Latest advances and current challenges in the treatment of multiple myeloma

Effectively treating patients with multiple myeloma is challenging. The development of therapeutic regimens over the past decade that incorporate the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has been the cornerstone of improving the outcome of patients with myeloma. Although these treatment regimens have improved patient survival, nearly all patients eventually relapse. Our improved understanding of the biology of the disease and the importance of the microenvironment has translated into ongoing work to help overcome the challenge of relapse. Several classes of agents including next-generation proteasome inhibitors, immunomodulatory agents, selective histone-deacetylase inhibitors, antibody and antitumor immunotherapy approaches are currently undergoing preclinical and clinical evaluation. This Review provides an update on the latest advances in the treatment of multiple myeloma. In particular, we focus on novel therapies including modulating protein homeostasis, kinases inhibitors, targeting accessory cells and cytokines, and immunomodulatory agents. A discussion of the challenges associated with these therapeutic approaches is also presented.     

Imaging the spread of reversible brain inactivations using fluorescent muscimol

Muscimol is a GABA_A-agonist that causes rapid and reversible suppression of neurophysiological activity. Interpretations of the effects of muscimol infusions into the brain have been limited because of uncertainty about spread of the drug around the injection site. To solve this problem, the present study explored the use of a fluorophore-conjugated muscimol molecule (FCM). Whole-cell recordings from horizontal brain slices demonstrated that bath-applied FCM acts like muscimol in reversibly suppressing excitatory synaptic transmission. Two types of in vivo experiments demonstrated that the behavioral effects of FCM infusion are similar to the behavioral effects of muscimol infusion. FCM infusion into the rat amygdala before fear conditioning impaired both cued and contextual freezing, which were tested 24 or 48 h later. Normal fear conditioning occurred when these same rats were subsequently given phosphate-buffered saline infusions. FCM infusion into the dorsomedial prefrontal cortex impaired accuracy during a delayed-response task. Histological analysis showed that the region of fluorescence was restricted to 0.5–1 mm from the injection site. Myelinated fiber tracts acted as diffusional barriers, thereby shaping the overall spread of fluorescence. The results suggest that FCM is indeed useful for exploring the function of small brain regions.     

SAFETY,EFFECTIVENESS AND COST EFFICACY OF DIAGNOSTIC ELECTROPHYSIOLOGY AND RADIOFREQUENCY ABLATION IN A DISTRICT GENERAL HOSPITAL

Electrophysiological studies (EPS) are now being performed in district general hospitals (DGH) in the UK. In order to audit our results, a prospective database was established for all patients undergoing EPS and radiofrequency (RF) ablation at Eastbourne District General Hospital, East Sussex. Between 1 January 1997 and 1 July 2000, 300 EPS procedures were performed, resulting in 155 RF ablations. The average RF ablation procedure time was 119.3 minutes with an average fluoroscopy time of 19.1 minutes. Cost per RF ablation procedure was £1166.79 excluding use of facilities, pacemaker devices, medical nursing and radiography staffing costs. The overall success rate for RF ablation was 93.6% with a major complication rate of 0.6%, a total complication rate of 3.9% and no associated mortality. We have shown that RF ablation can be performed safely, effectively and economically in a DGH setting with a high rate of success and a low complication rate.     

Comparative muscular strength of men and women: a review of the literature.

The results from nine separate studies reporting comparable static and dynamic muscle strength measurements between men and women have been reviewed. The statistical data from these studies are presented in graphical and tabular form illustrating, when appropriate, the mean +/- 1 S.D., and the mean percentage difference between men and women for the given measurement.     

Inducible nitric oxide synthase (iNOS) gene deficiency increases the mortality of sepsis in mice.

BACKGROUND: Nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS or NOS2) has been implicated in the hypotension, organ failure, and death that complicate sepsis. To avoid the confounding effects and limitations of iNOS inhibitors, we used iNOS gene "knockout" mice to examine the effect of inducible NO production in a model of polymicrobial abdominal sepsis treated with antibiotics. We hypothesized that iNOS gene deficiency would significantly alter outcome. METHODS: C57BL6 wild-type (control) and congenic iNOS knockout mice were studied concurrently. Under halothane anesthesia, the ceca were ligated with 4-0 silk suture and punctured twice with a 26-gauge needle (cecal ligation and puncture, CLP). Survival was followed for 7 days, after which necropsies were performed in surviving animals. In an accompanying study examining the acute effects of sepsis, organ injury at 18 hours after CLP as determined by histology and the degree of cell death by apoptosis were examined with the use of hematoxylin and eosin (H&E) and TUNEL staining and two-channel fluorescence-activated cell sorter (FACS) analysis. RESULTS: Sham laparotomy produced no lethality in either knockout (n = 3) or wild-type (n = 3) animals. Compared with survival in controls (n = 20), survival after CLP in iNOS knockout mice (n = 21) was significantly decreased (P < .01 at 2 days, P = .080 at 7 days, Mantel-Haenszel log-rank test). CLP-induced apoptotic cell death was significantly less in the thymus of iNOS knockout mice compared with wild-type mice. CONCLUSIONS: We conclude that iNOS gene function provides a survival benefit in septic mice and is associated with increased sepsis-induced thymocyte apoptosis. To our knowledge, this is the first survival study examining the effect of iNOS gene deficiency in a clinically relevant model of sepsis.     

Informed Consent in Neurosurgery: Patients' Recall of Preoperative Discussion

Summary ? Objective. Informed consent (IC) is an important principle of modern medicine and the quality of the process is likely to receive increasing attention in future due to complex surgical procedures and a development of social mistrust for medical treatment. Medico-legal action is also becoming an important influence on IC, in particular the extent of warning to be given about the degree of risk. Evaluation of IC, however, encounters various problems. One key element of a knowledgeable decision is an analysis based on the disclosed risks. Methods. In a prospective study, 104 consecutive patients were asked to write down as many items of the list of risks as possible two hours after consent interview. The sample included adults (mean age: 52 years) without any significant neuropsychological impairment who underwent elective intracranial (52%) or spinal (48%) surgery. Consent interview based on the proposals of the Deutsche Gesellschaft für Neurochirurgie and the Berufsverband Deutscher Neurochirurgen 1998. The average number of disclosed risks was 32 in intracranial and 25 in spinal surgery. According to the results in the literature 6 ‘typical major risks’ of the proposed treatment were selected. Results. The median value of the total of recalled risks was 4 in the spinal group and 5 in the intracranial group. The mean score of general information retention was 18%. 65% of the patients did not recall more than 2 of 6 ‘typical major risks’. No significant correlation between recall performance and age or education was found. Conclusion. The general principles of memory apply and have implications in states of emotional arousal. Whereas education and age, unlike in previous reports, did not appear to influence recall, thus indicating that we had succeeded in tailoring IC to the individual, recall rate was low in most cases. Physicians should highlight the discrepancy and conflict between the requirements for the defence of medical practice in the law courts and the actual interests of patients. They should promote research to establish what really is ‘appropriately informed consent’.