Myocardium-targeted delivery of endothelial progenitor cells by ultrasound-mediated microbubble destruction improves cardiac function via an angiogenic response

Application of ultrasound-mediated destruction of microbubbles (US + Bubble) to skeletal muscle creates capillary ruptures leading to leakage of the cell components. We studied whether US + Bubble combined with bone-marrow-derived mononuclear cells (BM-MNCs) infusion enables the targeted delivery of endothelial-lineage cells into the myocardium and improves cardiac function of the cardiomyopathy model due to the paucity of neocapillary formation. Pulsed US was applied to the anterior chest of BIOTO2 cardiomyopathy hamsters for 90 s after the intravenous injection of microbubble (Optison) followed by infusion of BM-MNCs. Cardiac samples from US + microbubble + BM-MNCs (US + Bubble + BM), US + Bubble, US + BM without Bubble, and saline infusion control groups were analyzed 12 weeks after treatment. Labeled BM-MNCs transplanted by US + Bubble were found to be mainly localized in the microvessels, but not by US stimulation without microbubble (121.2 +/- 24.5 vs. 2.80 +/- 1.30 cells/mm2, P < 0.001). Capillary densities in US + Bubble + BM group were increased 1.7-fold (P < 0.05) over the control, and neither US + Bubble nor US + BM enhanced neocapillary formation. 99mTc-Tetrofosmin scintigraphy revealed that blood perfusion area in the US + Bubble + BM group was 48% greater than the control (P < 0.01). US + Bubble stimulation induces the expression of adhesion molecules (VCAM-1 and ICAM-1) in capillaries, and the US + Bubble-mediated supply of BM-MNCs increased the myocardial content of VEGF and bFGF. The left ventricular wt/body wt, area of cardiac fibrosis, and apoptotic cell numbers in the US + Bubble + BM group significantly (P < 0.05) decreased by 82%, 73%, and 64% relative to the control, respectively. The cardiac function in myopathic hamsters (assessed by fractional shortening) was markedly improved 36% (P < 0.05) by US + Bubble + BM treatment. Targeted delivery of BM-MNCs by US + Bubble to the myocardium of the cardiomyopathic hamster increased the capillary densities and regional blood flow and inhibited cardiac remodeling, resulting in the prevention of heart failure. This non-invasive cell delivery system may be useful as a novel efficient approach for angiogenic cell therapy to the myocardium.     

Effects of differences in age and body height on normal values of central motor conduction time determined by F-waves

Objectives: To investigate the effect on central motor conduction time (CMCT) based on the relationship between age and height in normal subjects.

Design: Retrospective study.

Methods: One hundred and ninety nine normal subjects (107 men and 92?women; mean age 39.0?±?16.4 years; mean height 164.5?±?8.8?cm) participated in the study. The approximate ages of subjects were as follows: 82 (20–29 years old), 32 (30–39 years old), 32 (40–49 years old), 28 (50–59 years old), and 25 (≧60 years old). The heights of 9, 49, 79, 53, and 9 subjects were <150?cm, 150–160?cm, 160–170?cm, 170–180?cm, and >180?cm, respectively. CMCT- abductor digiti minimi (ADM) and abductor hallucis (AH) were calculated by subtracting the peripheral motor conduction time (PMCT) from the onset latency of motor evoked potentials (MEPs) evoked by transcranial magnetic stimulation. PMCT was calculated from the latencies of the compound muscle action potentials (CMAPs) and F-waves as follows: (latency of CMAPs?+?latency of F-waves -1)/2.

Outcome measures: CMCT-ADM and CMCT-AH.

Results: The normative values were 5.2?±?0.8?ms and 11.8?±?1.3?ms for CMCT-ADM and CMCT-AH, respectively. CMCT-ADM was not significantly correlated with age (P?=?0.196) and body height (P?=?0.158). CMCT-AH had significantly positive, linear correlations with age and body height (CMCT-AH?=?0.014?×?age?+?10.971, P?=?0.011, R?=?0.179 and CMCT-AH?=?0.026?×?body height?+?7.158, P?=?0.010, R?=?0.182).

Conclusions: We suggest normative values of 3.2–7.2?ms in CMCT-ADM for subjects exerting slight effort on ADM regardless age and body height. CMCT-AH had significantly positive, linear correlations with age and body height.     

Cervical ossification of the posterior longitudinal ligament: factors affecting the effect of posterior decompression

Objective: Decompression procedures for cervical myelopathy of ossification of the posterior longitudinal ligament (OPLL) are anterior decompression with fusion, laminoplasty, and posterior decompression with fusion. Preoperative and postoperative stress analyses were performed for compression from hill-shaped cervical OPLL using 3-dimensional finite element method (FEM) spinal cord models.

Methods: Three FEM models of vertebral arch, OPLL, and spinal cord were used to develop preoperative compression models of the spinal cord to which 10%, 20%, and 30% compression was applied; a posterior compression with fusion model of the posteriorly shifted vertebral arch; an advanced kyphosis model following posterior decompression with the spinal cord stretched in the kyphotic direction; and a combined model of advanced kyphosis following posterior decompression and intervertebral mobility. The combined model had discontinuity in the middle of OPLL, assuming the presence of residual intervertebral mobility at the level of maximum cord compression, and the spinal cord was mobile according to flexion of vertebral bodies by 5°, 10°, and 15°.

