Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain

Conditional mouse knock-outs provide an informative approach to drug target validation where no pharmacological blockers exist or global knock-outs are lethal. Here, we used the Cre-loxP system to delete BDNF in most nociceptive sensory neurons. Conditional null animals were healthy with no sensory neuron loss. However, pain-related behavior was substantially altered. Baseline thermal thresholds were reduced. Carrageenan-induced thermal hyperalgesia was inhibited. Formalin-induced pain behavior was attenuated in the second phase, and this correlated with abolition of NMDA receptor NR1 Ser896/897 phosphorylation and ERK1 and ERK2 activation in the dorsal horn; AMPA receptor phosphorylation (GluR1/Ser831) was unaffected. NGF-induced thermal hyperalgesia was halved, and mechanical secondary hyperalgesia caused by intramuscular NGF was abolished. By contrast, neuropathic pain behavior developed normally. Nociceptor-derived BDNF thus plays an important role in regulating inflammatory pain thresholds and secondary hyperalgesia, but BDNF released only from nociceptors plays no role in the development of neuropathic pain.     

Effect of fetal neural transplants in patients with Huntington's disease 6 years after surgery: a long-term follow-up study

BACKGROUND: Although we have shown in three out of five patients with Huntington's disease that motor and cognitive improvements 2 years after intracerebral fetal neural grafts are correlated with recovery of brain metabolic activity in grafted striatal areas and connected regions of the cerebral cortex, neural grafts are not known to have protective effects on the host brain per se. We undertook long-term follow-up of previously reported patients with the disease to ascertain the nature and extent of any secondary decline after grafting. METHODS: Five patients with Huntington's disease from our pilot study were assessed annually with the unified Huntington's disease rating scale, neuropsychological tests, and MRI, for up to 6 years after neural grafting. Resting cerebral activity was recorded at 2 and 6 years. FINDINGS: Clinical improvement plateaued after 2 years and then faded off variably 4-6 years after surgery. Dystonia deteriorated consistently, whereas chorea did not. Cognitive performance remained stable on non-timed tests, whereas progression of motor disability was shown by deterioration on timed tests. Hypometabolism also affected the brain heterogeneously, sparing the benefits in the frontal cortex and at the precise location of the grafts, but showing a progressive deterioration in other areas. Two patients who had no benefit from grafting at 2 years continued to decline in the same way as non-grafted patients. INTERPRETATION: Neuronal transplantation in Huntington's disease provides a period of several years of improvement and stability, but not a permanent cure for the disease. Improvement of the surgical procedure and in patient selection could improve the therapeutic value, but neuroprotective treatment seems to be unavoidable in the disease.     

The effect of two- and three-dimensional cell culture on the chondrogenic potential of human adipose-derived mesenchymal stem cells after subcutaneous transplantation with an injectable hydrogel

Articular cartilage is an avascular tissue composed of chondrocytes, a unique cell type responsible for abundant matrix synthesis and maintenance. When damaged, it never heals spontaneously under physiological circumstances. Therefore, the delivery of mesenchymal stem cells using hydrogel has been considered for cartilage repair. This study aims at investigating the influence of in vitro chondrogenic differentiation of human adipose tissue-derived stem cells (hATSCs) on in vivo cartilage formation when associated with a cellulose-based self-setting hydrogel (Si-HPMC). hATSCs were characterized for their proliferation, surface marker expression, and multipotency. The in vitro chondrogenic potential of hATSCs cultured within Si-HPMC in control or chondrogenic medium was evaluated by measuring COL2A1, ACAN, SOX9, and COMP expression by real-time PCR. Alcian blue and type II collagen staining were also performed. To determine whether in vitro chondrogenically differentiated hATSCs may give rise to cartilage in vivo, cells differentiated as a monolayer or in pellets were finally associated with Si-HPMC and implanted subcutaneously into nude mice. Cartilage formation was assessed histologically by alcian blue and type II collagen staining. Our data demonstrate that hATSCs exhibited proliferation and self-renewal. hATSCs also expressed typical stem cell surface markers and were able to differentiate towards the adipogenic, osteogenic, and chondrogenic lineages. Real-time PCR and histological analysis indicated that Si-HPMC enabled chondrogenic differentiation of hATSCs in inductive medium, as demonstrated by increased expression of chondrogenic markers. In addition, histological analysis of implants showed that chondrogenically differentiated hATSCs (monolayers or pellets) have the ability to form cartilaginous tissue, as indicated by the presence of sulphated glycosaminoglycans and type II collagen. This study therefore suggests that an in vitro induction of hATSCs in 2D was sufficient to obtain cartilaginous tissue formation in vivo. Si-HPMC associated with autologous hATSCs could thus be a significant tool for regenerative medicine in the context of cartilage damage.     

Endoscopic submucosal dissection versus local excision for early rectal neoplasms: a comparative study

Background  

Transanal local excision (LE) is a well-established treatment option for early rectal neoplasms not amenable to complete colonoscopic removal. Endoscopic submucosal dissection (ESD) has been introduced recently as a novel procedure that enables en bloc resection of large rectal neoplasms. To date, no report comparing the two approaches can be found in the literature. This study aimed to compare the short-term clinical outcomes between ESD and LE for early rectal neoplasms.