The influence of caloric nystagmus on flash evoked transient and steady-state potentials.

OBJECTIVE: Caloric stimulation leads to a reduction of the cerebral blood flow in the visual cortex. This reduction has been attributed to the suppression of visual input caused by nystagmus induced by caloric stimulation. We investigated the influence of caloric stimulation on transient flash and steady-state flash visual evoked potentials. METHODS: Visual evoked potentials to 1 and 10 Hz flash stimulation were recorded in 12 normal subjects at baseline, during nystagmus induced by caloric stimulation with cold water, and after the cessation of nystagmus. RESULTS: Neither the amplitude of the transient flash visual evoked potentials (1 Hz stimulation) nor the amplitude of the steady-state flash visual evoked potentials (10 Hz stimulation) was influenced by caloric stimulation compared to baseline. CONCLUSIONS: The deactivation of the visual cortex by caloric stimulation does not seem to affect transient flash or steady-state flash visual evoked potentials. Reduction of cerebral blood flow in the visual cortex does not affect the processing of visual qualities (e.g., luminance and pattern). SIGNIFICANCE: Caloric stimulation does not reduce the amplitudes of transient flash or steady-state flash visual evoked potentials.     

Cause-effect relation between hyperfibrinogenemia and vascular disease

Elevated plasma levels of fibrinogen are associated with the presence of cardiovascular disease, but it is controversial whether elevated fibrinogen causally imparts an increased risk, and as such is a true modifier of cardiovascular disease, or is merely associated with disease. By investigating a transgenic mouse model of hyperfibrinogenemia, we show that elevated plasma fibrinogen concentration (1) elicits augmented fibrin deposition in specific organs, (2) interacts with an independent modifier of hemostatic activity to regulate fibrin turnover/deposition, (3) exacerbates neointimal hyperplasia in an experimental model of stasis-induced vascular remodeling, yet (4) may suppress thrombin generation in response to a procoagulant challenge. These findings provide direct experimental evidence that hyperfibrinogenemia is more than a by-product of cardiovascular disease and may function independently or interactively to modulate the severity and/or progression of vascular disease.     

Phenotype and function of human B cells expressing CD70 (CD27 ligand)

CD70, the cellular ligand of the tumor necrosis factor receptor family member CD27, can be found on a limited number of germinal center (GC) B cells in some tonsils, on scattered lymphocytes residing in secondary lymphoid organs, and on a fraction of the circulating B cell population. Due to the restricted expression of CD70 in vivo, we analyzed signals that determine CD70 expression levels and characterized the phenotype and function of CD70⁺ B cells. Expression of CD70 on B cells activated in vitro was found to be dependent on the continuous presence of a B cell antigen receptor cross-linking agent, and induced or potentiated by CD40 ligation but was down-modulated by the Th2 cytokines interleukin (IL)-4 and IL-13. Both in peripheral blood and tonsil cell suspensions, CD70⁺ B cell subpopulations were found to be enriched for CD27-and IgG-expressing cells, but contained less IgD⁺ B cells. Additional analysis of markers which define specific differentiation stages (Bm1-5) of mature B cells within human tonsils did not place CD70-expressing B cells in one of these subsets. Functional experiments revealed that whereas both CD70⁻ and CD70⁺ B cells can secrete immunoglobulin after activation with a combination of Staphylococcus aureus Cowan strain I and IL-2, only CD70⁺ B cells can produce large quantities of antibodies when stimulated in a T cell-dependent fashion. Our combined data imply that CD70 is a marker for mature B cells which have recently been primed by antigen in vivo.     

The effect of short-term withdrawal from continuous positive airway pressure therapy on sympathetic activity and markers of vascular inflammation in subjects with obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is commonly associated with cardiovascular disease and sympathetic activation. However, it is unclear whether this association is independent of obesity and to what extent treatment with nasal continuous positive airway pressure (CPAP) alleviates the vascular inflammation that underpins cardiovascular disease. We therefore evaluated whether short-term withdrawal from CPAP therapy in subjects with moderate-severe OSA would result in increased levels of sympathetic activity and circulating inflammatory cytokines independent of weight. Vascular inflammatory markers (hsCRP, hsIL-6 and hsTNF-alpha) were assessed in 20 subjects after one and seven nights of withdrawal from CPAP together with the hypoxia-responsive angiogenic marker VEGF and urinary catecholamines. Compared with baseline on CPAP, withdrawal from therapy resulted in an immediate return of OSA with an increase in RDI to 26.7 +/- 5.2 and 39.0 +/- 5.9 events per hour after one and seven nights without CPAP, respectively (both P < 0.0001). This was accompanied by a concomitant rise in daytime urinary noradrenaline (P < 0.0001) after seven nights CPAP withdrawal that was positively associated with the severity of hypoxaemia. In contrast, withdrawal from CPAP therapy was not accompanied by any change in measured cytokines or VEGF (all P > 0.1). In conclusion, 1 week of CPAP withdrawal was associated with a return of OSA and a marked increase in sympathetic activity without a concomitant elevation of vascular inflammatory markers.     

