Microdeletion 9q22.3 syndrome includes metopic craniosynostosis, hydrocephalus, macrosomia, and developmental delay

Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (OMIM #109400) is a well-described rare autosomal dominant condition due to haploinsufficiency of PTCH1. With the availability of comparative genomic hybridization arrays, increasing numbers of individuals with microdeletions involving this locus are being identified. We present 10 previously unreported individuals with 9q22.3 deletions that include PTCH1. While 7 of the 10 patients (7 females, 3 males) did not meet strict clinical criteria for BCNS at the time of molecular diagnosis, almost all of the patients were too young to exhibit many of the diagnostic features. A number of the patients exhibited metopic craniosynostosis, severe obstructive hydrocephalus, and macrosomia, which are not typically observed in BCNS. All individuals older than a few months of age also had developmental delays and/or intellectual disability. Only facial features typical of BCNS, except in those with prominent midforeheads secondary to metopic craniosynostosis, were shared among the 10 patients. The deletions in these individuals ranged from 352 kb to 20.5 Mb in size, the largest spanning 9q21.33 through 9q31.2. There was significant overlap of the deleted segments among most of the patients. The smallest common regions shared among the deletions were identified in order to localize putative candidate genes that are potentially responsible for each of the non-BCNS features. These were a 929 kb region for metopic craniosynostosis, a 1.08 Mb region for obstructive hydrocephalus, and a 1.84 Mb region for macrosomia. Additional studies are needed to further characterize the candidate genes within these regions.     

Determination of Optimum Machining Parameters for Face Milling Process of Ti6A14V Metal Matrix Composite

This paper shows the novel approach of Taguchi-Based Grey Relational Analysis of Ti6Al4V Machining parameter. Ti6Al4V metal matrix composite has been fabricated using the powder metallurgy route. Here, all the components of TI6Al4V machining forces, including longitudinal force (F_x), radial force (F_y), tangential force (F_z), surface roughness and material removal rate (MRR) are measured during the facing operation. The effect of three process parameters, cutting speed, tool feed and cutting depth, is being studied on the matching responses. Orthogonal design of experiment (Taguchi L9) has been adopted to execute the process parameters in each level. To validate the process output parameters, the Grey Relational Analysis (GRA) optimization approach was applied. The percentage contribution of machining parameters to the parameter of response performance was interpreted through variance analysis (ANOVA). Through the GRA process, the emphasis was on the fact that for TI6Al4V metal matrix composite among all machining parameters, tool feed serves as the highest contribution to the output responses accompanied by the cutting depth with the cutting speed in addition. From optimal testing, it is found that for minimization of machining forces, maximization of MRR and minimization of Ra, the best combinations of input parameters are the 2nd stage of cutting speed (175 m/min), the 3rd stage of feed (0.25 mm/edge) as well as the 2nd stage of cutting depth (1.2 mm). It is also found that hardness of Ti6Al4V MMC is 59.4 HRA and composition of that material remain the same after milling operation.     

1,3-Bis(2-chloroethyl)-1-nitrosourea enhances the inhibitory effect of Resveratrol on 5-fluorouracil sensitive/ resistant colon cancer cells

AIM:To study the mechanism of 5-fluorouracil(5-FU)resistance in colon cancer cells and to develop strategies for overcoming such resistance by combination treatment.METHODS:We established and characterized a 5-FU resistance(5-FU-R)cell line derived from continuous exposure(25μmol/L)to 5-FU for 20 wk in 5-FU sensitive HCT-116 cells.The proliferation and expression of different representative apoptosis and anti-apoptosis markers in 5-FU sensitive and 5-FU resistance cells were measured by the MTT assay and by Western blotting,respectively,after treatment with Resveratrol(Res)and/or 1,3-Bis(2-chloroethyl)-1-nitrosourea(BCNU).Apoptosis and cell cycle arrest was measured by 4’,6’-diamidino-2-phenylindole hydrochloride staining and fluorescence-activated cell sorting analysis,respectively.The extent of DNA damage was measured by the Comet assay.We measured the visible changes in the DNA damage/repair cascade by Western blotting.RESULTS:The widely used chemotherapeutic agents BCNU and Res decreased the growth of 5-FU sensitive HCT-116 cells in a dose dependent manner.Combined application of BCNU and Res caused more apoptosis in5-FU sensitive cells in comparison to individual treatment.In addition,the combined application of BCNU and Res caused a significant decrease of major DNA base excision repair components in 5-FU sensitive cells.We established a 5-FU resistance cell line(5-FU-R)from 5-FU-sensitive HCT-116(mismatch repair deficient)cells that was not resistant to other chemotherapeutic agents(e.g.,BCNU,Res)except 5-FU.The 5-FU resistance of 5-FU-R cells was assessed by exposure to increasing concentrations of 5-FU followed by the MTT assay.There was no significant cell death noted in5-FU-R cells in comparison to 5-FU sensitive cells after5-FU treatment.This resistant cell line overexpressed anti-apoptotic[e.g.,AKT,nuclear factorκB,FLICE-like inhibitory protein),DNA repair(e.g.,DNA polymerase beta(POL-β),DNA polymerase eta(POLH),protein Flap endonuclease 1(FEN1),DNA damage-binding protein 2(DDB2)]and 5-FU-res     

Faster Rate of Initial Fluid Resuscitation in Severe Acute Pancreatitis Diminishes In-Hospital Mortality

Background/Aims:We evaluated the impact of the initial intravenous fluid resuscitation rate within the first 24 h of presentation to the emergency room on important outcomes in severe acute pancreatitis. Methods: Patients presenting directly with a diagnosis of severe acute pancreatitis were identified retrospectively. Patients were divided into two groups — those who received ≥.33% (‘early resuscitation’) and <33% (‘late resuscitation’) of their cumulative 72-hour intravenous fluid volume within the first 24 h of presentation.The primary clinical outcomes were in-hospital mortality, development of persistent organ failure, and duration of hospitalization. Results: 17 patients were identified in the ‘early resuscitation’ group and 28 in the ‘late resuscitation’ group and there were no baseline differences in clinical characteristics between groups. Patients in the ‘late resuscitation’ group experienced greater mortality than those in the ‘early resuscitation’ group (18 vs. 0%,p<0.04) and demonstrated a trend toward greater rates of persistent organ failure (43 vs. 35%, p = 0.31). There was no difference in the total amount of fluid given during the first 72 h. Conclusions: Patients with severe acute pancreatitis who do not receive at least one third of their initial 72-hour cumulative intravenous fluid volume during the first 24 h are at riskfor greater mortality than those who are initially resuscitated more aggressively.