Association of aggressive behavior with altered serotonergic function in patients who are not suicidal

OBJECTIVE: The purpose of this study was to determine whether aggression and serotonergic dysfunction are related in the absence of a history of suicidal behavior. Although serotonergic dysfunction has been implicated in aggressive and impulsive behavior, most studies of such behavior have included individuals with a history of suicide attempts. Low concentrations of CSF 5-hydroxyindoleacetic acid (5-HIAA) have been consistently associated with suicidal behavior, presenting a potential confound in the link between aggression and serotonergic dysfunction. METHOD: The authors examined the association between aggression and CSF 5-HIAA concentrations in a group of 64 patients who had different DSM-III-R axis I diagnoses and no past suicidal behavior. Aggressive (N=35) and nonaggressive (N=29) groups were defined by a median split on a six-item history of adulthood aggressive behavior. RESULTS: The aggressive group had significantly lower CSF 5-HIAA concentrations than the nonaggressive group. Aggressive individuals also scored significantly higher on self-report measures of hostility, impulsiveness, and sensation seeking. CSF 5-HIAA concentrations, however, did not correlate with self-reported hostility and impulsivity. CONCLUSIONS: There is an association between aggressive behavior and serotonergic dysfunction independent of suicidal behavior in patients with axis I disorders who exhibit relatively milder forms of aggressive behavior. Analogous to findings with suicidal behavior, a low concentration of CSF 5-HIAA is related to aggressive behavior but does not show the same relationship to the continuum of aggressive feelings and thoughts.     

Exploring the decision-making preferences of people with colorectal cancer

OBJECTIVES: To explore patient views on participation in treatment, physical care and psychological care decisions and factors that facilitate and hinder patients from making decisions. DESIGN: Qualitative study using semi-structured interviews with patients. SETTING AND PARTICIPANTS: Three NHS Trusts in the north-west of England. Theoretical sampling including 41 patients who had been treated for colorectal cancer. RESULTS: For patients, participation in the decision-making process was about being informed and feeling involved in the consultation process, whether patients actually made decisions or not. The perceived availability of treatment choices (surgery, radiotherapy, chemotherapy) was related to type of treatment. Factors that impacted on whether patients wanted to make decisions included a lack of information, a lack of medical knowledge and trust in medical expertise. Patients perceived that they could have a more participatory role in decisions related to physical and psychological care. CONCLUSION: This study has implications for health professionals aiming to implement policy guidelines that promote patient participation and shared partnerships. Patients in this study wanted to be well informed and involved in the consultation process but did not necessarily want to use the information they received to make decisions. The presentation of choices and preferences for participation may be context specific and it cannot be assumed that patients who do not want to make decisions about one aspect of their care and treatment do not want to make decisions about other aspects of their care and treatment.     

Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites.

Bortezomib [N-(2,3-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid] is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor that was approved in May 2003 in the United States for the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy. Bortezomib binds the proteasome via the boronic acid moiety, and therefore, the presence of this moiety is necessary to achieve proteasome inhibition. Metabolites in plasma obtained from patients receiving a single intravenous dose of bortezomib were identified and characterized by liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Metabolite standards that were synthesized and characterized by LC/MS/MS and high field nuclear magnetic resonance spectroscopy (NMR) were used to confirm metabolite structures. The principal biotransformation pathway observed was oxidative deboronation, most notably to a pair of diastereomeric carbinolamide metabolites. Further metabolism of the leucine and phenylalanine moieties produced tertiary hydroxylated metabolites and a metabolite hydroxylated at the benzylic position, respectively. Conversion of the carbinolamides to the corresponding amide and carboxylic acid was also observed. Human liver microsomes adequately modeled the in vivo metabolism of bortezomib, as the principal circulating metabolites were observed in vitro. Using cDNA-expressed cytochrome P450 isoenzymes, it was determined that several isoforms contributed to the metabolism of bortezomib, including CYP3A4, CYP2C19, CYP1A2, CYP2D6, and CYP2C9. The development of bortezomib has provided an opportunity to describe the metabolism of a novel boronic acid pharmacophore.     

Neuroprotective and symptomatological action of memantine relevant for alzheimer’s disease — a unified glutamatergic hypothesis on the mechanism of action

The involvement of glutamate mediated neurotoxicity in the pathogenesis of Alzheimer's disease is finding increasingly more acceptance in the scientific community. Central to this hypothesis is the assumption that in particular glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner. Such continuous mild activation leads under chronic conditions to neuronal damage. Moreover, one should consider that impairment of plasticity (learning) may result not only from neuronal damage per se but also from continuous activation of NMDA receptors. To investigate this possibility we tested whether overactivation of NMDA receptors using either non-toxic doses/concentrations of a direct NMDA agonist or through an indirect approach--decrease in magnesium concentration--produces deficits in plasticity. In fact NMDA both in vivo (passive avoidance test) and in vitro (LTP in CA1 region) impaired learning and synaptic plasticity. Under these conditions memantine which is an uncompetitive NMDA receptor antagonist with features of "improved magnesium" (voltage dependence, affinity) attenuated the deficit. The more direct proof that memantine can act as a surrogate for magnesium was obtained in LTP experiments under low magnesium conditions. In this case as well, impaired LTP was restored in the presence of therapeutically relevant concentrations of memantine (1 microM). In vivo, doses leading to similar brain/serum levels produce neuroprotection in animal models relevant for neurodegeneration in Alzheimer's disease such as neurotoxicity produced by inflammation in the NBM or beta-amyloid injection to the hippocampus. Hence, we postulate that if in Alzheimer's disease overactivation of NMDA receptors occurs indeed, memantine would be expected to improve both symptoms (cognition) and slow down disease progression because it takes over the physiological function of magnesium.     

Design details for overdose education and take‐home naloxone kits: Codesign with family medicine,emergency department,addictions medicine and community

IntroductionOverdose education and naloxone distribution (OEND) programmes equip and train people who are likely to witness an opioid overdose to respond with effective first aid interventions. Despite OEND expansion across North America, overdose rates are increasing, raising questions about how to improve OEND programmes. We conducted an iterative series of codesign stakeholder workshops to develop a prototype for take‐home naloxone (THN)‐kit (i.e., two doses of intranasal naloxone and training on how to administer it).MethodsWe recruited people who use opioids, frontline healthcare providers and public health representatives to participate in codesign workshops covering questions related to THN‐kit prototypes, training on how to use it, and implementation, including refinement of design artefacts using personas and journey maps. Completed over 9 months, the workshops were audio‐recorded and transcribed with visible results of the workshops (i.e., sticky notes, sketches) archived. We used thematic analyses of these materials to identify design requirements for THN‐kits and training.ResultsWe facilitated 13 codesign workshops to identify and address gaps in existing opioid overdose education training and THN‐kits and emphasize timely response and stigma in future THN‐kit design. Using an iterative process, we created 15 prototypes, 3 candidate prototypes and a final prototype THN‐kit from the synthesis of the codesign workshops.ConclusionThe final prototype is available for a variety of implementation and evaluation processes. The THN‐kit offers an integrated solution combining ultra‐brief training animation and physical packaging of nasal naloxone to be distributed in family practice clinics, emergency departments, addiction medicine clinics and community settings.Patient or Public ContributionThe codesign process was deliberately structured to involve community members (the public), with multiple opportunities for public contribution. In addition, patient/public participation was a principle for the management and structuring of the research team.