'Special K' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells: modulation of the adherens junction complex by ketamine

Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention

Vitamin B12 measurements across neurodegenerative disorders.

Background:Vitamin B12 deficiency causes a number of neurological features including cognitive and psychiatric disturbances, gait instability, neuropathy, and autonomic dysfunction. Clinical recognition of B12 deficiency in neurodegenerative disorders is more challenging because it causes defects that overlap with expected disease progression. We sought to determine whether B12 levels at the time of diagnosis in patients with Parkinson's disease (PD) differed from those in patients with other neurodegenerative disorders. Methods:We performed a cross-sectional analysis of B12 levels obtained around the time of diagnosis in patients with PD, Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB), Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), Frontotemporal Dementia (FTD), or Mild Cognitive Impairment (MCI). We also evaluated the rate of B12 decline in PD, AD, and MCI. Results:In multivariable analysis adjusted for age, sex, and B12 supplementation, we found that B12 levels were significantly lower at time of diagnosis in patients with PD than in patients with PSP, FTD, and DLB. In PD, AD, and MCI, the rate of B12 decline ranged from - 17 to - 47 pg/ml/year, much greater than that reported for the elderly population. Conclusions:Further studies are needed to determine whether comorbid B12 deficiency affects progression of these disorders

Trapped radiation experiment

Trapped radiation detector on Mariner IV space probe measurement of outer Van Allen belt - feasibility of detecting trapped radiation at Mar

Calcium-sensing receptor activation increases cell-cell adhesion and ß-cell function

Background/Aims: The extracellular calcium-sensing receptor (CaR) is expressed in pancreatic β-cells where it is thought to facilitate cell-to-cell communication and augment insulin secretion. However, it is unknown how CaR activation improves β-cell function. Methods: Immunocytochemistry and western blotting confirmed the expression of CaR in MIN6 β-cell line. The calcimimetic R568 (1µM) was used to increase the affinity of the CaR and specifically activate the receptor at a physiologically appropriate extracellular calcium concentration. Incorporation of 5-bromo-2’-deoxyuridine (BrdU) was used to measure cell proliferation, whilst changes in non-nutrient-evoked cytosolic calcium were assessed using fura-2-microfluorimetry. AFM-single-cell-force spectroscopy related CaR-evoked changes in epithelial (E)-cadherin expression to improved functional tethering between coupled cells. Results: Activation of the CaR over 48hr doubled the expression of E-cadherin (206±41%) and increased L-type voltage-dependent calcium channel expression by 70% compared to control. These changes produced a 30% increase in cell-cell tethering and elevated the basal-to-peak amplitude of ATP (50µM) and tolbutamide (100µM)-evoked changes in cytosolic calcium. Activation of the receptor also increased PD98059 (1-100µM) and SU1498 (1-100µM)-dependent β-cell proliferation. Conclusion: Our data suggest that activation of the CaR increases E-cadherin mediated functional tethering between β-cells and increases expression of L-type VDCC and secretagogue-evoked changes in [Ca2+]i. These findings could explain how local changes in calcium, co-released with insulin, activate the CaR on neighbouring cells to help ensure efficient and appropriate secretory function

Launch summary for 1978 - 1982

Data pertinent to the launching of space probes, soundings rockets, and satellites presented in tables include launch date, time, and site; agency rocket identification; sponsoring country or countries; instruments carried for experiments; the peak altitude achieved by the rockets; and the apoapsis and periapsis for satellites. The experimenter or institution involved in the launching is also cited

Investigation of energetic electron intensities in the earth's outer radiation zone with OGO 1

OGO outer zone observational data on electron intensities of earth geomagnetic fiel

Development of a fretting-fatigue mapping concept: The effect of material properties and surface treatments

Fretting-fatigue induced by combined localized cyclic contact motion and external bulk fatigue loadings may result in premature and dramatic failure of the contacting components. Depending on fretting and fatigue loading conditions, crack nucleation and possibly crack propagation can be activated. This paper proposes a procedure for estimating these two damage thresholds. The crack nucleation boundary is formalized by applying the Crossland high cycle fatigue criterion, taking into account the stress gradient and the ensuing #size##effect#. The prediction of the crack propagation condition is formalized using a short crack arrest description. Applied to an AISI 1034 steel, this methodology allows the development of an original material response fretting-fatigue map (FFM). The impact of material properties and surface treatments is investigated

