Kinetics of valproic acid glucuronidation: evidence for in vivo autoactivation.

Sigmoidal or autoactivation kinetics has been observed in vitro for both cytochrome P450- and UDP-glucuronosyltransferase-catalyzed enzymatic reactions. However, the in vivo relevance of sigmoidal kinetics has never been clearly demonstrated. In the current study we investigate the kinetics of valproic acid glucuronide (VPAG) formation both in vivo in adult sheep and in vitro in sheep liver microsomes (pool of 10). After a 100 mg/kg i.v. bolus dose of valproic acid (VPA) to adult sheep (n = 5), the majority of the dose was recovered in urine as VPAG (approximately 79%). Eadie-Hofstee plots of the VPAG formation rate (calculated from urinary excretion rate data for VPAG) were characteristic of autoactivation kinetics and provided estimates of the apparent maximum velocity of an enzymatic reaction (V(max)(app)), the substrate concentration resulting in 50% of V(max)(app) (S(50)(app)), and Hill coefficient (n) of 2.10 +/- 0.75 micromol/min/kg, 117 +/- 56 microM, and 1.34 +/- 0.14, respectively. Comparable estimates of V(max)(app) (2.63 +/- 0.33 micromol/min/kg), S(50)(app) (118 +/- 53 microM), and n (2.06 +/- 0.47) describing overall VPA elimination from plasma were obtained by fitting VPA unbound plasma concentration-time data to a two-compartment model with elimination described by the Hill equation. Consistent with our in vivo observations, Eadie-Hofstee plots of VPAG formation in sheep liver microsomes were characteristic of autoactivation kinetics. To our knowledge, these data provide the first clear demonstration that autoactivation kinetics observed in vitro in liver preparations can translate to the in vivo situation at least under certain experimental conditions and confirm its relevance.     

DBA/2J (Mls-1a) B-cell differentiation in BALB.xid recipients

Studies of superantigens (SAg) have focused primarily on their impact on CD4+ T cells, largely bypassing the impact of the sequelae of this interaction upon the antigen-presenting cell (APC). Sequelae of SAg-induced CD4+ T-cell activation include the 'bathing' of the SAg-presenting cell with cytokines that promote the differentiation of the APC. In this report, the SAg-induced differentiation of Mls+ DBA/2J B cells was studied in vivo by their transplantation into B-cell-defective BALB.xid recipients. Rapid, high-level serum immunoglobulin M (IgM) production was noted shortly after transfer, disappearing by 3 weeks. Donor B cells, as evidenced after their chemical and genetic impairment and by the use of an IgM allotype-disparate donor-recipient combination, contributed to this transient IgM production. These results clarify a discrepancy in the literature regarding donor B-cell contribution to IgM production and illustrate a model system to utilize SAg to study B-lymphocyte diversity.     

An observer scale to measure alexithymia

The authors developed a relatively brief observer alexithymia measure that can be used by patients' acquaintances and relatives. Items corresponding to the defining features of alexithymia (California Q-Set Alexithymia Prototype) were written, and the new instrument's psychometric properties were evaluated in 3 lay-rater samples. The 33-item Observer Alexithymia Scale (OAS) is internally consistent (coefficient alphas = 0.88 and 0.89) and stable (2-week test-retest reliability = 0.87). Moreover, it has an interpretable five-factor structure (based on exploratory and confirmatory factor analyses): distant, uninsightful, somatizing, humorless, and rigid. The OAS is a reliable instrument with a stable factor structure and good conceptual coverage and thus, it appears to be a useful tool for collecting observer data on the clinically relevant expressions of alexithymia that receive minimal attention.     

Risk for domestic violence: factors associated with perpetration and victimization

The extent and potential dangerousness of the problem of domestic violence warrants systematic screening and assessment in all mental health settings. Few empirical studies have approached the question of domestic violence with the aim of identifying risk markers, making it impossible to identify a particular characteristic or set of characteristics that can be used to identify individuals at risk for perpetrating or becoming the victims of domestic violence. However, there are a number of factors that have been identified as correlates of domestic violence that may eventually prove useful for identifying individuals at risk, but the extant literature does not provide the empirical support at this time. Because many of these correlates may be brought to the attention of mental health and medical professionals (e.g., depression, substance use/abuse, physical injuries) and given the absence of established risk factors for domestic violence, there is a need for clinicians to systematically assess for violence among all of their patients. By identifying factors that might help clinicians realize that many of their patients are at risk for domestic violence, we hope to encourage them to attend to this potentially dangerous problem. Ongoing assessment in the context of knowledge regarding correlates of domestic violence can provide important information for evaluating risk of a particular violent incident. In addition, we outline strategies for assessing violence and violence risk in both perpetrators and victims in order to assist clinicians in approaching this difficult topic in a clinical setting. A careful assessment of the potential for violence within clients' ongoing relationships is necessary for clinicians to provide appropriate clinical care.     

Challenges of coding ambulance service for reimbursement

Emergency medical transportation services have some different characteristics than other patient services that make billing for the services more difficult than for other providers. Payers have been less than systematic in their definition of medical necessity, a criterion that is required in order to justify reimbursement. As a result, documentation of an ambulance trip and appropriate coding of the activities carried out during the course of the trip are key elements in determining whether or not the service will be reimbursed. This article examines the many dilemmas associated with this issue.     

Clinical features of vascular thrombosis following varicella.

OBJECTIVE--To define the clinical characteristics, neuroimaging features, and outcome of five patients with post-primary varicella zoster virus infection hemiparesis and to offer a hypothesis to explain the predilection for the involvement of the cerebral vasculature in this condition. DESIGN--Patient series. SETTING--Five patients were treated during a 14-month period in a private pediatric neurology practice in a medium-size southwestern city. INTERVENTIONS--Steroids (two patients) and antiplatelet drugs (two patients). No observed effects of therapy. RESULTS--The onset of the hemiparesis occurred several weeks (mean, 5.4 weeks) following an episode of the chickenpox. Magnetic resonance imaging was more sensitive than computed tomography or angiography in demonstrating the area of involvement deep in the cerebral hemispheres. The prognosis was good regardless of the therapy administered, as all patients recovered completely or nearly completely. CONCLUSIONS--Primary varicella zoster virus infection with delayed-onset hemiparesis typically occurs approximately 6 weeks after primary varicella zoster virus infection. Magnetic resonance imaging is the most sensitive neuroimaging tool in these children. The prognosis is good, with recovery of function and no recurrences in our patients. The innervation of the carotid artery and the characteristics of the varicella zoster virus itself together provide the local and systemic factors that may trigger the vasculopathy responsible for this syndrome.