Opinions on the Preclinical Evaluation of Novel Therapies for Spinal Cord Injury: A Comparison between Researchers and Spinal Cord-Injured Individuals

Abstract We previously conducted a survey to gather the opinions and perspectives of scientific and clinical researchers on what levels of preclinical evidence were needed to justify translating a promising neuroprotective or neuroregenerative therapy in spinal cord injury (SCI) into a human clinical trial (Kwon et al., 2010 ). Here we conducted an analogous survey of individuals living with SCI in which we gathered their expectations for the levels of preclinical evidence achieved by researchers in substantiating the neuroprotective and neuroregenerative therapies being offered to them in clinical trials. In total, 214 individuals with SCI completed the survey, and their responses were compared to the responses of the 235 scientists and clinicians who completed our previous survey. SCI individuals were more likely than SCI researchers to opine that demonstrating efficacy and safety in rodent models of SCI alone is sufficient to proceed with clinical trials. However, SCI individuals also reported strong support for large animal and primate model studies, and in the case of the latter, were actually more in agreement for the need for primate studies than researchers. SCI individuals also reported strong support for independent replication studies. In general, individuals with SCI had high expectations for the levels of preclinical evidence required to justify translating novel therapies into clinical trials. These expectations should be considered in the decisions to translate specific experimental therapies for SCI.     

Variant histology as a significant predictor of survival after radical nephroureterectomy in patients with upper urinary tract urothelial carcinoma

Objectives

To investigate the effect of variant histology (VH) on survival after radical nephroureterectomy in patients with upper urinary tract urothelial carcinoma (UTUC) and the effect of adjuvant chemotherapy on the survival of patients with UTUC with VH.

Robotic or laparoscopic sacrohysteropexy versus open sacrohysteropexy for uterus preservation in pelvic organ prolapse

Introduction and hypothesis

The aim of this study was to compare robotic or laparoscopic sacrohysteropexy (RLSH) and open sacrohysteropexy (OSH) as a surgical treatment for pelvic organ prolapse (POP).

Methods

Among 111 consecutive patients who had undergone sacrohysteropexy for POP, surgical outcomes and postoperative symptoms were compared between the RLSH (n?=?54; robotic 14 cases and laparoscopic 40 cases) and OSH (n?=?57). groups The medical records of enrolled patients were reviewed retrospectively.

Results

Compared with the OSH group, the RLSH group had shorter operating time (120.2 vs 187.5 min, p?<?0.0001), less operative bleeding (median estimated blood loss 50 vs 150 ml; p?<?0.0001; mean hemoglobin drop 1.4 vs 2.0 g/dl; p?<?0.0001), and fewer postoperative symptoms (13 vs 45.6 %; p?<?0.0001). Patients’ overall satisfaction (94.4 vs 91.2 %; p?=?0.717) and required reoperation due to postoperative complications (3.7 vs 1.8 %; p?=?0.611) did not differ between groups.

Conclusions

RLSH could be a feasible and safe procedure in patients with POP and should be considered as a surgical option that allows preservation of the uterus. Prospective randomized trials will permit the evaluation of potential benefits of RLSH as a minimally invasive surgical approach.

     

Comparison of Bilateral Axillo-Breast Approach Robotic Thyroidectomy with Open Thyroidectomy for Graves’ Disease

Background

There is an ongoing debate about whether robotic thyroidectomy (RT) is appropriate for Graves’ disease. The aim of this study was to compare the safety of bilateral axillo-breast approach (BABA) RT with that of open thyroidectomy (OT) in patients with Graves’ disease.

Methods

From January 2008 to June 2014, 189 (44 BABA RT and 145 OT) patients underwent total thyroidectomy for Graves’ disease. Recurrence of Graves’ disease, intraoperative blood loss, hospital stay, and complication rates including recurrent laryngeal nerve (RLN) palsy and hypoparathyroidism were analyzed between BABA RT and OT groups, after propensity score matching according to age, gender, body mass index, surgical indication, the extent of operation, excised thyroid weight, and follow-up period.

Results

No patient experienced recurrence of Graves’ disease after median follow-up of 35.0 months. Intraoperative blood loss (151.8 ± 165.4 mL vs. 134.5 ± 75.4 mL; p = 0.534) and hospital stay (3.4 ± 0.7 day vs. 3.3 ± 0.7 day; p = 0.564) were not different between BABA RT and OT groups. Complication rates including transient RLN palsy (11.4 vs. 11.4 %; p = 1.000), transient hypoparathyroidism (18.2 vs. 20.5 %; p = 0.787), permanent RLN palsy (0 vs. 2.3 %; p = 0.315), and permanent hypoparathyroidism (2.3 vs. 2.3 %; p = 1.000) were also comparable between groups.

Conclusions

BABA RT for Graves’ disease showed comparable surgical completeness and complications to conventional OT. BABA RT can be recommended as an alternative surgical option for patients with Graves’ disease who are concerned about cosmesis.

