HIV vector-mediated targeted suicide gene therapy for adult T-cell leukemia

We investigated the potential efficacy of treating adult T-cell leukemia (ATL) using a gene therapeutic approach involving the use of a herpes simplex virus-thymidine kinase (HSV-TK)-mediated suicide system. Human immunodeficiency virus (HIV)-based vectors containing the HSV-TK gene were constructed to achieve targeted gene transfer into CD4-positive ATL cells, after which the transduced cells were selectively killed by treatment with ganciclovir (GCV). To examine the utility of HIV vectors in vivo, ATL-NOD-SCID mice were prepared by intraperitoneal injection of 1 x 10(7) MT2 cells into NK-depleted nonobese diabetic/severely compromised immunodeficient (NOD-SCID) mice. Thereafter, 1 ml of concentrated HIV vector expressing HSV-TK (HXCTKN) or GFP (HXGFP) stock was injected into the intraperitoneal cavity, and GCV was administered twice a day for 5 days. Fluorescence-activated cell sorting (FACS) analysis showed that 7-11% of MT2 or HUT102 cells recovered from the peritoneal cavity were transduced with the HXGFP. After 3 weeks, plasma sIL2-R alpha levels were significantly lower in mice administered HXCTKN than in those administered HXGFP. Moreover, HXCTKN-injected mice survived significantly longer than HXGFP-injected mice. Taken together, these findings suggest that HIV vectors could be used for in vivo targeted gene transfer into ATL cells and could thus serve as the basis for the development of effective new therapies for the treatment of ATL.     

Relationship between whole-blood interferon-gamma production and extent of radiographic disease in patients with pulmonary tuberculosis

The aim of this study was to determine whether whole-blood interferon-gamma (IFN-gamma) production correlates with the radiographic extent of pulmonary tuberculosis before treatment. The subjects were 40 human immunodeficiency virus-negative patients with pulmonary tuberculosis and 36 healthy volunteers. The concentrations of IFN-gamma in whole blood stimulated with Mycobactrium tuberculosis purified protein derivatives (tuberculous PPD) and phytohemagglutinin (PHA) were evaluated. PHA-stimulated IFN-gamma (PHA-IFN-gamma) was lower in the patients than in healthy volunteers (p < 0.05), and inversely correlated with the disease extent (p < 0.01). Tuberculous PPD-stimulated IFN-gamma as a percentage of PHA response (tuberculous PPD-IFN-gamma/PHA-IFN-gamma) was higher in the patients than in healthy volunteers (p < 0.05). However, tuberculous PPD-IFN-gamma/PHA-IFN-gamma did not correlate with the disease extent. Our results indicate that the tuberculous PPD-IFN-gamma/PHA-IFN-gamma may be useful for the diagnosis of tuberculosis but not for evaluating the disease severity, and suggest that PHA-IFN-gamma could be considered as a marker of disease severity.     

Effect of resuscitative endovascular balloon occlusion of the aorta in hemodynamically unstable patients with multiple severe torso trauma: a retrospective study

Background

Although resuscitative endovascular balloon occlusion of the aorta (REBOA) may be effective in trauma management, its effect in patients with severe multiple torso trauma remains unclear.

Methods

We performed a retrospective study to evaluate trauma management with REBOA in hemodynamically unstable patients with severe multiple trauma. Of 5899 severe trauma patients admitted to our hospital between January 2011 and January 2018, we selected 107 patients with severe torso trauma (Injury Severity Score >?16) who displayed persistent hypotension [≥?2 systolic blood pressure (SBP) values ≤?90 mmHg] regardless of primary resuscitation. Patients were divided into two groups: trauma management with REBOA (n?=?15) and without REBOA (n?=?92). The primary endpoint was the effectiveness of trauma management with REBOA with respect to in-hospital mortality. Secondary endpoints included time from arrival to the start of hemostasis. Multivariable logistic regression analysis, adjusted for clinically important variables, was performed to evaluate clinical outcomes.

Results

Trauma management with REBOA was significantly associated with decreased mortality (adjusted odds ratio of survival, 7.430; 95% confidence interval, 1.081–51.062; p?=?0.041). The median time (interquartile range) from admission to initiation of hemostasis was not significantly different between the two groups [with REBOA 53.0 (40.0–80.3) min vs. without REBOA 57.0 (35.0–100.0) min ]. The time from arrival to the start of balloon occlusion was 55.7?±?34.2 min. SBP before insertion of REBOA was 48.2?±?10.5 mmHg. Total balloon occlusion time was 32.5?±?18.2 min.