Results: In the preoperative compression model, intraspinal stress increased as compression increased. In the posterior decompression with fusion model, intraspinal stress decreased, but partially persisted under 30% compression. In the advanced kyphosis model, intraspinal stress increased again. As anterior compression was higher, the stress increased more. In the advanced kyphosis +?intervertebral mobility model, intraspinal stress increased more than in the only advanced kyphosis model following decompression. Intraspinal stress increased more as intervertebral mobility increased.

Conclusion: In high residual compression or instability after posterior decompression, anterior decompression with fusion or posterior decompression with instrumented fusion should be considered.     

Hematopoietic stem cell transplantation recovers insulin deficiency in type 1 diabetes mellitus associated with IPEX syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, and X‐linked (IPEX) syndrome is an autoimmune disorder caused by the dysfunction of FOXP3, which leads to regulatory T‐(Treg) cell dysfunction and subsequently autoimmunity including type 1 diabetes mellitus (T1D). Presently, allogeneic hematopoietic stem cell transplantation (HSCT) is a potential curative therapy for IPEX syndrome, but not for T1D. Generally, after complete loss of pancreatic β‐cells, HSCT cannot improve the prognosis of T1D. Here, we report the case of a 16‐year‐old adolescent with late‐onset of FOXP3 R347H mutation associated IPEX syndrome with T1D, where insulin dependency was ameliorated following HSCT. This patient with insulin‐dependent diabetes mellitus required insulin dosage of 1.28 U/kg/day for 1 month before HSCT. Although the results of glucose homeostasis before HSCT revealed impaired insulin secretion and low ΔC‐peptide immunoreactivity (CPR, 1.0 ng/mL), the patient withdrew insulin infusion and remained euglycemic at 15 months after HSCT, and had normal β‐cell function with improved ΔCPR (3.4 ng/mL) at 20 months after HSCT. The present case suggests that HSCT for T1D‐associated IPEX syndrome improves Treg deficiency and prevents elimination of β‐cells. We speculate that the period from the onset of T1D to HSCT could affect the therapeutic efficacy for T1D with IPEX, and early intervention with HSCT before or immediately after the onset of DM can rescue β‐cells and remit T1D completely. Our study elaborates not only the therapeutic strategy for T1D with IPEX, but also the pathogenic mechanism in general T1D.     

Clinical verification of sensitivity to preoperative chemotherapy in cases of androgen receptor-expressing positive breast cancer

Background:

Triple-negative breast cancer (TNBC) patients testing positive for androgen receptor (AR) expression are thought to be chemotherapy resistant, similar to other hormone receptor-positive breast cancers; however, this has not been substantially validated in the clinic. In this study, we investigated the association between chemotherapy sensitivity and AR expression in patients treated with neoadjuvant chemotherapy (NAC) using standardised chemotherapy criteria and regimens.

Methods:

A total of 177 patients with resectable early-stage breast cancer were treated with NAC. Oestrogen receptor, progesterone receptor, HER2, Ki67 and AR status were assessed immunohistochemically.

Results:

Sixty-one patients were diagnosed with TNBC; AR expression was identified in 23 (37.7%), which was significantly less common than that found in non-TNBC patients (103 of 116; 88.8% P<0.001). The rate of pathological complete response after NAC was significantly lower (P=0.001), and disease recurrence was more common (P=0.008) in patients with AR-positive compared with those with AR-negative TNBC. In TNBC cases, as expected, the non-recurrence period in cases that were negative for AR expression was significantly extended (P=0.006, log-rank).

Conclusions:

Androgen receptor expressions may be useful as biomarkers to predict treatment responses to NAC in TNBC. Moreover, induction of a change in subtype to the AR-negative phenotype was observed after NAC.     

Acute autoimmune transverse myelitis following COVID-19 vaccination: A case report

Rationale:Transverse myelitis is an infectious or noninfectious inflammatory spinal cord syndrome. We report a rare case of transverse myelitis following vaccination against COVID-19.Patient concerns:A 70-year-old male presented with progressive sensorimotor dysfunction of the bilateral lower limbs 7 days after receiving the mRNA-1273 vaccine against COVID-19. Spinal magnetic resonance imaging revealed intramedullary lesions with gadolinium enhancement on the Th1/2 and Th5/6 vertebral levels. Cerebrospinal fluid (CSF) testing showed a mildly increased level of total protein and positive oligoclonal bands (OCB).Diagnosis:The patient was diagnosed with acute transverse myelitis.Intervention:The patient received 5 days of intravenous methylprednisolone pulse (1000 mg/day) followed by oral prednisolone (30 mg/day with gradual tapering).Outcomes:The patient fully recovered from muscle weakness of the lower limbs. He was discharged from our hospital and able to independently walk without unsteadiness.Lesson:This is a rare case of transverse myelitis following COVID-19 vaccination. Positive OCB in CSF in the present case highlights the possibility of autoimmune processes, including polyclonal activation of B lymphocytes, following vaccination.