Surgical Correction of Patent Ductus Venosus in Three BroThers

We report the presence of a patent ductusvenosus in three brothers who underwent surgicalcorrection. Patent ductus venosus was demonstrated byultrasonography. Portosystemic venous shunt ratios asevaluated by [¹²³I]iodoamphetamine per rectalportal scintigraphy were 67%, 50%, and 77%,respectively. Histologic examination of liver biopsyspecimens revealed fatty degeneration in all cases.Portal vein pressure before and after temporarily occluding thepatent ductus venosus was estimated by an Anthron P-Ucatheter introduced into the portal vein via theligament teres hepatis. Portal venous pressure increased from 10 to 17 cm H₂O, 16 to 23 cmH₂O, and 14 to 27 cm H₂O,respectively. Therefore, banding of the ductus venosuswith Teflon tape was attempted to prevent portalhypertension following complete ligation. As a result, portal venous pressures afterstricture of the ductus venosus were 12, 21, and 20 cmH2), respectively. Bile acid and liver enzymes decreasedand returned to normal within 14 days after surgery. Interestingly, serum concentrations ofhepatocyte growth factor (HGF) increased significantlyafter restoration of the portal blood flow and thengradually decreased, but remained persistently elevated for at least two weeks in two cases measuredafter surgical correction. One month after correction,liver function returned to normal as assessed byserological and histological parameters in all cases. These results suggest that it is important todetermine whether stricture or complete ligation isindicated for a patent ductus venosus during surgicalcorrection, based on the portal venous pressure after temporal test occlusion of the duct. Inaddition, HGF may be a useful marker for normalizationof hepatic microcirculation after surgery.     

The Effect of Aligned Core–Shell Nanofibres Delivering NGF on the Promotion of Sciatic Nerve Regeneration

Recent bioengineering strategies for peripheral nerve regeneration have been focusing on the development of alternative treatments for nerve repair. In this study, we incorporated nerve growth factor (NGF) into aligned core–shell nanofibres by coaxial electrospinning, and reeled the scaffold into aligned fibrous nerve guidance conduits (NGCs) for nerve regeneration study. This aligned PLGA/NGF NGC combined physical guidance cues and biomolecular signals to closely mimic the native extracellular matrix (ECM). The effect of this aligned PLGA/NGF NGC on the promotion of nerve regeneration was evaluated in a 13-mm rat sciatic nerve defect using functional and morphological analysis. After 12 weeks implantation, the results of electrophysiological and muscle weight examination demonstrated that the functional recovery of the regenerated nerve in the PLGA/NGF NGC group was significantly better than that in the PLGA group, yet had no significant difference compared with the autograft group. The toluidine blue staining study showed that more nerve fibres were regenerated in the PLGA/NGF group, while the electron microscopy study indicated that the regenerated nerve in the PLGA/NGF group was more mature than that in the PLGA group. This study demonstrated that the aligned PLGA/NGF could greatly promote peripheral nerve regeneration and have a potential application in nerve regeneration.     

Hyperactive Transforming Growth Factor‐β1 Signaling Potentiates Skeletal Defects in a Neurofibromatosis Type 1 Mouse Model

Dysregulated transforming growth factor beta (TGF‐β) signaling is associated with a spectrum of osseous defects as seen in Loeys‐Dietz syndrome, Marfan syndrome, and Camurati‐Engelmann disease. Intriguingly, neurofibromatosis type 1 (NF1) patients exhibit many of these characteristic skeletal features, including kyphoscoliosis, osteoporosis, tibial dysplasia, and pseudarthrosis; however, the molecular mechanisms mediating these phenotypes remain unclear. Here, we provide genetic and pharmacologic evidence that hyperactive TGF‐β1 signaling pivotally underpins osseous defects in Nf1^flox/?;Col2.3Cre mice, a model which closely recapitulates the skeletal abnormalities found in the human disease. Compared to controls, we show that serum TGF‐β1 levels are fivefold to sixfold increased both in Nf1^flox/?;Col2.3Cre mice and in a cohort of NF1 patients. Nf1‐deficient osteoblasts, the principal source of TGF‐β1 in bone, overexpress TGF‐β1 in a gene dosage–dependent fashion. Moreover, Nf1‐deficient osteoblasts and osteoclasts are hyperresponsive to TGF‐β1 stimulation, potentiating osteoclast bone resorptive activity while inhibiting osteoblast differentiation. These cellular phenotypes are further accompanied by p21‐Ras–dependent hyperactivation of the canonical TGF‐β1–Smad pathway. Reexpression of the human, full‐length neurofibromin guanosine triphosphatase (GTPase)‐activating protein (GAP)‐related domain (NF1 GRD) in primary Nf1‐deficient osteoblast progenitors, attenuated TGF‐β1 expression levels and reduced Smad phosphorylation in response to TGF‐β1 stimulation. As an in vivo proof of principle, we demonstrate that administration of the TGF‐β receptor 1 (TβRI) kinase inhibitor, SD‐208, can rescue bone mass deficits and prevent tibial fracture nonunion in Nf1^flox/?;Col2.3Cre mice. In sum, these data demonstrate a pivotal role for hyperactive TGF‐β1 signaling in the pathogenesis of NF1‐associated osteoporosis and pseudarthrosis, thus implicating the TGF‐β signaling pathway as a potential therapeutic target in the treatment of NF1 osseous defects that are refractory to current therapies. © 2013 American Society for Bone and Mineral Research.     

The Effect of Laser Irradiation for Nucleus Pulposus: an Experimental Study

Abstract

Background: The radicular pain caused by disc herniation can be explained by two mechanisms: the compression of the nerve root by the herniated disc or the irritation of the nerve root due to chemical factors. Percutaneous laser disc decompression (PLDD) was introduced for the treatment of lumbar disc hernias in the 1980s. Decompression of the nerve root is assumed to be an effective therapeutic mechanism for PLDD. However, laser irradiation might reduce the chemical factors that cause nerve root irritation by altering intra–disc proteins. We used nerve conduction velocities (NCV) and levels of two chemical factors to evaluate the differences between the two groups in this in vivo study.

Methods: All rabbits had the nerve root in contact with the leakage from the nucleus pulposus. One group underwent laser irradiation for the leaking nucleus pulposus including the incision site of the disc and nucleus pulposus itself. The levels of two chemical factors, prostaglandin E2 and phospholipase E2, in the intervertebral disc were measured before and after laser irradiation.

Results: NCV in the laser–irradiated group was significantly faster than in the non–laser–irradiated group. The levels of chemical factors were significantly reduced after laser irradiation.

Conclusions: One of the mechanisms thought to be responsible for PLDD's effectiveness is a decrease in the chemical factors through protein alteration in the intervertebral disc by laser irradiation.     

Common genetic coagulation variants are not associated with ischemic stroke in a case-control study

Abstract

Objective: Abnormalities in the coagulation pathway are often included in the diagnostic work-up of stroke patients, especially in young adults with cryptogenic stroke.

Methods: Three common genetic variants within the coagulation cascade were investigated in 500 control subjects and in 167 patients with ischemic stroke defined by TOAST subclassification. Analysed variants were factor V Leiden, prothrombin 20210G→A and factor XIII Val34Leu.

Results: The factor V Leiden mutation was over-represented in patients with cardioembolic stroke for trend, whereas the prothrombin 20210G→A variant and the factor XIII polymorphism Val34Leu were not associated with stroke of any subtype. The three polymorphisms showed no association with stroke in subgroups of patients defined by age (<40, 40–49, 50–59, ≥60 years).

Discussion: This study suggests that the analysis of prothrombin 20210G→A and factor XIII Val34Leu is not a useful diagnostic procedure in the work-up of ischemic stroke.     

Preparation of Gelatin Microspheres Encapsulated with bFGF for Therapeutic Angiogenesis in a Canine Ischemic Hind Limb

There is urgent need for the treatment of limb ischemia. In order to avoid the risk of genetic materials or injury in collection of implanted cells, a basic fibroblast growth factor (bFGF) sustained release system using cross-linked gelatin microspheres was developed for therapeutic angiogenesis. In this study, gelatin microspheres (MSs) and the complex of MSs and bFGF (MSs–bFGF) were prepared. MSs and MSs–bFGF were analyzed for morphology, particle size, in vitro bFGF release and the bioactivity of the released medium. MSs–bFGF was intramuscularly implanted into the ischemic hind limb of a dog and free bFGF, empty MSs and untreated animals were used as controls. Histological examination was performed for angiogenesis evaluation. After immersion in an aqueous solution, the un-cross-linked MSs became deformed and adhered together. The cross-linked MSs showed a more stable character both in vivo and in vitro. The bFGF released from MSs remained bioactive. The histological examination indicated that the densities of micro-vessels in the MSs–bFGF-treated hind limb muscle were significantly greater than that in the untreated control, free bFGF and empty MSs groups. The MSs–bFGF sustained release system was a simple, safe and effective way to achieve therapeutic angiogenesis in an ischemic limb.