     

The flavonoid quercetin induces apoptosis and inhibits migration through a MAPK-dependent mechanism in osteoblasts

The present study was undertaken to evaluate effects of quercetin, a major dietary flavonoid occurring in foods of plant origin, on cell viability and migration of osteoblastic cells. Quercetin inhibited cell viability, which was largely attributed to apoptosis, in a dose-and time-dependent manner in osteoblastic cells. Similar cytotoxicity of quercetin was observed in adipose tissue-derived stromal cells. Quercetin exerted a protective effect against H₂O₂-induced cell death, whereas it increased TNF-α-induced cell death. Western blot analysis showed that quercetin induced activation of ERK and p38, but not JNK. Quercetin-induced cell death was prevented by the ERK inhibitor PD98059, but not by inhibitors of p38 and JNK. Quercetin increased Bax expression and caused depolarization of mitochondrial membrane potential, which were inhibited by PD98059. Quercetin induced caspase-3 activation, and the quercetininduced cell death was prevented by caspase inhibitors. Quercetin inhibited cell migration, and its effect was prevented by inhibitors of ERK and p38. Taken together, these findings suggest that quercetin induces apoptosis through a mitochondria-dependent mechanism involving ERK activation and inhibits migration through activation of ERK and p38 pathways. Quercetin may exert both protective and deleterious effects in bone repair.     

Complications of distraction lengthening in the hand

This study examined the features of 16 complications from 51 distraction lengthenings in the hands of 43 patients. From 1996 to 2006, 24 metacarpals and 27 phalanges were lengthened at a rate of 0.5 and 0.25 mm/day, respectively, using a callus distraction technique. The indications were congenital (33 cases in 27 patients) and traumatic (18 cases in 16 patients) deformities. The average percentage lengthening in the phalanges and metacarpals was 62% (16 mm) and 63% (34 mm), respectively. The distraction rates in the phalanges and metacarpals were 69 and 52 days/cm, respectively. The overall complication rate was 31%. Major complications requiring secondary procedures were non-union (one case), fracture (one case), premature union (one case), angulations (two cases) and dislodgment of pins (two cases). The minor complications encountered were delayed callus formation (four cases), joint stiffness (four cases) and soft tissue thinning (one case). Traumatic deformities had more complications than the congenital ones (nine of 18 cases and seven of 33 cases, respectively). The phalanges had a higher rate of complication than the metacarpals (11 of 27 cases and four of 24 cases, respectively). Most patients with complications except for two children with dislodgment were as satisfied with the final results as those without complications. Although callus distraction in the hand requires a long treatment period and has a relatively high rate of complication, it appears to be effective in achieving adequate bone length. A high level of patient compliance and prompt management of complications by an experienced surgeon are essential for achieving good results.     

Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats

Bone marrow stem cells participate in tissue repair processes and may have a role in wound healing. Diabetes is characterised by delayed and poor wound healing. We investigated the potential of bone marrow-derived mesenchymal stromal cells (BMSCs) to promote healing of fascial wounds in diabetic rats. After manifestation of streptozotocin (STZ)-induced diabetic state for 5 weeks in male adult Sprague-Dawley rats, healing of fascial wounds was severely compromised. Compromised wound healing in diabetic rats was characterised by excessive polymorphonuclear cell infiltration, lack of granulation tissue formation, deficit of collagen and growth factor [transforming growth factor (TGF-beta), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor PDGF-BB and keratinocyte growth factor (KGF)] expression in the wound tissue and significant decrease in biomechanical strength of wounds. Treatment with BMSC systemically or locally at the wound site improved the wound-breaking strength (WBS) of fascial wounds. The improvement in WBS was associated with an immediate and significant increase in collagen levels (types I-V) in the wound bed. In addition, treatment with BMSCs increased the expression of growth factors critical to proper repair and regeneration of the damaged tissue moderately (TGF-beta, KGF) to markedly (EGF, VEGF, PDGF-BB). These data suggest that cell therapy with BMSCs has the potential to augment healing of the diabetic wounds.     

Relations Between Pathological Markers and Radioiodine Scan and 18F-FDG PET/CT Findings in Papillary Thyroid Cancer Patients With Recurrent Cervical Nodal Metastases

Purpose

The aim of this study was to investigate relationships between the immunohistochemical results and radioiodine scan and ¹⁸F-FDG PET findings in papillary thyroid cancer (PTC) patients with recurrent cervical nodal metastases.

Methods

A total of 46 PTC patients who had undergone a radioiodine scan and/or ¹⁸F-FDG PET/CT and a subsequent operation on recurrent cervical lymph nodes were enrolled. Twenty-seven patients underwent ¹⁸F-FDG PET/CT, 8 underwent radioiodine scans, and 11 underwent both scans. In all surgical specimens, the immunoexpressions of thyroglobulin (Tg), sodium-iodide symporter (NIS), glucose transporter 1 (Glut-1), and somatostatin receptor 1 and 2A (SSTR1 and SSTR2A) were assessed, and associations between these expressions and radioiodine scan and ¹⁸F-FDG PET findings were evaluated.

