Pituitary adrenocortical unresponsiveness in lactate-induced panic

The hypothalamic-pituitary adrenal (HPA) axis responds to a variety of physical and emotional stimuli with increased output of adrenocorticotropic hormone (ACTH) and cortisol, yet there is little known about the activity of this system during episodes of severe anxiety in patients with DSM-III-defined anxiety disorders. To explore further whether alterations of the HPA axis occur during various anxiety states, we measured ACTH and cortisol during lactate infusion in patients with panic disorder and agoraphobia. In eight patients who panicked during lactate infusion, there were no elevations in either ACTH or cortisol. Further, the patterns of hormone secretion did not differ among patients who panicked, nonpanicking patients, or controls. This negative result suggests that the neurobiological mechanisms that mediate panic differ from those responsible for other fear responses.     

Assessment of Left Ventricular Viscoelastic Components Based on Ventricular Harmonic Behavior

Background: Assessment of left ventricular (LV) function with an emphasis on contractility has been a challenge in cardiac mechanics during the recent decades. The LV function is usually described by the LV pressure-volume (P-V) relationship. Based on this relationship, the ratio of instantaneous pressure to instantaneous volume is an index for LV chamber stiffness. The standard P-V diagrams are easy to interpret but difficult to obtain and require invasive instrumentation for measuring the corresponding volume and pressure data. In the present study, we introduce a technique that can estimate viscoelastic properties, not only the elastic component but also the viscous properties of the LV based on oscillatory behavior of the ventricular chamber and it can be applied non-invasively as well. Materials and Methods: The estimation technique is based on modeling the actual long axis displacement of the mitral annulus plane toward the cardiac base as a linear damped oscillator with time-varying coefficients. Elastic deformations resulting from the changes in the ventricular mechanical properties of myocardium are represented as a time-varying spring while the viscous components of the model include a time-varying viscous damper, representing relaxation and the frictional energy loss. To measure the left ventricular axial displacement ten healthy sheep underwent left thoracotomy and sonomicrometry transducers were implanted at the apex and base of the LV. The time-varying parameters of the model were estimated by a standard Recursive Linear Least Squares (RLLS) technique. Results: LV stiffness at end-systole and end-diastole was in the range of 61.86–136 dyne/g.cm and 1.25–21.02 dyne/g.cm, respectively. Univariate linear regression was performed to verify the agreement between the estimated parameters, and the measured values of stiffness. The averaged magnitude of the stiffness and damping coefficients during a complete cardiac cycle were estimated as 58.63±12.8 dyne/g.cm and 0 dyne.s/g.cm, respectively. Conclusion: The results for the estimated elastic coefficients are consistent with the ones obtained from force-displacement diagram. The trend of change in the estimated parameters is also in harmony with the previous studies done using P-V diagram. The only input used in this model is the long axis displacement of the annulus plane, which can also be obtained non-invasively using tissue Doppler or MR imaging.     

Tolerability and Pharmacokinetics of Delayed-Release Dimethyl Fumarate Administered With and Without Aspirin in Healthy Volunteers

Background

Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time.

Objective

The purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor.

Methods

Healthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored.

Results

DR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC_0–10h, or C_max. Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF–treated individuals, plasma concentrations of a prostaglandin D₂ (PGD₂) metabolite were increased.

Conclusions

In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD₂ in some DR-DMF–treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111.     

Posterior leaflet augmentation improves leaflet tethering in repair of ischemic mitral regurgitation

Objectives: Ischemic mitral regurgitation results from annular dilatation, leaflet tethering and leaflet flattening. Undersized annuloplasty corrects annular dilatation but worsens leaflet tethering and flattening. This exacerbation of abnormal leaflet geometry may contribute to poor repair results for ischemic mitral regurgitation (IMR). Using a sheep model of IMR, we hypothesized that posterior leaflet augmentation and less-extreme annular undersizing would relieve tethering and increase leaflet curvature. Methods: Eight weeks after posterolateral infarct, 10 sheep with ≥2+ IMR underwent either a 24-mm planar ring annuloplasty (n = 5) or a 30-mm planar ring annuloplasty with concomitant posterior leaflet augmentation (n = 5). Real-time three-dimensional echocardiography allowed measurement of indices of leaflet curvature and tethering before and after annuloplasty. Results: Comparing pre- and post-repair values in the P1, P2, and P3 leaflet regions, undersized 24-mm ring annuloplasty made no significant difference to mean septolateral curvature (0.23–0.26, 0.33–0.29, and 0.27–0.37 cm⁻¹, respectively), whereas leaflet augmentation in combination with a 30-mm ring annuloplasty increased septolateral curvature (P1 0.30–1.02, P2 0.31–1.23, and P3 0.35–0.84 cm⁻¹, p-values < 0.05). The mean tethering angle formed between the annular plane and the posterior leaflet increased in all three posterior regions for the 24-mm ring group (P1 12–23°, P2 26–31°, and P3 16–25°), but decreased in all regions for the group undergoing leaflet augmentation (P1 +5 to −6°, P2 +13 to −13°, P3 +16-15°, all p-values < 0.05). Conclusions: Undersized annuloplasty exacerbates leaflet tethering. Posterior leaflet augmentation with less severe annular reduction increases leaflet curvature and decreases tethering; this technique more completely addresses the pathogenic mechanism of IMR and may improve repair durability.     

A review of GP records relating to methadone-associated deaths in the Lothian region of Scotland 1997-9

Aims : To ascertain the characteristics of patients whose death was associated with methadone intoxication during the period 1997-9 in the Lothian region of Scotland. Design : Patients were identified from death certificates. General practitioner records relating to methadone-associated deaths were reviewed in association with autopsy, toxicology and police reports. Deprivation categories (DepCat) were derived from the postal code of residence and the Carstairs index. Findings : There were 77 methadone-associated deaths in the Lothian Health Board area. GP records were obtained for 60 patients registered with a general practitioner. The majority of methadone-associated deaths (73%) occurred in persons who were not prescribed methadone at the time of their death. Thirty-eight persons were prescribed medication other than methadone or dihydrocodeine at the time of death. Thirty (79%) of those being prescribed for were receiving benzodiazepines. Forty-seven per cent had a history of excessive alcohol consumption. Fifty per cent had a reported psychiatric history. Sixty per cent had previously attended Accident and Emergency through deliberate self-harm or accidental overdose. Low socioeconomic status was found to be associated with the highest rate of methadone-related deaths. Conclusions : Given the variety of characteristics outlined it is likely that reducing drug-related deaths is a longer term aim, not amenable to one particular solution.     

Haplotype association of calpain 10 gene variants with type 2 diabetes mellitus in an Irish sample

Background  

Calpain 10 (CAPN10) gene may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM).