Circumvention of multidrug resistance by a quinoline derivative, MS-209, in multidrug-resistant human small-cell lung cancer cells and its synergistic interaction with cyclosporin A or verapamil

Purpose and methods: To develop a clinically useful approach to circumvent P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MDR human small-cell lung cancer (SCLC), we examined the ability of a novel quinoline compound, MS-209, to reverse MDR by inhibition of P-gp function in combination with other MDR-reversing drugs using a cytotoxicity assay. Results: We established MDR human SCLC cells by culture in medium with gradually increasing concentrations of adriamycin (ADM). Compared with the parental human SCLC cells, SBC-3, the MDR variant SBC-3 cells obtained (SBC-3/ADM) were highly resistant to various chemotherapeutic agents due to P-gp expression. MS-209 reversed the resistance to ADM and vincristine (VCR) of SBC-3/ADM and H69/VP cells in a dose-dependent manner. Moreover, MS-209 in combination with cyclosporin A (CsA) or verapamil (VER) synergistically enhanced the antitumor effects of ADM and VCR on SBC-3/ADM cells. MS-209 restored ADM incorporation and this effect was enhanced by CsA and VER, suggesting that these synergistic effects were due to competitive inhibition of P-gp function. Conclusion: MS-209 in combination with CsA or VER might increase the efficacy of these chemotherapeutic agents against MDR human SCLC cells. Received: 10 December 1997 / Accepted: 16 April 1998     

The neurotoxic effect of astrocytes activated with toll-like receptor ligands

Toll-like receptors (TLRs) are key molecules in the innate immune system in the central nervous system. Although astrocytes are believed to play physiological roles in regulating neuronal activity and synaptic transmission, activated astrocytes may also be toxic to neurons. Here, we show that the ligands for TLRs 2, 4, 5 and 6 induce neuronal cell death in neuron–astrocytes co-cultures through the production of reactive oxygen species (ROS). Inhibition of ROS production by NADPH oxidase inhibitor apocynin significantly suppresses neuronal cell death. ROS induced in astrocytes via TLRs may be involved in neuroinflammation and a therapeutic target for neurotoxicity by activated astrocytes.     

Proving the robustness of a PEDOT:PSS-based thermistor via functionalized graphene oxide–poly(vinylidene fluoride) composite encapsulation for food logistics

The instability of poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) under a humid condition is the major limitation in the practical development of a flexible thermistor. Here, we introduced a functionalized graphene oxide–polyvinylidene fluoride (FGO–PVDF) composite as an encapsulation layer to prove the reliability of PEDOT:PSS thermistors under high-humidity conditions. The FGO–PVDF-encapsulated thermistor exhibited good linearity, a resolution of 1272.57 Ω per °C, a temperature coefficient of resistance equal to −3.95 × 10⁻³ per °C, stable performance, and an acceptable response time (∼40 s per °C) calibrated in the temperature range between −10 °C and 30 °C, resembling the temperature of a cold chain system. For applications in a food cold chain system, this thermistor was integrated into a roll-to-roll (R2R) gravure-printed NFC antenna, a microcontroller-embedded Si-chip transponder, and a printed battery to work as a smart label to wirelessly monitor the time–temperature history (TTH) of a food package. A proof-of-concept study was demonstrated by attaching an NFC-enabled hybrid TTH logger, a smart label, in a chicken package.

We introduced a FGO–PVDF composite as an encapsulation layer to prove the reliability of PEDOT:PSS thermistors under high-humidity conditions to realize an NFC-enabled smart label for monitoring time-temperature history of a food item along the cold chain.     

Comparison of acute physiology and chronic health evaluation II and acute physiology and chronic health evaluation IV to predict intensive care unit mortality

Context:

Clinical assessment of severity of illness is an essential component of medical practice to predict the outcome of critically ill-patient. Acute Physiology and Chronic Health Evaluation (APACHE) model is one of the widely used scoring systems.

Aims:

This study was designed to evaluate the Performance of APACHE II and IV scoring systems in our Intensive Care Unit (ICU).

Settings and Design:

A prospective study in 6 bedded ICU, including 76 patients all above 15 years.

Subjects and Methods:

APACHE II and APACHE IV scores were calculated based on the worst values in the first 24 h of admission. All enrolled patients were followed, and outcome was recorded as survivors or nonsurvivors.

Statistical Analysis Used:

SPSS version 17.

