Identification of seven novel germline mutations in the human E-cadherin (CDH1) gene

Hereditary diffuse gastric cancer (HDGC) is a cancer predisposition syndrome caused by germline mutation of the gene encoding the tumour-suppressor E-cadherin (CDH1). We describe the search for CDH1 mutations in 36 new diffuse gastric cancer families. All 16 CDH1 exons, neighbouring intronic sequence and an essential promoter region were screened by DNA sequencing. We detected nine different mutations, seven of which were novel. Of the seven novel mutations, five were identified in families who met the IGCLC clinical criteria for HDGC. Two mutations resulted in a premature stop codon and truncation of the protein. Three mutations affected splice sites; two of the splice-site mutations were shown by RT-PCR to disturb normal CDH1 splicing, while the third splice-site mutation was present in two unrelated HDGC families. The remaining two mutations resulted in amino acid substitutions and impaired the ability of E-cadherin protein to form cellular aggregates and suppress invasion in vitro. Together with the occurrence of extra-gastric tumours such as lobular breast and colorectal cancer, these findings further extend the types of CDH1 mutations and the spectrum of tumours associated with HDGC.     

Who needs vitamin supplements?

Supplementation for breast-fed babies should begin at six months, or from one month if the mother's vitamin status during pregnancy is doubtful, and should continue for five years. Any teenager or woman who could become pregnant should receive 400 microg folic acid daily. Pregnant and breast-feeding women, anyone over 65 years of age and anyone who is housebound should be advised to take vitamin D supplements. The two new Healthy Start vitamin formulations offer low-cost vitamin D and folic acid supplementation, free to those so entitled. RDAs (recommended daily amounts) are for adults and should not be used for children. RNIs (reference nutrient intakes for different ages) are the appropriate guide.     

Outcome of optical penetrating keratoplasties at a tertiary care eye institute in Western India

Aim:

To study the indications, risk factors, postoperative course, and long-term survival of corneal transplants done for optical purposes.

Design:

Retrospective case series.

Materials and Methods:

Data were obtained by reviewing the records of 181 patients operated at our institute (H.V. Desai Eye Hospital) between October 2005 and October 2007 for optical penetrating keratoplasty. Patients with less than one year of follow up, pediatric cases, therapeutic, tectonic, and lamellar keratoplasties were excluded. Kaplan Meier survival analysis was used to calculate median survival time of grafts and to see correlation between nine variables viz. age, gender, corneal vascularization, previous failed grafts, previous Herpes Simplex keratitis, post-perforation corneal scars, donor tissue quality, graft size, type of surgery and follow-up. These variables were also used for univariate and multivariate analysis using Cox Proportional Hazard Regression Modeling.

Results:

Median survival of the cohort was 27 months (95% confidence interval: 20.47-33.52). One- and two-year survival rates were 65% and 52.5%, respectively. Median survival was significantly lower in poor prognosis cases (14 months) than good prognosis cases (27 months, P = 0.0405). Graft survival was lower in vascularized corneas (18.55 months, P = 0.030) and in post-perforation corneal scars (17.96 months, P = 0.09, borderline significance). Multivariate analysis showed that the same factors were predictive of graft failure.

Conclusion:

Long-term survival of grafts at our center is different from centers in western world. More high-risk cases, paucity of excellent quality donor corneas, and differences in patient profile could be the contributory factors.     

A randomized, double-blind trial of Lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn's disease

Probiotics are widely used by patients with Crohn's disease (CD) in an attempt to improve their health, but few controlled studies have been done to evaluate the efficacy of these therapies. We conducted a randomized, placebo-controlled trial of the probiotic Lactobacillus rhamnosus strain GG (LGG) to see if the addition of LGG to standard therapy prolonged remission in children with CD. Concomitant medications allowed in the study included aminosalicylates, 6-mercaptopurine, azathioprine, and low-dose alternate day corticosteroids. Seventy-five children (age range, 5-21 yr) with CD in remission were randomized to either LGG (n=39) or placebo (n=36) and followed for up to 2 years. The median time to relapse was 9.8 months in the LGG group and 11.0 months in the placebo group (P=0.24); 31% (12/39) of patients in the LGG group developed a relapse compared with 6/36 (17%) of the placebo group (P=0.18). The LGG was well tolerated, with a side effect profile comparable with placebo. This study suggests that LGG does not prolong time to relapse in children with CD when given as an adjunct to standard therapy.     

