Collateral sensitivity to nitrosoureas in multidrug-resistant cells selected with verapamil.

We have examined the effects of the nitrosoureas, streptozotocin (STZ) and 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), on a human multiple myeloma cell line, RPMI 8226, and its drug-resistant variants. Cell lines selected for doxorubicin (DOX) resistance alone displayed a STZ and BCNU cytotoxicity profile similar to that of the parent cell line. In contrast, two of the drug-resistant variants selected with DOX plus verapamil, an agent which inhibits P-glycoprotein-mediated multidrug resistance, displayed a collateral sensitivity to STZ and BCNU. Verapamil was included in the selection protocol because it has been shown to inhibit the P-glycoprotein-mediated multidrug resistance phenotype and is now in clinical trials as a chemosensitizing agent. The collateral sensitivity to these nitrosoureas seen in the DOX plus verapamil-selected cell lines is due to the functional loss of a DNA repair molecule, O6-Methylguanine DNA methyltransferase (MGMT). The functional loss of MGMT is secondary to the loss of MGMT gene expression. The loss of MGMT gene expression is not due to loss or gross rearrangement of the MGMT-coding region. If this selection pressure applied in vitro reflects the in vivo situation, then new chemotherapeutic strategies may be devised to exploit this phenomenon. These cell lines will serve as useful models for delineating mechanisms which govern MGMT expression.     

Lessons from the United Kingdom: fightback on workplace hazards, 1979-1992.

For the past 13 years there has been an aggressive anti-union government in the United Kingdom. Yet despite this fact, very real advances have been made in the area of working-class activity over the issue of workplace hazards. Trade unions, because of membership concern and activity, have been forced to keep this topic on their agenda. The European Community has been a big factor in these advances. This article describes some of the issues and elements of the fightback. In the 1990s, with the rediscovery of environmental issues, the hazards movement of the United Kingdom, and elsewhere, is here to stay and set to expand.     

Different mechanisms of decreased drug accumulation in doxorubicin and mitoxantrone resistant variants of the MCF7 human breast cancer cell line.

We selected two drug resistant variants of the MCF7 human breast cancer cell line by chronic in vitro exposure to doxorubicin (MCF7/D40 cell line) and mitoxantrone (MCF7/Mitox cell line), respectively. The cell lines are similar in growth characteristics including doubling time, DNA synthetic phase and cell size. Resistance to mitoxantrone conferred only partial resistance to doxorubicin; whereas resistance selected for doxorubicin appeared to confer complete resistance to mitoxantrone. Both agents selected for cross resistance to the Vinca alkaloids. MCF7/D40 cells display a classic-multi-drug resistance phenotype with expression of P-glycoprotein, decreased drug accumulation relative to the parental line and reversal of drug accumulation and drug resistance by verapamil. MCF7/Mitox cells likewise display resistance to multiple drugs, but in contrast to MCF7/D40 cells do not express P-glycoprotein by immunoblot or RNA blot analysis. Net drug accumulation in MCF7/Mitox cells was decreased relative to the parental cells but there was no selective modulation of drug accumulation or in vitro drug resistance by the addition of verapamil. Efflux of mitoxantrone was enhanced in both the MCF7/D40 and MCF7/Mitox cell lines relative to the MCF7/S cell line. We conclude that the two drug resistant cell lines have different mechanisms of decreased drug accumulation.     

Safer, more expensive iodinated contrast agents: how do we decide?

The advantages of the new, safer, but more expensive iodinated contrast agents are discussed, and opinions on which patient groups should receive the agents are presented.     

Enterovesical fistula secondary to mucinous adenocarcinoma of appendix

We report an unusual case of an enterovesical fistula secondary to adenocarcinoma of the appendix.     

Delayed Haemolytic Transfusion Reaction Due to Simultaneous Appearance of Anti-Fya and Anti-Fy5

We report here the development of anti-Fy5 in a young Negro female with sickle cell disease. The antibody was responsible for a delayed hemolytic transfusion reaction. We believe this is the first report of such an antibody in Europe.     

抗胆碱药3-(2-苯基-2-环戊基-2-羟基-乙氧基)奎宁环烷的立体化学和构效关系

研究了强效抗胆碱药dl-3-(2-苯基-2-环戊基-2-羟基-乙氧基)-奎宁环烷的四个光学异构体的两种不对称合成方法,用HPLC检测了异构体含量,讨论了构效关系。     

Acoustic myography of the human quadriceps muscle during intermittent fatiguing activity.

Integrated acoustic myography (IAMG) and electromyography (IEMG) were recorded over rectus femoris (RF) in six healthy subjects during a series of intermittent isometric contractions of quadriceps. Contractions were held for 10 sec with 10 sec rest between each, commencing at 75% maximum voluntary contraction (MVC) force and continuing to 40% MVC. The IAMG activity initially decreased (75%-60% MVC) in a linear relationship (r = 0.9) with fatigue (i.e. force loss) but then plateaued and increased once force fell below 52% MVC. The AMG/force relationship for the whole fatiguing protocol (i.e. 75%-40% MVC) was quadratic (r = 0.87). The IEMG also showed a quadratic relationship with force (r = 0.85) but activity initially increased before decreasing. The results of the present study quantify the relationship between AMG and force in quadriceps during fatigue from intermittent contractions commencing at 75% MVC. The findings confirm previous observations that AMG decreases with fatigue during strong contractions but the quadratic relationship found in the present study differs to that for other muscles during sustained contractions. The results also suggest that simultaneous recordings of AMG and EMG may help distinguish central and peripheral fatigue. Acoustic myography may therefore be a useful non-invasive monitor of force during early fatiguing activity using the present protocol but the need to study AMG during fatigue of different muscles and force levels is stressed.     

Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat

The purposes of this study were (1) to document the histopathological consequences of moderate traumatic brain injury (TBI) in anesthetized Sprague-Dawley rats, and (2) to determine whether posttraumatic brain hypothermia (30°C) would protect histopathologically. Twenty-four hours prior to TBI, the fluid percussion interface was positioned over the right cerebral cortex. On the 2nd day, fasted rats were anesthetized with 70% nitrous oxide, 1% halothane, and 30% oxygen. Under controlled physiological conditions and normothermic brain temperature (37.5°C), rats were injured with a fluid percussion pulse ranging from 1.7 to 2.2 atmospheres. In one group, brain temperature was maintained at normothermic levels for 3 h after injury. In a second group, brain temperature was reduced to 30°C at 5 min post-trauma and maintained for 3 h. Three days after TBI, brains were perfusion-fixed for routine histopathological analysis. In the normothermic group, damage at the site of impact was seen in only one of nine rats. In contrast, all normothermic animals displayed necrotic neurons within ipsilateral cortical regions lateral and remote from the impact site. Intracerebral hemorrhagic contusions were present in all rats at the gray-white interface underlying the injured cortical areas. Selective neuronal necrosis was also present within the CA3 and CA4 hippocampal subsectors and thalamus. Post-traumatic brain hypothermia significantly reduced the overall sum of necrotic cortical neurons (519±122 vs 952±130, mean ±SE, P=0.03, Kruskal-Wallis test) as well as contusion volume (0.50±0.14 vs 2.14±0.71 mm³, P=0.004). These data document a consistent pattern of histopathological vulnerability following normothermic TBI and demonstrate hypothermic protection in the post-traumatic setting.Supported by USPHS Grants NS30291 and NS27127