Results

Of the 38 patients who underwent ¹⁸F-FDG PET/CT, all patients with weak Tg expression had positive ¹⁸F-FDG uptake, while only 45 % of the patients with moderate or strong Tg expression showed positive uptake (p = 0.01). The proportion of patients with positive ¹⁸F-FDG uptake increased as the degree of Glut-1 expression with luminal accentuation increased. Of the 19 patients who underwent a radioiodine scan, the proportion with positive radioiodine uptake was greater among patients with strong NIS and SSTR2A expression than among patients expressing these markers at weak levels (p = 0.04 for all). All three patients with weak Tg expression were negative for radioiodine uptake.

Conclusion

The ¹⁸F-FDG uptakes of recurrent cervical nodes are related to strong Glut-1 expression with luminal accentuation and weak Tg expression, whereas radioiodine uptake is related to the strong expressions of NIS and SSTR2A.     

The usefulness of the three-dimensional enhanced T1 high-resolution isotropic volume excitation MR in the evaluation of shoulder pathology: comparison with two-dimensional enhanced T1 fat saturation MR

Objective:

To evaluate the diagnostic accuracy of three-dimensional (3D) enhanced T₁ high-resolution isotropic volume excitation (eTHRIVE) shoulder MR for variable shoulder pathology such as rotator cuff tear, labral injury and synovial pathology in comparison with two-dimensional enhanced fast spin echo T₁ fat saturation (2D T1 FS) sequences MR.

Methods:

This retrospective study included 86 patients who underwent MRI of the shoulder using eTHRIVE technique. Two radiologists evaluated anatomic identification of the supraspinatus, glenoid labrum and acromioclavicular joint (AC joint) on routine MRI sequences (2D T1 FS) and compared them with the reformatted eTHRIVE images. Subjective scoring of the images was performed with a four-point scale that rated the degree of discrimination of the shape of the supraspinatus, glenoid labrum and AC joint. The diagnostic accuracy of eTHRIVE compared with routine MR images was evaluated in terms of rotator cuff pathology, labral pathology and synovial pathology.

Results:

Anatomic identification scores of the supraspinatus tendon and labrum were significantly lower for eTHRIVE than for 2D T1 FS. There were no significant differences between eTHRIVE and 2D T1 FS in anatomic identification of the AC joint. There were no significant differences between eTHRIVE and 2D T1 FS in diagnosing the three disease categories.

Conclusion:

eTHRIVE had comparable diagnostic accuracy to 2D T1 FS imaging in the evaluation of rotator cuff tears, labral injury and synovial pathology, but anatomic identification was inferior to that of 2D T1 FS.

Advances in knowledge:

The accuracy of 3D eTHRIVE imaging is comparable to that of 2D T1 FS for the diagnosis of rotator cuff tears, labral injury and synovial pathology.     

Increased apical targeting of renal epithelial sodium channel subunits and decreased expression of type 2 11beta-hydroxysteroid dehydrogenase in rats with CCl4-induced decompensated liver cirrhosis

It was hypothesized that dysregulation of renal epithelial sodium channel (ENaC) subunits and/or 11beta-hydroxysteroid dehydrogenase (11betaHSD2) may play a role in the increased sodium retention in liver cirrhosis (LC). Experimental LC was induced in rats by CCl(4) (1 ml/kg, intraperitoneally, twice a week) for 12 wk (protocol 1) or for 11 wk (protocol 2). In both protocols, one group of rats with cirrhosis showed significantly decreased urinary sodium excretion and urinary Na/K ratio (group A), whereas a second group exhibited normal urinary sodium excretion (group B) compared with controls, even though extensive ascites was seen in both groups of rats with cirrhosis. In group A, protein abundance of alpha-ENaC was unchanged, whereas beta-ENaC abundance was decreased in the cortex/outer stripe of outer medulla compared with controls. The gamma-ENaC underwent a complex change associated with increased abundance of the 70-kD band with a concomitant decrease in the main 85-kD band, corresponding to an aldosterone effect. In contrast, no changes in the abundance of ENaC subunit were observed in group B. Immunoperoxidase microscopy revealed an increased apical targeting of alpha-, beta-, and gamma-ENaC subunits in distal convoluted tubule (DCT2), connecting tubule (CNT), and cortical and medullary collecting duct segments in group A but not in group B. Immunolabeling intensity of 11betaHSD2 in the DCT2, CNT, and cortical collecting duct was significantly reduced in group A but not in group B, and this was confirmed by immunoblotting. In conclusion, increased apical targeting of ENaC subunits combined with diminished abundance of 11betaHSD2 in the DCT2, CNT, and cortical collecting duct is likely to play a role in the sodium retaining stage of liver cirrhosis.