Respiratory syncytial virus uses a Vps4-independent budding mechanism controlled by Rab11-FIP2

Respiratory syncytial virus (RSV) infects polarized epithelia, which have tightly regulated trafficking because of the separation and maintenance of the apical and basolateral membranes. Previously we established a link between the apical recycling endosome (ARE) and the assembly of RSV. The current studies tested the role of a major ARE-associated protein, Rab11 family interacting protein 2 (FIP2) in the virus life cycle. A dominant-negative form of FIP2 lacking its N-terminal C2 domain reduced the supernatant-associated RSV titer 1,000-fold and also caused the cell-associated virus titer to increase. These data suggested that the FIP2 C2 mutant caused a failure at the final budding step in the virus life cycle. Additionally, truncation of the Rab-binding domain from FIP2 caused its accumulation into mature filamentous virions. RSV budding was independent of the ESCRT machinery, the only well-defined budding mechanism for enveloped RNA viruses. Therefore, RSV uses a virus budding mechanism that is controlled by FIP2.     

Failed thrombolysis in myocardial infarction

Prompt treatment with thrombolytic therapy in acute myocardial infarction has been proven to reduce infarct size and mortality. However, reperfusion fails to occur in 30-50% of patients, either due to impaired epicardial artery flow or microvascular occlusion, with these patients experiencing a higher morbidity and mortality. We review the diagnosis and management of failed thrombolysis in acute myocardial infarction.     

Effect of aqueous extract of Solanum xanthocarpum Schrad. ＆ Wendl. on postmenopausal syndrome in ovariectomized rats

OBJECTIVE： Solanum xanthocarpum Schrad. ＆ Wendl. （Solanaceae） is present in many Ayurveda compound formulations including Chavanaprasha and Dasamoolarishta. The whole plant is used in conditions such as inflammation, constipation and promoting conception in females. In the present study, we carried out different tests to evaluate the effect of aqueous extract of Solanum xanthocarpum （SXE） in postmenopausal syndrome. METHODS： The study was carried out in bilaterally ovariectomized one-month-old Wistar rats （40-50 g）. Bilaterally ovariectomized （OVX） Wistar rats were divided into four groups （n=6） receiving different treatments, consisting of a vehicle （distilled water）, aqueous extract of Solanum xanthocarpum at two different doses （200 and 400 mg/kg） administered orally daily for 90 d and standard drug β estradiol at a dose of 1 mg/kg administered subcutaneously biweekly for 90 d. Estrogenic activity was assessed by vaginal cornification, sexual behavior, serum estradiol and uterine weight to body weight ratio. Antiosteoporotic activity was assessed on the basis of biomechanical and biochemical parameters followed by histopathological studies, and antidepressant activity was assessed by forced swim test. RESULTS： SXE showed presence of steroids. At the dose of 200 mg/kg, it significantly improved all the parameters of sexual behavior （P〈0.01）, caused vaginal cornification, and increased serum estradiol and uterine weight （P〈0.01）. It also significantly improved all the parameters of bone strength as well as depression （P〈0.01）. Histopathology of bones confirmed the above findings. CONCLUSION： The study indicated that SXE may provide an effective treatment in the prevention of postmenopausal symptoms.     

Brain angiogenesis: variations in vascular basement membrane glycoprotein immunoreactivity.

Changes in the distribution and quantity of laminin and fibronectin within the basement membranes of developing or regenerating CNS blood vessels were investigated using two immunocytochemical techniques. Three models of angiogenesis were studied: normal pre- and postnatal development, wound healing, and vascularization of fetal neocortical transplants placed in the adult rat brain. Although all brain vessels were stained in enzymatically pretreated immunoreacted paraffin sections, those associated with wound and transplant sites were the most intensely reactive with both antisera during the first postoperative week. When 40-microns vibratome sections of normal adult brains were immunoprocessed, only the meninges and vessels of the circumventricular organs were stained. The remainder of the brain vasculature was immunoreactive only if sections were enzymatically treated prior to immunoprocessing. In contrast, the nascent vasculature in developing brain and the regenerating vessels at wound and transplant sites were reactive to both antisera without enzymatic pretreatment of the sections. This immunoreactivity decreased by 11 days postnatal in normal animals and 4 weeks postoperative in experimental animals, coinciding with the period of astrocytic contact and complete vascular basement membrane formation in both cases. The variations in staining pattern and intensity may be reflections of differences in the quantity of laminin and fibronectin within the basement membranes of proliferating and/or non-blood-brain barrier vasculature. However, the results of the different experimental protocols suggest that immature vascular basement membranes may have a molecular configuration that does not require an enzymatic unmasking step to react with the antisera. Alternatively, the looseness of the surrounding neuropil inherent in developing and injured CNS could allow the antisera greater access to basement membrane antigens.     

Effects of esomeprazole treatment for gastroesophageal reflux disease on quality of life in 12- to 17-year-old adolescents: an international health outcomes study

Background  

Although gastroesophageal reflux disease (GERD) is common in adolescents, the burden of GERD on health-related quality of life (HRQOL) in adolescents has not been previously evaluated. Therefore, the objective of the study was to examine the effect of GERD on HRQOL in adolescents.