Miyazaki Welfare Medical College

AimsThe clinical impact of tricuspid regurgitation (TR) in patients after acute myocardial infarction (AMI) is largely unknown. The aim of this study was to clarify the prevalence and prognostic impact of TR in post‐AMI patients treated with appropriate primary percutaneous coronary intervention (PCI).Methods and resultsThree hundred fifty‐one consecutive patients with first‐onset AMI who underwent successful primary PCI from July 2014 to December 2018 were retrospectively examined. Standard two‐ and three‐dimensional echocardiography were performed at discharge. Based on the presence or absence of mild or greater TR, patients were divided into TR (+) and TR (−) groups, respectively. The primary outcome was the incidence of major adverse cardiac events (MACE), defined as the composite of death, re‐hospitalization for congestive heart failure and recurrent MI. Seventy‐eight (22.2%) patients had mild or greater TR. Kaplan–Meier analysis showed that the cumulative 6‐year incidence of MACE was significantly higher in the TR (+) group (hazard ratio, 2.56 [95% confidence interval, 1.48–4.44]; P < 0.001). In the analysis of the severity of TR, the prognosis of patients with mild TR was significantly worse than that of patients without TR (P = 0.026). Multivariable analysis identified the left anterior descending coronary artery as the culprit vessel, left atrial dilation (>34 mL/m2), reduced left ventricular ejection fraction (<50%) and the presence of significant (≥mild) ischaemic mitral regurgitation as independent predictors of mild or greater residual TR after primary PCI for AMI at discharge. Following adjustment for significant clinical parameters, mild or greater TR at discharge was still associated with a significant hazard ratio for the occurrence of MACE (1.87, [95% confidence interval, 1.01–3.48]; P = 0.048).ConclusionsThe presence of mild or greater TR at discharge may serve as a poor prognostic marker in patients with first‐onset AMI. In addition to traditional clinical risk factors, it is important to pay more attention to TR and to manage it appropriately.

We have previously reported that the proanthocyanidin (PAC) fraction of blueberry leaf extract (BB‐PAC) inhibits the proliferation of HTLV‐1‐infected adult T‐cell leukemia (ATL) by inducing apoptosis. In the present study, we further analyzed the structure of BB‐PAC and elucidated the molecular mechanism underlying the inhibitory function of HTLV‐1‐infected and ATL cells. After hot water extraction with fractionation with methanol‐acetone, BB‐PAC was found to be concentrated in fractions 4 to 7 (Fr7). The strongest inhibition of ATL cell growth was observed with Fr7, which contained the highest BB‐PAC polymerization degree of 14. The basic structure of BB‐PAC is mainly B‐type bonds, with A‐type bonds (7.1%) and cinchonain I units as the terminal unit (6.1%). The molecular mechanism of cytotoxicity observed around Fr7 against ATL cells was the degradation of JAK1 to 3 and the dephosphorylation of STAT3/5, which occurs by proteasome‐dependent proteolysis, confirming that PAC directly binds to heat shock protein 90 (HSP90). JAK degradation was caused by proteasome‐dependent proteolysis, and we identified the direct binding of PAC to HSP90. In addition, the binding of cochaperone ATPase homolog 1 (AHA1) to HSP90, which is required for activation of the cofactor HSP90, was inhibited by BB‐PAC treatment. Therefore, BB‐PAC inhibited the formation of the HSP90/AHA1 complex and promoted the degradation of JAK protein due to HSP90 dysfunction. These results suggest that the highly polymerized PAC component from blueberry leaves has great potential as a preventive and therapeutic agent against HTLV‐1‐infected and ATL cells.

IscU is a central component of the ISC machinery and serves as a scaffold for de novo assembly of Fe-S clusters. The dedicated chaperone system composed of the Hsp70-chaperone HscA and the J-protein cochaperone HscB synergistically interacts with IscU and facilitates cluster transfer from IscU to recipient apo-proteins. Here, we report that the otherwise essential roles of HscA and HscB can be bypassed in vivo by a number of single amino acid substitutions in IscU. CD spectroscopic studies of the variant IscU proteins capable of this bypass activity revealed dynamic interconversion between two conformations: the denatured (D) and the structured (S) state in the absence and presence of Zn2+ , respectively, which was far more prominent than interconversion observed in wild-type IscU. Furthermore, we found that neither the S-shifted (more structured) variants of IscU nor the perpetually denatured variants could perform their in vivo role regardless of whether the chaperone system was present or not. The present study thus provides for the first time evidence that an in vivo D-state of IscU exists and implies that conformational interconversion between the S- and D-states of the scaffolding protein is a fundamental requirement for the assembly and transfer of the Fe-S cluster.

Tumor necrosis factor-α (TNF-α) is not only a key regulator of inflammatory response but also an important pain modulator. TNF-α enhances both tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant Na channel currents in dorsal root ganglion (DRG) neurons. However, it remains unknown whether TNF-α affects the function and expression of the TTX-S NaV1.7 Na channel, which plays crucial roles in pain generation. We used cultured bovine adrenal chromaffin cells expressing the NaV1.7 Na channel isoform and compared them with cultured rat DRG neurons. The expression of TNF receptor 1 and 2 (TNFR1 and TNFR2) in adrenal chromaffin cells was studied by Semiquantitative reverse transcription-polymerase chain reaction. The effects of TNF-α on the expression of NaV1.7 were examined with reverse transcription-polymerase chain reaction and Western blot analysis. Results were expressed as mean ± SEM. TNFR1 and TNFR2 were expressed in adrenal chromaffin cells, as well as reported in DRG neurons. TNF-α up-regulated NaV1.7 mRNA by 132% ± 9% (N = 5, P = 0.004) in adrenal chromaffin cells, as well as 117% ± 2% (N = 5, P < 0.0001) in DRG neurons. Western blot analysis showed that TNF-α increased NaV1.7 protein up to 166% ± 24% (N = 5, corrected P < 0.0001) in adrenal chromaffin cells, concentration- and time-dependently. TNF-α up-regulated NaV1.7 mRNA in both adrenal chromaffin cells and DRG neurons. In addition, TNF-α up-regulated the protein expression of the TTX-S NaV1.7 channel in adrenal chromaffin cells. Our findings may contribute to understanding the peripheral nociceptive mechanism of TNF-α.

The mechanism of synchronizing uterine contractions is not fully understood. We present a case of twin pregnancy in a uterus didelphys and objectively analyze the synchrony of bilateral uterine contractions. A 32-year-old woman, with a history of vaginal septal resection during her previous vaginal delivery, became pregnant with twins in a uterus didelphys in which each uterine horn had one fetus. At 37 weeks and 6 days, the first baby was delivered vaginally. The second baby was delivered by cesarean section due to recurrent late decelerations. Operative findings confirmed the didelphys uterus. We retrospectively reviewed the timing of contractions of both uteruses. The timing was determined by visual analysis as synchronous if both uteruses contracted within 5 s. Otherwise, contractions were considered solitary. Both uterine horns contracted independently in 90% of the incidence throughout labor and delivery. From this rare case of an 'experiment by nature', we speculated that the myometrium must be histologically connected in order to synchronize uterine contractions.