Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment.

Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events

Terahertz Kerr effect

We have observed optical birefringence in liquids induced by single-cycle terahertz pulses with field strengths exceeding 100 kV/cm. The induced change in polarization is proportional to the square of the terahertz electric field. The time-dependent terahertz Kerr signal is composed of a fast electronic response that follows the individual cycles of the electric field and a slow exponential response associated with molecular orientation.United States. Office of Naval Research (ONR Grant. No. N00014–06–1–0459

Trace element and stable isotope analyses of deep sea fish from the Sulu sea, Philippines

Thirty-five deep sea fishes belonging to 22 species and one unidentified specimen obtained from the Sulu Sea, located in the southwestern area of the Philippines were analyzed in the late 2002, for 23 trace elements using ICP-MS, HGAAS and CV-AAS. Predominant accumulation of strontium (Sr) was observed in all the samples. This stems from the fact that the whole body of fish was homogenized since Sr is known to accumulate in bones and hard tissues. Mercury concentrations in all the 36 samples were below the detection limit. Cadmium concentrations were generally below 1ìg/g dry weight (dw) except in Pterygotrigla spp. (4.29 ìg/g dw) and Sternoptyx pseudodiaphana (2.89 ìg/g dw). Concentrations of Pb were predominantly low with about 90% of the specimens having less than 1 ìg/g dw. In general, concentrations of Sr, Zn, Cu, Se and Cd appeared to increase with increasing depth of occurrence of the species.Manganese, Tl, Pb, Bi, In, Cs and As showed significant positive correlation (p < 0.05) with d15N, suggesting that these elements were biomagnified. To our knowledge, this is the first study reporting Tl biomagnification in fish. Rubidium and Cs showed significant positive correlation with d13C, implying that Rb and Cs would originate from offshore waters as oceanic plankton has high d13C. Comparing results from this study to the dietary standards and guidelines for Hg, Pb, Cu and Zn in fish and shellfish of the Ministry of Agriculture, Fisheries and Food of the United Kingdom,these levels were not high to warrant concern if they were to be consumed by humans. However, 16.7% of the fish samples had high Cr levels when compared with the Hong Kong’s safe limit of 4 ìg/g dw for Cr in sea food. This constitutes a health risk to humans, as Cr is potentially toxic

Trial Protocol: Randomised controlled trial of the effects of very low calorie diet, modest dietary restriction, and sequential behavioural programme on hunger, urges to smoke, abstinence and weight gain in overweight smokers stopping smoking

Background\ud Weight gain accompanies smoking cessation, but dieting during quitting is controversial as hunger may increase urges to smoke. This is a feasibility trial for the investigation of a very low calorie diet (VLCD), individual modest energy restriction, and usual advice on hunger, ketosis, urges to smoke, abstinence and weight gain in overweight smokers trying to quit. \ud \ud Methods\ud This is a 3 armed, unblinded, randomized controlled trial in overweight (BMI > 25 kg/$m^2$), daily smokers (CO > 10 ppm); with at least 30 participants in each group. Each group receives identical behavioural support and NRT patches (25 mg(8 weeks),15 mg(2 weeks),10 mg(2 weeks)). The VLCD group receive a 429-559 kcal/day liquid formula beginning 1 week before quitting and continuing for 4 weeks afterwards. The modest energy restricted group (termed individual dietary and activity planning(IDAP)) engage in goal-setting and receive an energy prescription based on individual basal metabolic rate(BMR) aiming for daily reduction of 600 kcal. The control group receive usual dietary advice that accompanies smoking cessation i.e. avoiding feeling hungry but eating healthy snacks. After this, the VLCD participants receive IDAP to provide support for changing eating habits in the longer term; the IDAP group continues receiving this support. The control group receive IDAP 8 weeks after quitting. This allows us to compare IDAP following a successful quit attempt with dieting concurrently during quitting. It also aims to prevent attrition in the unblinded, control group by meeting their need for weight management. Follow-up occurs at 6 and 12 months. \ud \ud Outcome measures include participant acceptability, measured qualitatively by semi-structured interviewing and quantitatively by recruitment and attrition rates. Feasibility of running the trial within primary care is measured by interview and questionnaire of the treatment providers. Adherence to the VLCD is verified by the presence of urinary ketones measured weekly. Daily urges to smoke, hunger and withdrawal are measured using the Mood and Physical Symptoms Scale-Combined (MPSS-C) and a Hunger Craving Score (HCS). 24 hour, 7 day point prevalence and 4-week prolonged abstinence (Russell Standard) is confirmed by CO < 10 ppm. Weight, waist and hip circumference and percentage body fat are measured at each visit. \ud \ud Trial Registration\ud Current controlled trials ISRCTN83865809\ud \u

Transmembrane helix dynamics of bacterial chemoreceptors supports a piston model of signalling.

