Loss of CB1 receptors leads to decreased cathepsin D levels and accelerated lipofuscin accumulation in the hippocampus

Early onset of age-related changes in the brain of cannabinoid 1 receptor knockout (Cnr1^−/−) mice suggests that cannabinoid 1 (CB1) receptor activity significantly influences the progression of brain aging. In the present study we show that lack of CB1 receptors leads to a significant increase in lipofuscin accumulation and a reduced expression and activity of cathepsin D, lysosomal protease implicated in the degradation of damaged macromolecules, in the hippocampus of 12-month-old mice. The impaired clearance of damaged macromolecules due to the low cathepsin D levels and not enhanced oxidative stress may be responsible for the lipofuscin accumulation because macromolecule oxidation levels were comparable between the genotypes within the same age group. The altered levels of autophagy markers p62 and LC3-II suggest that autophagy is upregulated in CB1 knockout mice. Increased autophagic flux in the absence of CB1 receptors is probably a compensatory mechanism to partially counteract decreased lysosomal degradation capacity. Together, these results suggest that CB1 receptor activity affects lysosomal activity, degradation of damaged macromolecules and thus it may influence the course and onset of brain aging.     

Left ventricular systolic and diastolic function after total correction of tetralogy of Fallot

Left ventricular (LV) systolic and diastolic function was assessed in 12 patients after total correction of tetralogy of Fallot (age range 5 to 18 years, mean 10) and compared with 10 control patients. Only 1 patient had a shunt before total correction that was performed at a mean age of 3.5 years, (range 0.3 to 8). At cardiac catheterization the following indexed LV parameters were measured: end-diastolic and end-systolic volumes, wall mass, ejection fraction, stroke volume and end-diastolic and end-systolic pressures and stresses. The rate-corrected mean velocity of fiber shortening was calculated. LV diastolic operant chamber stiffness and myocardial stiffness were calculated from simultaneous diastolic pressures and volumes in mid- and late diastole using monoexponential formulas. The 2 groups were compared by unpaired t tests. The tetralogy group had higher mean end-diastolic (93 vs 74 ml/m2), end-systolic (29 vs 19 ml/m2) and stroke (64 vs 55 ml/m2) volumes than controls. Rate-corrected mean velocity of fiber shortening was lower in the tetralogy group (1.07 vs 1.24). Myocardial stiffness was higher in the tetralogy group (16 vs 11). Other indexes were not significantly different. Thus, LV function after total correction of tetralogy of Fallot may be abnormal with larger than normal LV size, decreased contractile function and increased myocardial stiffness.     

Retrievable Inferior Vena Cava Filters: Initial Clinical Results

Anticoagulation is the accepted therapy for patients with thromboembolic disease. When contraindications to anticoagulant therapy are present, however, interruption of the inferior vena cava (IVC) may prevent pulmonary embolism (PE). The objective of this study was to report our early technical and clinical results with retrievable IVC filters (IVCFs) for the prevention of PE. One hundred and twenty-seven multitrauma patients between December 1, 2002, and December 31, 2004, underwent placement of Gunther-Tulip (n = 49), Recovery (n = 41), or OptEase (n = 37) retrievable IVCFs under real-time intravascular ultrasound (IVUS) guidance. All patients had abdominal X-rays to verify filter location. Prior to IVCF retrieval, all patients underwent femoral vein color flow ultrasonography to rule out deep vein thrombosis (DVT) and vena-cavography to assess the IVCF for trapped emboli, filter tilt, or retrained thrombus. Thirty-nine patients died of their injuries; no deaths were related to IVCF placement. One PE occurred during follow-up after filter retrieval, and two femoral vein insertion-site DVTs occurred. One hundred twenty (94.4%) of IVCFs were placed without complication at the L2-3 level, as verified by abdominal X-rays. Filter-related complications included three groin hematomas (2.9%) and three IVCFs misplaced in the right iliac vein early in our experience (2.3%); these filters were uneventfully retrieved and replaced in the IVC within 24 hr. Sixty-six patients underwent uneventful retrieval of IVCFs after DVT or PE anticoagulation prophylaxis was initiated. Forty-five IVCFs were not removed: 41 due to contraindications due to anticoagulation and four because of trapped thrombus within the filter. The role of retrievable IVCFs continues to evolve, but in this study of 127 patients, prophylactic temporary IVCF placement was simple and safe, prevented fatal PE, and served as an effective “bridge” to anticoagulation. Further investigation of this bedside IVUS technique and the role of temporary IVCFs in different patient populations is warranted. SECTION EDITOR: Samuel S. Ahn, MD     

Effects of EGIS-7625, a Selective and Competitive 5-HT2B Receptor Antagonist

Our aim was to specify the 5-HT(2) subtype selectivity of EGIS-7625 (1-benzyl-4-[(2-nitro-4-methyl-5-amino)-phenyl]-piperazine), a new 5-HT(2B) ligand, in receptor binding studies and characterize its pharmacology at 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors in in vivo experiments and in isolated organs, in vitro. EGIS-7625 had high affinity for recombinant human 5-HT(2B) receptors (pK(i) = 9.0) but much weaker affinity for 5-HT(2A) and 5-HT(2C) receptors (pK(i) = 6.2 and 7.7, respectively). In the classic 5-HT(2B) test, EGIS-7625 produced a concentration-related parallel rightward shift in the concentration-response relationship for the 5-HT-induced smooth muscle constriction in rat stomach fundus strips with a pA(2) of 9.4. On the other hand, EGIS-7625 was a weak competitive antagonist at 5-HT(2A) receptors as it shifted 5-HT-induced concentration-response curves to the right at high concentrations (pA(2) = 6.7) in rabbit pulmonary artery strips. The m-chlorophenylpiperazine-induced hypomotility and hypophagia was only partially attenuated by EGIS-7625 even at a dose of 30 mg/kg i.p. while mianserin, a non-selective 5-HT antagonist was almost fully effective in these tests at 3 mg/kg i.p., suggesting weak antagonistic effect of EGIS-7625 at neuronal 5-HT(2C) receptors, in vivo. In conclusion, EGIS-7625 is a potent, selective and competitive 5-HT(2B) antagonist that seems to be a good research tool for the separation of the functional roles of vascular 5-HT(2A) and 5-HT(2B) receptors.     

Plasma contact factors as therapeutic targets

Direct oral anticoagulants (DOACs) are small molecule inhibitors of the coagulation proteases thrombin and factor Xa that demonstrate comparable efficacy to warfarin for several common indications, while causing less serious bleeding. However, because their targets are required for the normal host-response to bleeding (hemostasis), DOACs are associated with therapy-induced bleeding that limits their use in certain patient populations and clinical situations. The plasma contact factors (factor XII, factor XI, and prekallikrein) initiate blood coagulation in the activated partial thromboplastin time assay. While serving limited roles in hemostasis, pre-clinical and epidemiologic data indicate that these proteins contribute to pathologic coagulation. It is anticipated that drugs targeting the contact factors will reduce risk of thrombosis with minimal impact on hemostasis. Here, we discuss the biochemistry of contact activation, the contributions of contact factors in thrombosis, and novel antithrombotic agents targeting contact factors that are undergoing pre-clinical and early clinical testing.