Modeling the Instantaneous Pressure–Volume Relation of the Left Ventricle: A Comparison of Six Models

Simulations are useful to study the heart’s ability to generate flow and the interaction between contractility and loading conditions. The left ventricular pressure–volume (PV) relation has been shown to be nonlinear, but it is unknown whether a linear model is accurate enough for simulations. Six models were fitted to the PV-data measured in five sheep and the estimated parameters were used to simulate PV-loops. Simulated and measured PV-loops were compared with the Akaike information criterion (AIC) and the Hamming distance, a measure for geometric shape similarity. The compared models were: a time-varying elastance model with fixed volume intercept (LinFix); a time-varying elastance model with varying volume intercept (LinFree); a Langewouter’s pressure-dependent elasticity model (Langew); a sigmoidal model (Sigm); a time-varying elastance model with a systolic flow-dependent resistance (Shroff) and a model with a linear systolic and an exponential diastolic relation (Burkh). Overall, the best model is LinFree (lowest AIC), closely followed by Langew. The remaining models rank: Sigm, Shroff, LinFix and Burkh. If only the shape of the PV-loops is important, all models perform nearly identically (Hamming distance between 20 and 23%). For realistic simulation of the instantaneous PV-relation a linear model suffices.     

Predicting Return to Work in Employees Sick-Listed Due to Minor Mental Disorders

Objective To investigate which factors predict return to work (RTW) after 3 and 6 months in employees sick-listed due to minor mental disorders. Methods Seventy GPs recruited 194 subjects at the start of sick leave due to minor mental disorders. At baseline (T0), 3 and 6 months later (T1 and T2, respectively), subjects received a questionnaire and were interviewed by telephone. Using multivariate logistic regression analyses, we developed three prediction models to predict RTW at T1 and T2. Results The RTW rates were 38% after 3 months (T1) and 61% after 6 months (T2). The main negative predictors of RTW at T1 were: (a) a duration of the problems of more than 3 months before sick leave; and (b) somatisation. The main negative predictors of RTW at T2 were: (a) a duration of the problems of more than 3 months before sick leave; (b) more than 3 weeks of sick leave before inclusion in the study; and (c) anxiety. The main negative predictors of RTW at T2 for those who had not resumed work at T1 were: (a) more than 3 weeks of sick leave before inclusion in the study; and (b) depression at T1. The predictive power of the models was moderate with AUC-values between 0.695 and 0.763. Conclusions The main predictors of RTW were associated with the severity of the problems. A long duration of the problems before the occurrence of sick leave and a long duration of sick leave before seeking help predict a relatively small probability to RTW within 3–6 months. High baseline somatisation and anxiety, and high depression after 3 months make the prospect even worse. Since these predictors are readily assessable with just a few questions and a symptom questionnaire, this opens the opportunity to select high-risk employees for a targeted intervention to prevent long-term absenteeism.     

Rapamycin enhances the number of alloantigen-induced human CD103+CD8+ regulatory T cells in vitro

BACKGROUND: Regulatory T cells (T(reg) cells) may be operational in both the induction and maintenance of transplantation tolerance. We recently showed that alloantigen-induced CD103+ CD8+ T cells strongly suppressed T-cell proliferation in mixed lymphocyte culture (MLC) via a contact-dependent mechanism. CD103 directs T lymphocytes to their ligand E-cadherin, which is expressed on renal tubular epithelial cells, and CD103+ CD8+ T cells have been described to be present in late renal allograft rejection. METHODS: We studied the influence of prednisolone, cyclosporin, tacrolimus, CD25 monoclonal antibodies, rapamycin, and mycophenolate mofetil (MMF) on the development and functional activity of alloantigen-activated CD103+ CD8+ T cells in MLC. RESULTS: Calcineurin inhibitors, MMF, and CD25mAb did not influence the number of CD103 expressing CD8+ T cells. In contrast, corticosteroids diminished CD103 expression on alloactivated CD8+ T cells, which appeared to be caused by their inhibitory action on myeloid dendritic cells. Addition of rapamycin to allocultures led to an increased percentage of CD103+ CD8+ alloreactive T cells. Moreover, in the presence of rapamycin, these cells tended to show higher suppressive capacity. CONCLUSIONS: Alloreactive CD103+ CD8+ T(reg) cells may expand and exert their suppressive function during immunosuppressive treatment with rapamycin. These data are relevant in the design of immunosuppressive drug regimens intended to induce and/or maintain transplantation tolerance.     

