Neuropathy-induced osteopenia in rats is not due to a reduction in weight born on the affected limb.

Changes in bone mineral density (BMD) are associated with clinical neuropathies. Following nerve injury in the rat, there is a loss of BMD, which may be related to nerve injury or reduced mechanical loading. The purpose of this study was to investigate if altered mechanical loading is solely responsible for the observed loss of BMD in neuropathic pain models. In addition, we sought to study the action of chronic bisphosphonate treatment on both neuropathy-induced osteopenia and pain. We therefore had two hypotheses: firstly, that nerve injuries can have variable effects on hind limb bone loss in rats which are not attributable to differences in the extent of hind limb disuse and, secondly, that bisphosphonate treatment can reverse bone loss in a rat mononeuropathy model, and this is not attributable to bisphosphonate effects on nociception or hind paw unweighting. Male Sprague-Dawley rats were subject to chronic constriction injury (CCI), partial sciatic nerve ligation (PSN) or L5 + L6 spinal nerve ligation (SNL). Loss of BMD, defined as a numerically lower BMD as compared to control animals, was extreme following CCI (maximum ipsilateral/contralateral difference of 0.023 +/- 0.011); BMD loss following either PSN or SNL in the rat was subtle (0.010 +/- 0.002 and 0.013 +/- 0.012 g/cm2, respectively), significant only at early time points and had resolved by 7 weeks post-surgery. Chronic bisphosphonate treatment significantly inhibited CCI-induced osteopenia in the rat without inhibiting the reduction in weight-bearing tactile allodynia or mechanical hyperalgesia. Loss of BMD is observed in rats in a variety of neuropathic pain models. Lack of correlation between neuropathy-induced bone loss and weight bearing demonstrates that the bone loss is not simply a function of reduced mechanical loading and suggests that altered bone-nerve signaling is involved. Furthermore, chronic bisphosphonate treatment inhibits neuropathy-induced osteopenia without affecting behavioral measurements of neuropathic pain. This indicates that osteopenia is not directly related to neuropathic pain behaviors.

Development and pharmacological characterization of a rat model of osteoarthritis pain.

Osteoarthritis (OA) is an age-related joint disease characterized by degeneration of articular cartilage and is associated with chronic pain. Although several experimental models of OA have been employed to investigate the underlying etiologies of the disease, there has been relatively little investigation into development of animal models of OA to study the pain associated with the condition. In the present study, we investigated OA induced by injection of either iodoacetate or papain into the knee joint of rats, and assessed the joint degeneration with radiographic analyses and measured pain behavior using hind limb weight bearing. We found that injection of iodoacetate, but not papain, resulted in a chronic joint degeneration as measured by decreased bone mineral content and bone mineral density, necrosis of articular cartilage and osteophyte formation. These pathological changes were associated with pain that manifested as time- and concentration-dependent alterations in hind limb weight bearing. These alterations in hind limb weight bearing were reversed with morphine, but were not significantly affected by acute administration of either indomethacin or celecoxib. However, administration of 30 mg/kg celecoxib twice daily for 10 days resulted in a significant restoration of hind limb weight bearing. We conclude that the iodoacetate model of OA is a relevant animal model to study pain associated with OA, and can be used to test potential therapeutic agents.

New tools for laparoscopic division of the pancreas: a comparative animal study.

We tested the hypothesis that the pancreas can be safely divided laparoscopically using non-suture devices. Twelve pigs were randomized into 4 groups: 1) laparoscopic distal pancreatectomy (LDP) using an ultrasonic scalpel; 2) LDP using an ultrasonic scalpel with pancreatic stump suture reinforcement; 3) LDP using a 35-mm laparoscopic linear vascular stapler; 4) LDP using a prototype 35-mm radio-frequency laparoscopic linear vascular stapler. There were no serious complications related to distal pancreatectomy. All groups gained weight by postoperative day (POD) 14. Serum amylase, glucose, electrolytes and total bilirubin levels were measured preoperatively and on POD 1, 3, 7, and 14, and peripancreatic peritoneal fluid amylase levels were measured on POD 7 and 14; all remained normal in all groups. Fewer adhesions to the pancreatic stump were found in the ultrasonic scalpel groups as compared with the stapler groups. Ultrasonic dissection may be the superior means oflaparoscopic transection of the pancreas.

Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome.

Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1-3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome. Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta (TGF-beta) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.

Toxicity of intracranial and intraperitoneal O6-benzyl guanine in combination with BCNU delivered locally in a mouse model.

PURPOSE: The DNA-repair protein, O6-alkylguanine-DNA alkyl transferase, may account for resistance of CNS tumors to DNA-alkylating drugs, such as bis-(2-chloroethyl)-1-nitrosourea (BCNU). The therapeutic effects of BCNU can be potentiated by inhibiting the repair protein with an alkylated guanine analog, O6-benzyl guanine (O6BG). To investigate potential toxicity of this inhibition, we examined the effects of O6BG in mice treated with intracranial (i.c.) BCNU given via a biodegradable polymer. METHODS: Mice were treated with escalating doses of BCNU chronically delivered i.c., and with chronically delivered O6BG. The O6BG was delivered via a 7-day intraperitoneal (i.p.) or i.c. osmotic minipump. Toxicity of the combination therapies was measured from survival data. Bone marrow response was estimated from white blood cell counts. RESULTS: Combining systemic (i.p.) O6BG with locally (i.c.) delivered BCNU resulted in a decrease in the maximum tolerated dose (MTD) of local BCNU. With local delivery of O6BG, the MTD of BCNU in combination with O6BG was increased. CONCLUSIONS: Based on the results of this study, a dose escalation study will be necessary when combining systemic O6BG with the higher doses of i.c. BCNU.