Conclusions

The use of REBOA without a delay in initiating resuscitative hemostasis may improve the outcomes in patients with multiple severe torso trauma. However, optimal use may be essential for success.

     

Association between adherence to evidence-based guidelines for the prescription of non-steroidal anti-inflammatory drugs and the incidence of gastric mucosal lesions in Japanese patients

Objective  

Recently, guidelines for the treatment and prevention of ulcers induced by non-steroidal anti-inflammatory drugs (NSAIDs) were established. This study investigated the association between the current adherence to the guidelines and the incidence of gastric mucosal lesions caused by NSAIDs.     

Endoluminal MR imaging of porcine gastric structure in vivo

Background and aims

Recently, several new endoscopic instruments have been developed. However, even with the full use of current modalities, the safety of endoscopic surgery is not guaranteed. Information regarding factors such as fibrosis and the blood vessels under the mucosa is very important for avoiding procedure-related complications. The aim of this study was to define the detailed anatomy of the gastric wall structure in vivo using original endoluminal radiofrequency coils for safer endoscopic therapy.

Methods

Swine were used as the subjects and controlled with general anesthesia. Anatomical images were obtained with T1-weighted fast spin echo (T1FSE) and T2-weighted fast spin echo (T2FSE). Dynamic magnetic resonance (MR) angiography was also obtained with three-dimensional T1-weighted fast spoiled gradient recalled acquisition in the steady state (3D-DMRA) following the injection of hyaluronic acid sodium into the submucosal layer.

Results

Porcine gastric wall structure was visualized, and four layers were discriminated in the T1FSE and T2FSE images. The vascular structure was clearly recognized in the submucosa on 3D-DMRA.

Conclusion

Endoluminal MR imaging was able to visualize the porcine stomach with similar quality to endoscopic ultrasonography imaging. Additionally, it was possible to visualize the vascular structures in the submucosal layer. This is the first report to show that blood vessels under the gastric mucosa can be depicted in vivo.     

A Na+/Ca2+ exchanger isoform, NCX1, is involved in retinal cell death after N-methyl-D-aspartate injection and ischemia-reperfusion

We investigated the expression of Na(+)/Ca(2+) exchanger (NCX) and the functional role of NCX in retinal damage by using NCX1-heterozygous deficient mice (NCX1(+/-)) and SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy] phenoxy]-5-ethoxyaniline), a selective NCX inhibitor in vivo. We also examined the role of NCX in oxygen-glucose deprivation (OGD) stress with a retinal ganglion cell line (RGC-5) cell culture in vitro. The expression of NCX1 was confirmed and entirely localized in retina by immunoblotting and immunohistochemistry, respectively. NCX1(+/-) mice possessed significant protection against retinal damage induced by intravitreal injection of N-methyl-D-aspartate (NMDA). SEA0400 at 3 and 10 mg/kg significantly reduced NMDA- or high intraocular pressure-induced retinal cell damage in mice. Furthermore, SEA0400 reduced the number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells and the expression of phosphorylated mitogen-activated protein kinases (ERK1/2, JNK, p38) induced by NMDA injection. In RGC-5, SEA0400 at 0.3 and 1 microM significantly inhibited OGD-induced cell damage. OGD-induced cell damage was aggravated by ouabain (a Na(+),K(+)-ATPase inhibitor) at 100 microM, and this increased damage was significantly reduced by SEA0400 at 1 microM. In conclusion, these results suggest that NCX1 may play a role in retinal cell death induced by NMDA and ischemia-reperfusion.     

Non-specific activities against ruthenium crosslinker as a new cause of assay interference in an electrochemilluminescent immunoassay

Clinical assays are very important for the diagnosis and management of clinical disorders. Each assay system consists of a specific method to detect and/or quantify a substance of interest in the clinical specimen. However, clinical assays can be unfavorably influenced by non-specific activities concomitantly present in the specimen, which may mislead clinical decisions. Thus, it is very important to know how each assay works, and how and when the assay is non-specifically influenced. Here, we report three cases shown clinical data of thyroid function influenced by new type of assay interference.