ALMA Temporal Phase Stability and the Effectiveness of Water Vapor Radiometer

Atacama Large Millimeter/submillimeter Array (ALMA) will be the world largest mm/submm interferometer, and currently the Early Science is ongoing, together with the commissioning and science verification (CSV). Here we present a study of the temporal phase stability of the entire ALMA system from antennas to the correlator. We verified the temporal phase stability of ALMA using data, taken during the last two years of CSV activities. The data consist of integrations on strong point sources (i.e., bright quasars) at various frequency bands, and at various baseline lengths (up to 600 m). From the observations of strong quasars for a long time (from a few tens of minutes, up to an hour), we derived the 2-point Allan Standard Deviation after the atmospheric phase correction using the 183 GHz Water Vapor Radiometer (WVR) installed in each 12 m antenna, and confirmed that the phase stability of all the baselines reached the ALMA specification. Since we applied the WVR phase correction to all the data mentioned above, we also studied the effectiveness of the WVR phase correction at various frequencies, baseline lengths, and weather conditions. The phase stability often improves a factor of 2 - 3 after the correction, and sometimes a factor of 7 improvement can be obtained. However, the corrected data still displays an increasing phase fluctuation as a function of baseline length, suggesting that the dry component (e.g., N2 and O2) in the atmosphere also contributes the phase fluctuation in the data, although the imperfection of the WVR phase correction cannot be ruled out at this moment.Comment: Proc. SPIE 8444-125, in press (7 pages, 4 figures, 1 table

No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML 10 and 12 trials

Fetal liver tyrosine kinase 3 (FLT3) internal tandem duplications (ITDs) are powerful adverse prognostic indicators for relapse in acute myelold leukemia (AML) but the most efficacious therapy for FLT3/ ITD+ patients is currently unknown. We evaluated outcome according to FLT3/ITD status in 1135 adult patients treated according to United Kingdom Medical Research Council (UK MRC) AML protocols: 141 received an autograft, and 170 received a matched sibling allograft in first complete remission (CR). An FLT3/ITD was detected in 25% of patients and was an independent predictor for relapse (P < .001). It remained prognostic for increased relapse in patients who received a transplant (odds ratio [OR] = 1.91; 95% confidence intervals [CIs] 1.13-3.21; P = .02), with no evidence of a difference in effect between patients who received an autograft (OR = 2.39; CIs = 1.24-4.62) and patients who received an allograft (OR = 1.31; CIs = 0.56-3.06) (test for interaction, P = .3) or between patients who did or did not receive a transplant (P = .4). These results were confirmed in an analysis of 186 patients randomized to receive or not receive an autograft in first CR and in a donor-versus-no donor analysis of 683 patients to assess the role of allograft (for latter, FLT3/ITD- OR = 0.70, CIs = 0.53-0.92; FLT3/ITD+ OR = 0.59, CIs = 0.40-0.87; test for interaction, P = .5). These results suggest that at present there is no strong evidence that FLT3 status should influence the decision to proceed to transplantation

Establishment and characterization of single and triple‐agent resistant osteosarcoma cell lines

Two human osteosarcoma cell lines (MG-63 and HOS-143B) are developed into drug-resistant models using a short-term drug exposure and recovery in drug-free media. Cisplatin, doxorubicin, and methotrexate are used as single agents and in triple combination. The highest level of resistance to cisplatin is observed in MG-63/CISR8, doxorubicin in HOS-143B/DOXR8, and methotrexate in HOS-143B/MTXR8. The MG-63/TRIR8 and HOS-143B/TRIR8 tripleresistance models show lower levels of resistance to combination treatment and are not resistant to the drugs individually. Apoptosis assays suggest that the resistance in MG-63/TRIR8 isfrom cisplatin and methotrexate and not doxorubicin. In contrast, the resistance in HOS-143B/TRIR8 is from doxorubicin and methotrexate instead of cisplatin. Upregulation of P-glycoprotein is seen in all resistant models except those developed with single-agent methotrexate. However, P-glycoprotein is not causing resistance in all cell lines as the inhibitor elacridar only reverses the resistance of doxorubicin on MG-63/ DOXR8 and HOS-143B/TRIR8. The migration of the MG-63 resistant models is significantly increased, their invasion rate tends to increase, and RT-PCR shows a switch from epithelial to mesenchymal gene signaling. In contrast, a significant decrease in migration is seen in HOS-143B resistant models with their invasion rate tending to decrease and a switch from mesenchymal to epithelial gene signaling