Myocardial velocity gradient as a noninvasively determined index of left ventricular diastolic dysfunction in patients with hypertrophic cardiomyopathy

AbstractObjectivesWe investigated the utility of the peak negative myocardial velocity gradient (MVG) derived from tissue Doppler imaging (TDI) for evaluation of diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM).BackgroundHypertrophic cardiomyopathy is characterized by impaired diastolic function with abnormal stiffness and prolonged relaxation. However, it remains difficult to evaluate these defects noninvasively.MethodsBoth TDI and conventional echocardiography were performed in 36 patients with HCM and in 47 control subjects. Left ventricular (LV) pressure was measured simultaneously in all HCM patients and in 26 controls.ResultsThe peak negative MVG occurred soon after the isovolumic relaxation period during the initial phase of rapid filling (auxotonic relaxation). It was significantly smaller in HCM patients than in control subjects (2.32 ± 0.52/s vs. 4.82 ± 1.15/s, p < 0.0001); the cutoff value for differentiation between all HCM patients and 47 normal individuals was determined as 3.2/s. Both the left ventricular end-diastolic pressure (LVEDP) (19.6 ± 6.1 mm Hg vs. 6.5 ± 1.7 mm Hg, p < 0.0001) and the time constant of LV pressure decay during isovolumic diastole (tau) (44.0 ± 6.7 ms vs. 32.1 ± 5.5 ms, p < 0.0001) were increased in HCM patients compared with controls. The peak negative MVG was negatively correlated with both LVEDP (r= −0.75, p < 0.0001) and tau (r= −0.58, p < 0.0001).ConclusionsA reduced peak negative MVG reflects both prolonged relaxation and elevated LVEDP. The peak negative MVG might thus provide a noninvasive index of diastolic function, yielding unique information about auxotonic relaxation in patients with HCM

Thrombomodulin induces anti-inflammatory effects by inhibiting the rolling adhesion of leukocytes in vivo

Thrombomodulin (TM) is an integral membrane protein expressed on the surface of vascular endothelial cells that suppresses blood coagulation. Recent studies have shown that TM exhibits anti-inflammatory effects by inhibiting leukocyte recruitment. However, the actual modes of action of TM in vivo remain unclear. Here, we describe the pharmacological effects of recombinant human soluble TM (TM alfa) on leukocyte dynamics in living mice using intravital imaging techniques. Under control conditions, neutrophils exhibited three distinct types of adhesion behavior in vessels: 1) “non-adhesion”, in which cells flowed without vessel adhesion; 2) “rolling adhesion”, in which cells transiently interacted with the endothelium; and 3) “tight binding”, in which cells bound strongly to the endothelial cells. Compared to control conditions, local lipopolysaccharide stimulation resulted in an increased frequency of rolling adhesion that was not homogeneously distributed on vessel walls but occurred at specific endothelial sites. Under inflammatory conditions, TM alfa, particularly the D1 domain which is a lectin-like region of TM, significantly decreased the frequency of rolling adhesion, but did not influence the number of tight bindings. This was the first study to demonstrate that TM alfa exerts anti-inflammatory effects by inhibiting rolling adhesion of neutrophils to vascular endothelial cells in living mice.Nishizawa S., Kikuta J., Seno S., et al. Thrombomodulin induces anti-inflammatory effects by inhibiting the rolling adhesion of leukocytes in vivo. Journal of Pharmacological Sciences 143, 17 (2020); https://doi.org/10.1016/j.jphs.2020.01.001

Predictive Value of Cetuximab-Induced Skin Toxicity in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and NECK

Background: Skin toxicity is a common adverse event during cetuximab (Cmab) treatment. However, few reports have investigated the correlation between skin toxicity and the efficacy of Cmab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).Methods: We retrospectively reviewed 112 R/M SCCHN patients who received palliative chemotherapy with Cmab. Main eligibility criteria included primary disease in the oral cavity, hypopharynx, nasopharynx, oropharynx, or larynx; no prior history of EGFR-directed therapy; receipt of Cmab plus chemotherapy as first-line therapy for recurrent or metastatic disease; and follow-up for more than 90 days. We analyzed the time to first occurrence and time of maximum grade skin toxicity, and its predictive value with regard to treatment efficacy.Results: After a median follow-up of 393 days (range 109–1501 days), 105 (94%) and 20 (18%) patients had skin toxicity of any grade and grade 3, respectively. Among them, 8 patients with grade 3 acneiform rash, skin rash, or paronychia within 90 days after treatment initiation (“early skin toxicity”) had improved progression-free survival (PFS) (log-rank test, P = 0.045; 2-year PFS, 25.0 vs. 2.9%) and overall survival (OS) (log-rank test, P = 0.023, 2-year OS, 50.0 vs. 14.4%) compared with those with &lt; grade 3 toxicity. A greater proportion of patients with early skin toxicity than patients without this toxicity could proceed with Cmab maintenance (88 vs. 44%, P = 0.021). Multivariate analysis identified early skin toxicity as an independent predictor of better PFS (hazard ratio [HR] = 0.363, 95% confidence interval [CI] 0.142–0.924, P = 0.034) and OS (HR = 0.187, 95% CI: 0.045–0.781, P = 0.022).Conclusion: Grade 3 Cmab-induced skin toxicity within 90 days was associated with better survival in R/M SCCHN. Effective rash management therefore seems necessary to realize the benefit of Cmab treatment

Host-Catalyzed Cyclodehydration–Rearrangement Cascade Reaction of Unsaturated Tertiary Alcohols

The Brønsted acidic resorcin[4]arene hexamer can be applied as an effective catalyst in the dehydrative cyclization and subsequent rearrangement of unsaturated tertiary alcohols. This is the first report on catalyzing such a reaction with a Brønsted acid. Scope and limitations of this cyclopentene-forming reaction sequence are presented. Furthermore, substrate-selective conversion as well as competitive inhibition are described and provide evidence that the reactions proceed within the cavity of the self-assembled structure. Additionally, a cyclobutanone-forming intramolecular hydride transfer of an encapsulated cyclopropyl acetate is reported