes than subjects without the risk genotypes. We conclude that the -308A allele of the promoter polymorphism (G-308A) of the TNF-alpha gene is a predictor for the conversion from IGT to type 2 diabetes. Furthermore, this polymorphism seems to have a gene-gene interaction with the C-174C genotype of the IL-6 gene.