Ventilation heterogeneity is a major determinant of airway hyperresponsiveness in asthma, independent of airway inflammation

BACKGROUND: Airway hyperresponsiveness is the ability of airways to narrow excessively in response to inhaled stimuli and is a key feature of asthma. Airway inflammation and ventilation heterogeneity have been separately shown to be associated with airway hyperresponsiveness. A study was undertaken to establish whether ventilation heterogeneity is associated with airway hyperresponsiveness independently of airway inflammation in subjects with asthma and to determine the effect of inhaled corticosteroids on this relationship. METHODS: Airway inflammation was measured in 40 subjects with asthma by exhaled nitric oxide, ventilation heterogeneity by multiple breath nitrogen washout and airway hyperresponsiveness by methacholine challenge. In 18 of these subjects with uncontrolled symptoms, measurements were repeated after 3 months of treatment with inhaled beclomethasone dipropionate. RESULTS: At baseline, airway hyperresponsiveness was independently predicted by airway inflammation (partial r2 = 0.20, p<0.001) and ventilation heterogeneity (partial r2 = 0.39, p<0.001). Inhaled corticosteroid treatment decreased airway inflammation (p = 0.002), ventilation heterogeneity (p = 0.009) and airway hyperresponsiveness (p<0.001). After treatment, ventilation heterogeneity was the sole predictor of airway hyperresponsiveness (r2 = 0.64, p<0.001). CONCLUSIONS: Baseline ventilation heterogeneity is a strong predictor of airway hyperresponsiveness, independent of airway inflammation in subjects with asthma. Its persistent relationship with airway hyperresponsiveness following anti-inflammatory treatment suggests that it is an important independent determinant of airway hyperresponsiveness. Normalisation of ventilation heterogeneity is therefore a potential goal of treatment that may lead to improved long-term outcomes.     

Chronic paroxetine treatment does not affect sexual behavior in hormonally sub-primed female rats despite 5-HT₁(A) receptor desensitization

IntroductionSelective serotonin reuptake inhibitors (SSRIs) cause sexual dysfunctions in humans. However, because SSRIs are used to treat depression, it is unclear whether the problems are caused by the drug, by the depression itself, or an interaction between both.AimThe present study investigated the effects of chronic paroxetine treatment on sexual behavior in female rats. Furthermore, we tested whether 5‐hydroxytryptamine (5‐HT)_1A receptors were desensitized in these females.MethodsOvariectomized female rats, either sub‐primed with estradiol or fully primed with estradiol and progesterone, were tested in a paced mating test. Proceptive (darting and hopping), receptive (lordosis), and paced mating‐related (percentages of exits and contact‐return latencies) behaviors were quantified during the course of 56 days of chronic paroxetine treatment (10 mg/kg and 20 mg/kg per day). The 5‐HT_1A/5‐HT₇ receptor agonist (±)‐8‐hydroxy‐2‐(dipropylamino)tetralin hydrobromide ((±)8‐OH‐DPAT) alone and in combination with the selective 5‐HT_1A receptor antagonist WAY‐100635 was administered to study putative 5‐HT_1A desensitization in the same females.Main Outcome MeasuresProceptive, receptive, and paced mating behaviors were quantified.ResultsAcute and chronic paroxetine treatment did not change proceptive and receptive behaviors in both sub‐primed and fully primed female rats. In all groups, (±)8‐OH‐DPAT showed a clear dose‐dependent inhibition of sexual behaviors in vehicle‐treated females and a right‐shifted dose–response effect in the paroxetine‐treated rats. WAY‐100635 attenuated the inhibiting effect of the 5‐HT_1A receptor agonist in all females. These data suggest 5‐HT_1A receptor desensitization after chronic paroxetine treatment.ConclusionsChronic paroxetine treatment does not cause sexual side effects in sub‐ or fully hormonally primed female rats. Furthermore, chronic treatment causes adaptive changes in the serotonin system such as desensitization of 5‐HT_1A receptors, which may counteract the inhibiting effects of increased extracellular serotonin levels in the chronic paroxetine‐treated rats. Snoeren EMS, Refsgaard LK, Waldinger MD, Olivier B, and Oosting RS. Chronic paroxetine treatment does not affect sexual behavior in hormonally sub‐primed female rats despite 5‐HT_1A receptor desensitization.     

Interictal regional polyspikes in noninvasive EEG suggest cortical dysplasia as etiology of focal epilepsies

Purpose: To evaluate the clinical significance of interictal regional polyspikes in focal epilepsies secondary to cortical dysplasia.
Methods: We performed a data search for the term "regional polyspikes" in the database of our epilepsy-monitoring unit. Patients with generalized epilepsies including Lennox-Gastaut syndrome were excluded. Regional interictal epileptiform discharges were recorded in 513 patients with noninvasive EEG.
Results: We identified 29 patients with interictal regional polyspikes and focal epilepsies. Another 484 patients showed regional epileptiform discharges other than polyspikes. The etiology of the epilepsy was significantly more frequently cortical dysplasia in the group of patients with regional polyspikes (35%, 10 of 29 patients) than in the patients with other regional epileptiform discharges (5%, 24 of 484 patients) (p < 0.01). The polyspikes were significantly more frequently localized to the extratemporal (72%; n = 21) than temporal (28%; n = 8) regions (p < 0.01). In contrast, regional epileptiform discharges other than polyspikes were significantly more frequently localized to the temporal lobe (75%; n = 362) than extratemporal regions (25%; n = 122) (p < 0.01). Eight of the 10 patients with focal cortical dysplasia had extratemporal polyspikes.
Discussion: Noninvasively recorded regional polyspikes suggest cortical dysplasias as etiology of predominantly extratemporal epilepsies.