Results:

The mean APACHE score was significantly higher among nonsurvivors than survivors (P < 0.005). Discrimination for APACHE II and APACHE IV was fair with area under receiver operating characteristic curve of 0.73 and 0.79 respectively. The cut-off point with best Youden index for APACHE II was 17 and for APACHE IV was 85. Above cut-off point, mortality was higher for both models (P < 0.005). Hosmer–Lemeshow Chi-square coefficient test showed better calibration for APACHE II than APACHE IV. A positive correlation was seen between the models with Spearman''s correlation coefficient of 0.748 (P < 0.01).

Conclusions:

Discrimination was better for APACHE IV than APACHE II model however Calibration was better for APACHE II than APACHE IV model in our study. There was good correlation between the two models observed in our study.     

Nature,timing, and severity of complications from ultrasound‐guided percutaneous renal transplant biopsy

We sought to review our kidney transplant biopsy experience to assess the incidence, type, presenting symptoms, and timing of renal transplant biopsy complications, as well as determine any modifiable risk factors for postbiopsy complications. This is an observational analysis of patients at the University of Wisconsin between January 1, 2000, and December 31, 2009. Patients with an INR ≥1.5 or platelet counts less than 50 000 were not biopsied. An 18‐gauge needle was used for biopsy. Over the study period, 3738 biopsies were performed with 66 complications (1.8%). No deaths occurred. A total of 0.7% were mild complications, 0.7% were moderate complications, 0.21% were severe complications, and 0.19% were life‐threatening. Most complications occurred within the 4‐h postbiopsy period, although serious complications were often delayed: 67% of complications requiring surgical intervention presented greater than 4 h after biopsy. Biopsy within 1 week of transplant had a 311% increased risk of a complication. Postbiopsy reduction in hematocrit and hemoglobin at 4 h was associated with a complication. In conclusion, life‐threatening complications after renal allograft biopsy occurred in 0.19% of patients. Most complications occurred within 4 h postprocedure; however, many serious complications occurred with a time delay after initially uneventful monitoring. The only clinically significant laboratory predictor of a complication was a fall in the hematocrit or hemoglobin within 4 h. Patients biopsied within a week of transplant were at the highest risk for a complication and should therefore be most closely monitored.     

Lipid lowering in dialysis patients with cardiovascular disease who are awaiting kidney transplantation

Dyslipidemias are highly prevalent in chronic kidney disease, end‐stage renal disease, and kidney transplant patients. These dyslipidemias are associated with high cardiovascular risk and mortality. Many clinical trials have shown that statin therapy can significantly reduce adverse cardiovascular events in chronic kidney disease patients and kidney transplant recipients. However, three major trials did not show a benefit of statin therapy in end‐stage renal disease patients on dialysis. Major guidelines either recommend against the use of statins in patients on dialysis or provide no recommendations about statin use for this complex patient population. As a result, we suspect many patients on dialysis are not on statins, even if they have known atherosclerotic cardiovascular disease. When these patients receive kidney transplants, the risk of adverse cardiovascular events increases in the peri‐operative period. Although there are no randomized clinical trials looking at statin use in these patients, we suggest that statin use be considered in patients with a history of atherosclerotic cardiovascular disease, to potentially minimize peri‐operative cardiovascular complications. We also recommend further research to determine whether statin therapy in dialysis patients awaiting kidney transplant is associated with better survival.     

Concurrent biopsies of both grafts in recipients of simultaneous pancreas and kidney demonstrate high rates of discordance for rejection as well as discordance in type of rejection – a retrospective study

It is commonly assumed that in simultaneous pancreas and kidney (SPK) recipients, rejection of the two organs is concordant. As a result, concurrent biopsies of both organs are rarely performed and there are limited histological data on how often rejection is in fact discordant. We reviewed all SPK recipients transplanted at the University of Wisconsin between January 01, 2001, and December 31, 2016, that underwent biopsy of both organs. We included all patients whose biopsies were within 30 days. If patients were treated for rejection between biopsies, they were excluded if the biopsies were more than 4 days apart. Ninety‐one simultaneous biopsies were performed within 30 days of each other, and 40 met our inclusion criteria. A total of 25 (62.5%) patients had concordance of biopsy findings: 11 had rejection of both organs, and 14 had no rejection of either organ. The other 15 (37.5%) were discordant for rejection, with 10 having pancreas‐only rejection and five kidney‐only rejection. It was striking to find that four of the 11 patients with concordance for rejection (36%) had different types (AMR, ACR, or mixed) of rejection in the two organs. This large series of simultaneous pancreas and kidney biopsies demonstrates the continued utility of performing biopsies of both organs.