Transmembrane α-helices play a key role in many receptors, transmitting a signal from one side to the other of the lipid bilayer membrane. Bacterial chemoreceptors are one of the best studied such systems, with a wealth of biophysical and mutational data indicating a key role for the TM2 helix in signalling. In particular, aromatic (Trp and Tyr) and basic (Arg) residues help to lock α-helices into a membrane. Mutants in TM2 of E. coli Tar and related chemoreceptors involving these residues implicate changes in helix location and/or orientation in signalling. We have investigated the detailed structural basis of this via high throughput coarse-grained molecular dynamics (CG-MD) of Tar TM2 and its mutants in lipid bilayers. We focus on the position (shift) and orientation (tilt, rotation) of TM2 relative to the bilayer and how these are perturbed in mutants relative to the wildtype. The simulations reveal a clear correlation between small (ca. 1.5 Å) shift in position of TM2 along the bilayer normal and downstream changes in signalling activity. Weaker correlations are seen with helix tilt, and little/none between signalling and helix twist. This analysis of relatively subtle changes was only possible because the high throughput simulation method allowed us to run large (n = 100) ensembles for substantial numbers of different helix sequences, amounting to ca. 2000 simulations in total. Overall, this analysis supports a swinging-piston model of transmembrane signalling by Tar and related chemoreceptors

Phase II study of weekly oxaliplatin and 24-h infusion of high-dose 5-fluorouracil and folinic acid in the treatment of advanced gastric cancer

[[abstract]]To investigate the efficacy and safety of combining weekly oxaliplatin with weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and folinic acid ( FA) in treatment of patients with advanced gastric cancer. Patients with histologically confirmed, locally advanced or recurrent/metastatic gastric cancer were studied. Oxaliplatin 65 mg m(-2) 2-h intravenous infusion, and 5-FU 2600 mg m(-2) plus FA 300 mg m(-2) 24-h intravenous infusion, were given on days 1 and 8, repeated every 3 weeks. Between January 2001 through January 2002, 55 patients were enrolled. The median age was 64 years (range: 22-75). In all, 52 patients (94.5%) had recurrent or metastatic disease and three patients had locally advanced disease. Among 50 patients evaluable for tumour response, 28 patients achieved partial response, with an overall response rate of 56% (95% confidence interval (CI): 41.8-70.3%). All 55 patients were evaluated for survival and toxicities. Median time to progression and overall survival were 5.2 and 10.0 months, respectively, during median follow-up time of 24.0 months. Major grades 3-4 toxicities were neutropenia in 23 cycles (7.1%) and thrombocytopenia in 16 cycles (5.0%). Treatment was discontinued for treatment-related toxicities in nine patients (16.4%), of whom eight were due to oxaliplatin-related neurotoxicity. One patient (1.8%) died of neutropenic sepsis. This oxaliplatin-containing regimen is effective in the treatment of advanced gastric cancer. Except for neurotoxicity that often develops after prolonged use of oxaliplatin, the regimen is well tolerated

Endoscopic treatment of prepatellar bursitis

Operative treatment of prepatellar bursitis is indicated in intractable bursitis. The most common complication of surgical treatment for prepatellar bursitis is skin problems. For traumatic prepatellar bursitis, we propose a protocol of outpatient endoscopic surgery under local anaesthesia. From September 1996 to February 2001, 60 cases of failed nonoperative treatment for prepatellar bursitis were included. The average age was 33.5 ± 11.1 years (range 21–55). The average operation duration was 18 minutes. Two to three mini-arthroscopic portals were used in our series. No sutures or a simple suture was needed for the portals after operation. After follow-up for an average of 36.3 months, all patients are were symptom-free and had regained knee function. None of the population had local tenderness or hypo-aesthesia around their wound. Their radiographic and sonographic examinations showed no recurrence of bursitis. Outpatient arthroscopic bursectomy under local anaesthesia is an effective procedure for the treatment of post-traumatic prepatellar bursitis after failed conservative treatments. Both the cosmetic results and functional results were satisfactory

Risk Factors of Peritoneal Recurrence and Outcome of Resected Peritoneal Recurrence After Liver Resection in Hepatocellular Carcinoma: Review of 1222 Cases of Hepatectomy in a Tertiary Institution

10.1245/s10434-012-2260-3Annals of Surgical Oncology1972246-225

Reversion-induced LIM interaction with Src reveals a novel Src inactivation cycle

Aberrant Src activation plays prominent roles in cancer progression. However, how Src is activated in cancer cells is largely unknown. Genetic Src-activating mutations are rare and, therefore, are insufficient to account for Src activation commonly found in human cancers. In this study, we show that reversion-induced LIM (RIL), which is frequently lost in colon and other cancers as a result of epigenetic silencing, suppresses Src activation. Mechanistically, RIL suppresses Src activation through interacting with Src and PTPL1, allowing PTPL1-dependent dephosphorylation of Src at the activation loop. Importantly, the binding of RIL to Src is drastically reduced upon Src inactivation. Our results reveal a novel Src inactivation cycle in which RIL preferentially recognizes active Src and facilitates PTPL1-mediated inactivation of Src. Inactivation of Src, in turn, promotes dissociation of RIL from Src, allowing the initiation of a new Src inactivation cycle. Epigenetic silencing of RIL breaks this Src inactivation cycle and thereby contributes to aberrant Src activation in human cancers