The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13

Dendritic cells (DCs) are indispensable for defense against pathogens but may also contribute to immunopathology. Activation of DCs upon the sensing of pathogens by Toll-like receptors (TLRs) is largely mediated by pattern recognition receptor/nuclear factor-κB (NF-κB) signaling and depends on the appropriate ubiquitination of the respective signaling molecules. However, the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely understood. Here, we reveal that the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide challenge. Stimulation of DCs with the TLR11/12 ligand T. gondii profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-κB activation in OTUB1-competent cells, resulting in elevated interleukin-6 (IL-6), IL-12, and tumor necrosis factor (TNF) production, which was also observed upon the specific stimulation of TLR2, TLR3, TLR7, and TLR9. Mechanistically, OTUB1 promoted NF-κB activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13, resulting in increased K63-linked ubiquitination of IRAK1 (IL-1 receptor-associated kinase 1) and TRAF6 (TNF receptor-associated factor 6). Consequently, DC-specific deletion of OTUB1 impaired the production of cytokines, in particular IL-12, by DCs over the first 2 days of T. gondii infection, resulting in the diminished production of protective interferon-γ (IFN-γ) by natural killer cells, impaired control of parasite replication, and, finally, death from chronic T. encephalitis, all of which could be prevented by low-dose IL-12 treatment in the first 3 days of infection. In contrast, impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced immunopathology. Collectively, these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.     

The arterial Windkessel

Frank’s Windkessel model described the hemodynamics of the arterial system in terms of resistance and compliance. It explained aortic pressure decay in diastole, but fell short in systole. Therefore characteristic impedance was introduced as a third element of the Windkessel model. Characteristic impedance links the lumped Windkessel to transmission phenomena (e.g., wave travel). Windkessels are used as hydraulic load for isolated hearts and in studies of the entire circulation. Furthermore, they are used to estimate total arterial compliance from pressure and flow; several of these methods are reviewed. Windkessels describe the general features of the input impedance, with physiologically interpretable parameters. Since it is a lumped model it is not suitable for the assessment of spatially distributed phenomena and aspects of wave travel, but it is a simple and fairly accurate approximation of ventricular afterload. J.-W. Lankhaar is supported by a grant from the Netherlands Heart Foundation, the Hague, the Netherlands (NHS2003B274).     

Auditory development in progressive motor neuronopathy mouse mutants

The present study was performed to elucidate the hearing development in the progressive motor neuronopathy (pmn) mouse mutant. This mouse has been used as a model for human motoneuron disease. A missense mutation in the tubulin-specific chaperon E (Tbce) gene on mouse chromosome 13 was localized as the underlying genetic defect. The protein encoded by the Tbce gene is essential for the formation of primary tubulin complexes. Studies on motoneurons show disorganization in microtubules and disturbed axonal transport, followed by retrograde degeneration of the motoneurons. A similar pathomechanism is also possible for hearing disorders where disrupted microtubules could cause functional deficits in spiral ganglion neurons or in cochlear hair cells. Click auditory brainstem response (ABR) audiometry in homozygous pmn mutants showed a normal onset of hearing, but an increasing hearing threshold from postnatal day 26 (P26) on to death, compared to heterozygous mutants and wild-type mice. Histological sections of the cochlea at different ages showed a regular morphology. Additionally, spiral ganglion explants from mutant and wild-type mice were cultured. The neurite length from pmn mutants was shorter than in wild-type mice, and the neurite number/explant was significantly decreased in pmn mutants. We show that the pmn mouse mutant is a model for a progressive rapid hearing loss from P26 on, after initially normal hearing development. Heterozygous mice are not affected by this defect. With the knowledge of the well-known pathomechanism of this defect in motoneurons, a dysfunction of cellular mechanisms regulating tubulin assembling suggests that tubulin assembling plays an essential role in hearing function and maintenance.     

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.     

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.